Longevity Wiki - User contributions [en-GB]

Aging and longevity

2024-07-21T12:35:18Z

Geroscientist: /* What is aging? */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has not been a concerted research effort to address biological aging as a cause of disease. In the modern era, humanity supports research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organization that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for biological aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) views the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5.<ref name=":32" /> This disparity is projected to widen with a rapidly aging population.<ref name=":32">Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> challenging old assumptions that aging is simply a result of time passing.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, [[mTOR]] and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing, such as in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
[[File:Aging & CVD.jpg|left|thumb|Aging as an etiological cause of cardiovascular disease (CVD). Age-associated cardiovascular (CV) dysfunction is a key antecedent to the development of CV disease (CVD). CV dysfunction with aging is characterized by impaired vascular endothelial function and stiffening of the large elastic arteries, each of which is an independent predictor of CVD. These processes are largely mediated by an excess production of reactive oxygen species (ROS) and an increase in chronic, low-grade inflammation (inflammaging) that ultimately leads to a reduction in bioavailability of the vasodilatory molecule nitric oxide.<ref>Murray, K. O., Mahoney, S. A., Venkatasubramanian, R., Seals, D. R., & Clayton, Z. S. (2023). Aging, aerobic exercise, and cardiovascular health: Barriers, alternative strategies and future directions. Experimental gerontology, 173, 112105.PMID: 36731386 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068966/ 10068966] DOI: 10.1016/j.exger.2023.112105</ref>]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== Healthspan versus lifespan ====
'''The concept of healthspan refers to the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== Lack of consensus on what defines aging ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2024-07-21T12:30:03Z

Geroscientist: /* Dietary restriction mimetics and mTOR inhibitors */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has not been a concerted research effort to address the aging of cells, tissues and and organs. In the modern era, humanity supports research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organization that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5.<ref name=":32" /> This disparity is projected to only widen further with a rapidly aging population.<ref name=":32">Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> challenging old assumptions that aging is simply a result of time passing.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, [[mTOR]] and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing, such as in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
[[File:Aging & CVD.jpg|left|thumb|Aging as an etiological cause of cardiovascular disease (CVD). Age-associated cardiovascular (CV) dysfunction is a key antecedent to the development of CV disease (CVD). CV dysfunction with aging is characterized by impaired vascular endothelial function and stiffening of the large elastic arteries, each of which is an independent predictor of CVD. These processes are largely mediated by an excess production of reactive oxygen species (ROS) and an increase in chronic, low-grade inflammation (inflammaging) that ultimately leads to a reduction in bioavailability of the vasodilatory molecule nitric oxide.<ref>Murray, K. O., Mahoney, S. A., Venkatasubramanian, R., Seals, D. R., & Clayton, Z. S. (2023). Aging, aerobic exercise, and cardiovascular health: Barriers, alternative strategies and future directions. Experimental gerontology, 173, 112105.PMID: 36731386 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068966/ 10068966] DOI: 10.1016/j.exger.2023.112105</ref>]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== Healthspan versus lifespan ====
'''The concept of healthspan refers to the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== Lack of consensus on what defines aging ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2024-07-21T12:25:02Z

Geroscientist: /* Epigenetic reprogramming */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5.<ref name=":32" /> This disparity is projected to only widen further with a rapidly aging population.<ref name=":32">Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> challenging old assumptions that aging is simply a result of time passing.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and [[mTOR]] inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing, such as in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
[[File:Aging & CVD.jpg|left|thumb|Aging as an etiological cause of cardiovascular disease (CVD). Age-associated cardiovascular (CV) dysfunction is a key antecedent to the development of CV disease (CVD). CV dysfunction with aging is characterized by impaired vascular endothelial function and stiffening of the large elastic arteries, each of which is an independent predictor of CVD. These processes are largely mediated by an excess production of reactive oxygen species (ROS) and an increase in chronic, low-grade inflammation (inflammaging) that ultimately leads to a reduction in bioavailability of the vasodilatory molecule nitric oxide.<ref>Murray, K. O., Mahoney, S. A., Venkatasubramanian, R., Seals, D. R., & Clayton, Z. S. (2023). Aging, aerobic exercise, and cardiovascular health: Barriers, alternative strategies and future directions. Experimental gerontology, 173, 112105.PMID: 36731386 PMC:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068966/ 10068966] DOI: 10.1016/j.exger.2023.112105</ref>]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== Healthspan versus lifespan ====
'''The concept of healthspan refers to the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== Lack of consensus on what defines aging ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

FAQ

2024-07-09T06:00:05Z

Geroscientist: /* Which billionaires are funding longevity biotechnology? */

Longevity biotechnology is a new field of medical research that aims delay, prevent or reverse age-related diseases to extend healthy human lifespan. This article provides an overview of the field through answering frequently asked questions.

== Why is aging a problem? ==
[[File:Aging graph.png|thumb|750x750px|The aging process results in the risk of age-related diseases increasing exponentially over time.]][[File:Gompertz-Makeham law of mortality.png|alt=Gompertz-Makeham law of mortality|thumb|257x257px|Gompertz-Makeham law of mortality<ref name=":0">En.wikipedia.org. 2021. ''Gompertz–Makeham law of mortality - Wikipedia''. [online] Available at: <nowiki>https://en.wikipedia.org/wiki/Gompertz%E2%80%93Makeham_law_of_mortality</nowiki> [Accessed 13 December 2021].</ref>]]Aging is the largest risk factor for the diseases that kill most people worldwide, including cancer, heart diseases and Alzheimer's disease.<ref name=":9" />

In the US in 2020, 9 of the 10 leading causes of death were strongly age-related.<ref name=":19">Ahmad, F. B., & Anderson, R. N. (2021). The leading causes of death in the US for 2020. ''JAMA'', ''325''(18), 1829-1830.https://jamanetwork.com/journals/jama/fullarticle/2778234</ref> Globally, approximately 70% of deaths annually are the result of aging.<ref name=":8" />

Aging substantially reduces quality of life. Deaths due to aging are usually preceded by many years of diseases such as arthritis, type 2 diabetes and Alzheimer’s, leading to loss of function and independence.

As a result of the aging process, the risk of an individual dying increases exponentially, notably after around 30 years old.<ref name=":26">Olshansky, S. J., & Carnes, B. A. (1997). Ever since gompertz. ''Demography'', ''34''(1), 1-15.</ref> This increase in mortality rate is known as the Gompertz-Makeham law of mortality.<ref name=":0" /><ref name=":26" />
== How many people die from aging per day? ==
Aging and its related diseases result in the deaths of 100,000 people per day; more than twice the sum of all other causes of death combined.<ref name=":8">Ritchie, H. and Roser, M., 2021. ''Causes of Death''. [online] Our World in Data. Available at: <<nowiki>https://ourworldindata.org/causes-of-death</nowiki>> [Accessed 13 December 2021].
</ref> This equates to over 37 million people dying per year of aging - a population the size of Canada. This is because aging results in the exponential increasing risk of age-related diseases such as cancer and type 2 diabetes. Aging also accounts for more than 30% of all disability-adjusted life years lost (DALYs); more than any other single cause.<ref>Vizhub.healthdata.org. 2021. ''GBD Compare | IHME Viz Hub''. [online] Available at: <<nowiki>https://vizhub.healthdata.org/gbd-compare/</nowiki>> [Accessed 13 December 2021].</ref>
[[File:Leading causes of death.png|center|thumb|713x713px|9 of the top 10 causes of death in the US in 2020 were strongly age-related.<ref name=":19" />]]

== Can healthy lifespan be extended? ==
[[File:Life extension mice.jpg|alt=Life extension mice|thumb|431x431px|Dietary manipulation, genetic manipulation, and drugs have been shown to increase the healthy lifespan of mice by up to 30%. <ref name=":1">de Magalhaes, J., 2021. ''DrugAge: Species Detail''. [online] Genomics.senescence.info. Available at: <<nowiki>https://genomics.senescence.info/drugs/species_details.php</nowiki>> [Accessed 14 December 2021].</ref>]]Clinical trials for longevity drugs in humans are in-progress, and there is not yet evidence that drugs can slow aging in humans. However, recent experimental breakthroughs over the last few decades have shown that in mice, worms and flies, healthy lifespan can be modified.<ref name=":27">Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.</ref> Many clinical trials in humans today are testing whether these results can be replicated in humans.<ref>Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.</ref>

In animal models, slowing the aging process in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs. In mice, over 100 drugs have been shown to extend healthy lifespan by up to 30%.<ref name=":1" /><ref name=":27" />

The effect of longevity drugs on mice is often significant, delaying or eliminating the burden of age-related problems such as [[frailty]], cataracts, cancer, and sarcopenia. For example, a new class of drugs called senolytics have been shown to extend healthy lifespan in mice by over 30% whilst delaying age-related dysfunction.

== Which therapies may extend healthy lifespan? ==
Several drugs are known to extend healthy lifespan in animals. While there is no conclusive data that suggests these drugs would work the same in humans, many of these drugs are now being tested in clinical trials. [[File:Unity Mice.jpg|alt=Unity Mice|thumb|723x723px|Senolytic drugs eliminate senescent cells that accumulate with age, partially reversing multiple age-related diseases and extending the healthy lifespan of mice by up to 35%.<ref name=":16" /> ]]

=== Senolytics ===
Senolytics are drugs that remove senescent cells. These are cells which accumulate in the body with age and are linked with age-related diseases such as cancer.<ref>Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., ... & Kirkland, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. ''Nature medicine'', ''24''(8), 1246-1256.</ref>
[[File:Metformin2.jpg|thumb|258x258px|Metformin extends lifespan in mice by 6%, and may extend lifespan in humans.<ref name=":13">Kulkarni, A. S., Gubbi, S., & Barzilai, N. (2020). Benefits of metformin in attenuating the hallmarks of aging. ''Cell metabolism'', ''32''(1), 15-30.</ref>]]
In mice, senolytics have been shown to increase the healthy lifespan by up to 35%.<ref name=":16">Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. ''Nature'', ''530''(7589), 184-189.</ref> The first clinical trials of senolytics in humans began in 2016, demonstrating improved inflammation biomarkers and function, suggestive of benefit in humans.<ref>https://clinicaltrials.gov/ct2/show/NCT02874989</ref><ref>https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext</ref>

=== [[Metformin]] ===
Metformin is an approved drug for type 2 diabetes that extends lifespan in multiple species. In mice, Metformin extends lifespan by up to 6%.<ref>Anisimov, V. N., Berstein, L. M., Popovich, I. G., Zabezhinski, M. A., Egormin, P. A., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., Yurova, M. N., Kovalenko, I. G., & Poroshina, T. E. (2011). If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. ''Aging'', ''3''(2), 148–157. <nowiki>https://doi.org/10.18632/aging.100273</nowiki></ref> Metformin works in part by improving insulin sensitivity and may target several hallmarks of aging.<ref name=":13" /> Metformin is being tested as a longevity therapy in the largest clinical trial of its kind, the Targeting Aging with Metformin (TAME) trial in the US.<ref name=":14">''TAME - Targeting Aging with Metformin - American Federation for Aging Research''. (n.d.). American Federation for Aging Research. <nowiki>https://www.afar.org/tame-trial</nowiki></ref> This is a randomized clinical trial of 3000 elderly patients comparing metformin against placebo for the onset of age-related diseases.<ref name=":14" /> Whether it slows aging in humans is unproven; the TAME trial may provide some insight.

=== [[Rapamycin]] ===
[[File:Rapamune .jpg|alt=Rapamune |thumb|253x253px|Rapamycin, also known as Rapamune© is being tested as a drug to extend healthy lifespan in humans. <ref name=":15" />]]
Rapamycin, also known as Rapamune©, is a drug used to prevent the rejection of organ transplants by the immune system. Rapamycin has been shown to extend lifespan by up to 26% when given at middle age, and 14% when given in late life.<ref name=":20">Harrison, D., Strong, R., Sharp, Z. ''et al.'' Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''Nature'' 460, 392–395 (2009). <nowiki>https://doi.org/10.1038/nature08221</nowiki>
</ref><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., Javors, M. A., Li, X., Nadon, N. L., Nelson, J. F., Pletcher, S., Salmon, A. B., Sharp, Z. D., Van Roekel, S., Winkleman, L., & Strong, R. (2014). Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468–477. <nowiki>https://doi.org/10.1111/acel.12194</nowiki></ref>

Among the hundreds of interventions known to target aging, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref name=":25">Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref>

Rapamycin is being tested in a large-scale clinical trial called the Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study (PEARL). This is a randomized clinical trial aiming to enroll 1000 elderly patients comparing rapamycin against placebo for age-related outcomes.<ref name=":15">Clinicaltrials.gov. 2021. ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. [online] Available at: <<nowiki>https://clinicaltrials.gov/ct2/show/NCT04488601</nowiki>> [Accessed 14 December 2021].
</ref>

=== [[Epigenetic reprogramming]] ===
Epigenetic reprogramming refers to remodeling of epigenetic marks, such as methylation tags on the DNA within cells. A specific version of this technique was used in 2020 to restore vision to blind mice by fully regrowing the optic nerve.<ref>Lu, Y., Brommer, B., Tian, X. ''et al.'' Reprogramming to recover youthful epigenetic information and restore vision. ''Nature'' 588, 124–129 (2020). <nowiki>https://doi.org/10.1038/s41586-020-2975-4</nowiki></ref> The lead researcher David Sinclair at Harvard Medical School believes this approach could one day be used to regenerate other tissues of the body as a longevity strategy.<ref>''Reversing The Aging Clock With Epigenetic Reprogramming''. (n.d.). Pubs - Bio-IT World. <nowiki>https://www.bio-itworld.com/news/2021/01/13/reversing-the-aging-clock-with-epigenetic-reprogramming</nowiki></ref>

In addition, over [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap 50 other drugs] are being tested in human clinical trials for targeting aging, to prevent or reverse various diseases.<ref name=":2">Lifespan.io. 2021. ''The Rejuvenation Roadmap | Lifespan.io''. [online] Available at: <<nowiki>https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/</nowiki>> [Accessed 13 December 2021].</ref>

== What is the goal of longevity biotechnology? ==
[[File:Healthy lifespan extension.png|alt=Healthy lifespan extension|thumb|643x643px|Healthy lifespan extension involves early intervention to prevent or delay the decline associated with aging.<ref>''Longevity companies to watch in 2021 - Longevity.Technology''. (n.d.). Longevity.Technology. <nowiki>https://www.longevity.technology/longevity-companies-to-watch-in-2021/</nowiki></ref> ]]
Longevity biotechnology aims to slow or reverse the aging process to extend the healthy lifespan (‘healthspan’) of the population. Instead of treating diseases when they arise, one by one, longevity biotechnology aims to keep people healthy by slowing the aging process. The aim is to thereby prevent or reverse multiple age-related diseases at once.

The longevity biotechnology sector is rapidly growing, and there are currently over 170 private companies working on developing therapeutics to slow the aging process.<ref name=":4">Pfleger, K., 2021. ''Aging Companies''. [online] Agingbiotech.info. Available at: <<nowiki>https://agingbiotech.info/companies</nowiki>> [Accessed 13 December 2021].</ref> These companies are working on slowing or reversing the aging process by targeting one or more of the hallmarks of aging.

== Will healthy or unhealthy lifespan be extended? ==
[[File:Extending healthy lifespan.png|alt=Extending healthy lifespan|thumb|364x364px|Extending healthy versus unhealthy lifespan.<ref>''How to save Medicare: the anti-aging remedy''. (2012, March). <nowiki>https://www.researchgate.net/figure/From-longer-life-span-to-longer-health-span-and-life-span-From-A-to-B-Standard_fig1_230724035</nowiki>.</ref>]]
The stated goal of longevity biotechnology is to extend the healthy period of lifespan, particularly before age-related diseases set in. This is in contrast to many of today's medical interventions, which extend life only after diseases (e.g. cancer, Alzheimer's) have reached a clinical level.

Age-related diseases are preceded by a long period of subclinical aging, i.e. aging that has not yet progressed far enough to produce clinical symptoms. By slowing, delaying or reversing the aging process, the hypothesis is that the healthy period of life can be extended.<ref name=":24" />

Studies in mice have demonstrated that life extending drugs such as rapamycin are capable of extending the healthy, rather than unhealthy period of life.<ref name=":20" />
== Should we treat specific diseases such as cancer, or focus on aging? ==
[[File:Slowing aging versus curing cancer.jpg|alt=Slowing aging is potentially a more effective means of extending healthy lifespan than treating individual diseases due to the comorbid nature of age-related diseases. [6]|thumb|421x421px|Slowing aging is potentially a more effective means of extending healthy lifespan than treating individual diseases due to the comorbid nature of age-related diseases.<ref name=":18" /> ]]
Longevity biotechnology offers a potentially greater likelihood of extending healthy lifespan than the current approach - attempting to find cures for the individual diseases of aging. This is because biological aging is associated with many diseases of aging. These diseases develop as comorbidities, which occur in sequence. Even if a person survives one age-related disease such as cancer, another (e.g. dementia, heart disease) is likely to next kill the person, because the underlying aging process is not treated.

This phenomenon is known as the Taeuber paradox<ref name=":28">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref>, and accounts for the much smaller projected increase in healthy lifespan associated with curing the diseases of aging, such as cancer (2-3 years), versus slowing aging itself (30+ years).<ref name=":18">Matt Kaeberlein, PhD, It is Time to Embrace 21st-Century Medicine, ''Public Policy & Aging Report'', Volume 29, Issue 4, 2019, Pages 111–115, <nowiki>https://doi.org/10.1093/ppar/prz022</nowiki></ref><ref name=":28" /><ref>Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> The life expectancy estimate of the latter is based on calculations by Professor Kaeberlein at the University of Washington, using lifespan data from rapamycin-treated mice.<ref>https://twitter.com/mkaeberlein/status/1463580145126567936</ref>
== What is biological aging? ==
There are two main types of 'age': chronological age - the number of years since birth, and biological age - a measure of the physical health of a person and their position in their lifespan. Biological age is more difficult to measure, but recent technologies are now available to estimate biological age. Over time, we age biologically. This occurs due to many processes in the body, which are generally categorized into 9 processes or 'hallmarks'.<ref name=":9" />
== What are the 9 Hallmarks of Aging? ==
[[File:Hallmarks of aging.jpg|alt=Hallmarks of aging|thumb|444x444px|The nine hallmarks of aging.<ref name=":9" />]]

The hallmarks of aging framework is considered to broadly represent key biological mechanisms of the biological aging process.<ref name=":9">López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.</ref> Although there are limitations of the hallmarks framework, it has become the central framework for understanding aging biology. The nine forms of cellular and molecular ‘damage’ that comprise the hallmarks of aging are<ref name=":9" />:

* Genomic instability
* Telomere attrition
* Epigenetic alterations
* Loss of proteostasis
* Deregulated nutrient-sensing
* Mitochondrial dysfunction
* Cellular senescence
* Stem cell exhaustion
* Altered intercellular communication

These are thought to be the lowest common denominators of the aging process, on a cellular or subcellular level. All of the physiological changes associated with aging, such as greying hair, wrinkles, frailty and an increased risk of disease are thought to stem from these underlying processes.<ref name=":9" />

== How does the aging cause disease? ==
The nine hallmarks of aging have been shown to play an integral role in the development of many age-related diseases such as dementia, cancer, and a multitude of others:
=== [[Aging and Neurodegeneration|Neurodegenerative disease]] ===
[[File:Prevalence of neuro disorders.jpg|alt=Prevalence of neuro disorders|thumb|469x469px|The prevalence of neurodegenerative disorders increases exponentially with age, due to the biological aging process.<ref name=":12">Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. ''Nature reviews. Neurology'', ''15''(10), 565–581. <nowiki>https://doi.org/10.1038/s41582-019-0244-7</nowiki></ref> ]]
All of the hallmarks of aging are associated with an increased risk of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.<ref>Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. ''Dialogues in clinical neuroscience'', ''11''(2), 111.</ref> For example, several types of DNA damage are associated with neurodegeneration. The shortening of telomeres occurs as part of biological aging and causes cellular senescence, and is associated with neurodegeneration and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.<ref name=":12" /> Additionally, mitochondrial dysfunction, altered metabolism, stem cell exhaustion and loss of proteostasis are also involved in the development of neurodegenerative diseases.<ref name=":12" />
=== [[Aging and Cancer|Cancer]] ===
Several of the hallmarks of aging such as cellular senescence and alterations in the extracellular matrix are responsible for increasing the likelihood of tumorigenesis.<ref name=":5">Fane, M., & Weeraratna, A. T. (2020). How the ageing microenvironment influences tumour progression. ''Nature Reviews Cancer'', ''20''(2), 89-106.</ref>

Other hallmarks of aging such as genomic instability (DNA mutations), loss of proteostasis (e.g. proteotoxic stress), altered intercellular communication (e.g. inflammation) and epigenetic alterations (e.g. aberrant DNA methylation) are also involved in cancer development.<ref name=":5" />
== How is biological age measured? ==
[[File:Epigenetic clock.png|alt=Epigenetic clock|thumb|605x605px|The epigenetic clock measures biological age based on marks on the epigenome.<ref name=":6" /> ]]
Recent technologies have helped the measure of biological age, including:

=== [[Epigenetic clock|Epigenetic clocks]] ===
The first generation of aging clocks are known as [[Epigenetic clock|epigenetic clocks or Horvath’s clock]].<ref name=":6">Horvath, S., & Raj, K. (2018). DNA methylation-based biomarkers and the epigenetic clock theory of ageing. ''Nature Reviews Genetics'', ''19''(6), 371-384.</ref> This clock is based on the finding that with aging, the body accumulates methylation tags on the DNA in a pattern that can be predicted with machine learning. These changes to the epigenome are influenced by lifestyle and environment, and can be used to measure biological age.<ref name=":6" /> Factors such as exercise frequency and a low BMI have been shown to reduce the rate of epigenetic aging, whereas obesity and smoking can accelerate this rate.<ref>Quach, A., Levine, M. E., Tanaka, T., Lu, A. T., Chen, B. H., Ferrucci, L., ... & Horvath, S. (2017). Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. ''Aging (Albany NY)'', ''9''(2), 419.</ref><ref>Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. ''Clinical Epigenetics'', ''11''(1), 183. <nowiki>https://doi.org/10.1186/s13148-019-0777-z</nowiki>

[[Epigenetic clock#cite%20ref-12|↑]]</ref><ref>Horvath, S., Erhart, W., Brosch, M., Ammerpohl, O., von Schönfels, W., Ahrens, M., Heits, N., Bell, J. T., Tsai, P.-C., Spector, T. D., Deloukas, P., Siebert, R., Sipos, B., Becker, T., Röcken, C., Schafmayer, C., & Hampe, J. (2014). Obesity accelerates epigenetic aging of human liver. ''Proceedings of the National Academy of Sciences'', ''111''(43), 15538–15543. <nowiki>https://doi.org/10.1073/pnas.1412759111</nowiki>

[[Epigenetic clock#cite%20ref-13|↑]]</ref> Horvath's clock has been used to accurately predict mortality risk among human populations.<ref>Fransquet, P. D., Wrigglesworth, J., Woods, R. L., Ernst, M. E., & Ryan, J. (2019). The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis. ''Clinical epigenetics'', ''11''(1), 1-17.</ref>

=== Multi-omic clocks ===
Epigenetic clocks are being developed that incorporate data from several sources. This may include multi-omic clocks which include metabolomics, proteomics, or non-molecular biomarkers such as body imaging and fitness tests.<ref name=":21" /> These clocks are built using machine learning to estimate biological age. These aging clocks are being developed that combine multiple biological functional tests to create a unique aging signature, which can be monitored over time.<ref name=":21">Kudryashova, K. S., Burka, K., Kulaga, A. Y., Vorobyeva, N. S., & Kennedy, B. K. (2020). Aging Biomarkers: From Functional Tests to Multi‐Omics Approaches. ''Proteomics'', ''20''(5-6), 1900408.</ref>
[[File:Multiomic aging clock.jpg|alt=Multiomic clocks|center|thumb|542x542px|Multiomic clocks integrate various data sources to create a unique biological aging signature that can be tracked over time.<ref name=":21" /> ]]
== Which companies are trying to solve aging? ==
[[File:Calico Labs.png|alt=T|thumb|Calico Labs, a subsidiary of Google, is a billion-dollar company searching for treatments for aging.<ref name=":22" /> ]]
There are over [https://agingbiotech.info/companies 170 longevity biotechnology companies] trying to create therapies to slow or reverse the aging process.<ref name=":4" /> There are over [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ 50 longevity drugs] currently in clinical trials in humans.<ref name=":2" />

Many of the longevity biotechnology companies are targeting specific hallmarks of aging. For example, [https://www.clearabiotech.com/#DiscoveryTimeline Cleara Biotech] are attempting to reduce cellular senescence by developing a drug that can eliminate senescent cells.<ref>Cleara Biotech. 2021. ''Cleara Biotech''. [online] Available at: <<nowiki>https://www.clearabiotech.com/#DiscoveryTimeline</nowiki>> [Accessed 15 December 2021].</ref>

Calico Labs is a Google-backed biotech company with the goal of combating aging and age-related diseases. In 2014, the company created a partnership with pharmaceutical giant AbbVie, which has since developed into a [https://www.cnbc.com/2018/06/26/alphabet-backed-calico-and-abbvie-chip-in-1-billion-to-cure-aging.html $2.5 billion venture] in the pursuit of improving “health, wellbeing and longevity.” <ref name=":22">2021. ''Google sister company and drug giant chip in another $1 billion to cure age-related diseases''. [online] Available at: <<nowiki>https://www.cnbc.com/2018/06/26/alphabet-backed-calico-and-abbvie-chip-in-1-billion-to-cure-aging.html</nowiki>> [Accessed 15 December 2021].</ref>

Since aging is not currently considered a disease by regulatory bodies such as the Food and Drug Administration (FDA), drug developers are currently focused on specific diseases of aging such as glaucoma and osteoarthritis.<ref>Clinicaltrialsarena.com. 2021. ''Unity's Phase II osteoarthritis study of UBX0101 misses primary goal''. [online] Available at: <<nowiki>https://www.clinicaltrialsarena.com/news/unity-ubx0101-osteoarthritis/</nowiki>> [Accessed 15 December 2021].</ref>

== Which billionaires are funding longevity biotechnology? ==
[[File:Jeff Bezos is funding longevity research.jpg|alt=Jeff Bezos is funding longevity research|thumb|Jeff Bezos is funding longevity research through financing Atlos Labs.<ref name=":7">MIT Technology Review. 2021. ''Meet Altos Labs, Silicon Valley’s latest wild bet on living forever''. [online] Available at: <<nowiki>https://www.technologyreview.com/2021/09/04/1034364/altos-labs-silicon-valleys-jeff-bezos-milner-bet-living-forever/</nowiki>> [Accessed 15 December 2021].</ref>]]
Several billionaires have funded companies or initiatives to slow or reverse human aging. These include:
* [[wikipedia:Jeff_Bezos|Jeff Bezos]], co-founder of Amazon, helped raise [https://www.technologyreview.com/2021/09/04/1034364/altos-labs-silicon-valleys-jeff-bezos-milner-bet-living-forever/ $3 billion for new anti-aging drug company Altos Labs] in 2021.<ref name=":7" />
* [[wikipedia:Sam_Altman|Sam Altman]], CEO of OpenAI, invested [https://www.technologyreview.com/2023/03/08/1069523/sam-altman-investment-180-million-retro-biosciences-longevity-death/ $180 million into RetroBiosciences whose goal is to add] 10 years to healthy human lifespan.<ref>MIT Technology Review. 2023. Sam Altman invested $180 million into a company trying to delay death. [online] Available at: <https://www.technologyreview.com/2023/03/08/1069523/sam-altman-investment-180-million-retro-biosciences-longevity-death/> [Accessed 09 July 2024].</ref>
* [[wikipedia:Peter_Thiel|Peter Thiel]], co-founder of PayPal, was an [https://www.cnbc.com/2018/08/29/-jeff-bezos-is-backing-this-scientist-who-is-working-on-a-cure-for-aging.html early investor in Unity Biotechnology].<ref>CNBC. 2021. ''Why Jeff Bezos is backing this Silicon Valley scientist who is working on a cure for aging''. [online] Available at: <<nowiki>https://www.cnbc.com/2018/08/29/-jeff-bezos-is-backing-this-scientist-who-is-working-on-a-cure-for-aging.html</nowiki>> [Accessed 15 December 2021].</ref>
* [[wikipedia:Sergey_Brin|Sergey Brin]], co-founder of Google, donated [https://www.cnbc.com/2017/03/31/google-co-founders-and-silicon-valley-billionaires-try-to-live-forever.html $25 million for the National Academy of Medicine’s Grand Challenge in Health Longevity] to 'end aging forever'.<ref>Google’s co-founders and other Silicon Valley billionaires are trying to live forever. (2021). Retrieved 15 December 2021, from <nowiki>https://www.cnbc.com/2017/03/31/google-co-founders-and-silicon-valley-billionaires-try-to-live-forever.html</nowiki></ref>
* [[wikipedia:Larry_Page|Larry Page]], co-founder of Google, co-founded the [[wikipedia:Calico_(company)|billion-dollar aging research company Calico Labs.]]<ref>Contributors to Wikimedia projects. (2013, September 19). ''Calico (company) - Wikipedia''. Wikipedia, the free encyclopedia. <nowiki>https://en.wikipedia.org/wiki/Calico_(company)</nowiki>
</ref>
* [[wikipedia:Mike_Cannon-Brookes|Mike Cannon-Brookes]], billionaire cofounder of Australian software giant Atlassian, has invested [https://www.forbes.com/sites/samshead/2019/08/19/billionaire-backs-uk-startup-trying-to-extend-human-lifespans/ $10 million into longevity company Juvenescence].<ref>Shead, S. (2019, August 19). ''Billionaire Backs U.K. Startup Trying To Extend Human Life Spans''. Forbes. <nowiki>https://www.forbes.com/sites/samshead/2019/08/19/billionaire-backs-uk-startup-trying-to-extend-human-lifespans/</nowiki></ref>
* [[wikipedia:Jim_Mellon|Jim Mellon]], UK billionaire investor who co-founded longevity company [https://www.juvlabs.com/people/co-founder/jim-mellon Juvenescence].<ref>''Jim Mellon - Chairman & Co-Founder''. (n.d.). Juvenescence - Science of Healthy Aging & Extended Lifespan. <nowiki>https://www.juvlabs.com/people/co-founder/jim-mellon</nowiki></ref>
* [[wikipedia:Larry_Ellison|Larry Ellison]], founder of Oracle, has spent [https://www.townandcountrymag.com/society/money-and-power/a9202324/science-of-longevity/ $430 million on longevity research].<ref>Tullis, P. (2017, March 30). ''Are You Rich Enough To Live Forever?'' Town & Country. <nowiki>https://www.townandcountrymag.com/society/money-and-power/a9202324/science-of-longevity/</nowiki></ref>
*Michael Greve, founder of Kizoo Technology, who has pledged [https://Longevity.Technology. https://www.longevity.technology/michael-greve-commits-e300m-for-rejuvenation-start-ups/ €300m to rejuvenation biotechnology companies.]<ref>''Michael Greve commits €300m for rejuvenation start-ups''. (2021, May 6). Longevity.Technology. <nowiki>https://www.longevity.technology/michael-greve-commits-e300m-for-rejuvenation-start-ups/</nowiki></ref>
*[[wikipedia:Naveen_Jain|Naveen Jain]], billionaire entrepreneur who has raised [https://www.geekwire.com/2021/gut-health-startup-viome-raises-54m-develop-cancer-diagnostics-sell-microbiome-kits/ $54 million for his startup Viome].<ref>''Gut health startup Viome raises $54M to develop cancer diagnostics and sell microbiome kits''. (2021, November 10). Geekwire. <nowiki>https://www.geekwire.com/2021/gut-health-startup-viome-raises-54m-develop-cancer-diagnostics-sell-microbiome-kits/</nowiki></ref>
* [[wikipedia:Yuri_Milner|Yuri Milner]], billionaire tech investor who helped Altos Labs raise $3 billion, with Jeff Bezos.<ref name=":7" />
*[[wikipedia:Brian_Armstrong_(businessman)|Brian Armstrong]], CEO of CoinBase, who helped found and raise [https://www.dailymail.co.uk/sciencetech/article-10310475/Billionaire-launches-new-start-hopes-REVERSE-ageing-process.html $105 million for the epigenetic reprogramming startup NewLimit.]<ref>Liberatore, S. (2021, December 14). ''Billionaire launches new start-up to REVERSE the ageing process''. Mail Online. <nowiki>https://www.dailymail.co.uk/sciencetech/article-10310475/Billionaire-launches-new-start-hopes-REVERSE-ageing-process.html</nowiki></ref>
* [[wikipedia:Vitalik_Buterin|Vitalik Buterin]], founder of the cryptocurrency Ethereum, who has donated over $2.4 million to anti-aging research organization SENS, among various other biotech projects.<ref>Foundation, S. R. (n.d.). ''SENS Research Foundation Receives $2.4 Million Ethereum Donation From Vitalik Buterin''. GlobeNewswire News Room. <nowiki>https://www.globenewswire.com/news-release/2018/02/02/1332410/0/en/SENS-Research-Foundation-Receives-2-4-Million-Ethereum-Donation-From-Vitalik-Buterin.html</nowiki></ref>

== How large will the longevity biotechnology field be? ==
Analysts from the Bank of America have predicted that the market size of longevity biotechnology will reach $600 billion by 2025.<ref>2021. ''Human lifespan could soon pass 100 years thanks to medical tech, says BofA''. [online] Available at: <<nowiki>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</nowiki>> [Accessed 14 December 2021].</ref> Others have speculated that it is a trillion dollar industry owing to the immense savings associated with delaying or preventing chronic diseases.<ref>Colangelo, M., 2021. ''AI Will Drive The Multi-Trillion Dollar Longevity Economy''. [online] Forbes. Available at: <<nowiki>https://www.forbes.com/sites/cognitiveworld/2019/12/07/ai-will-drive-the-multi-trillion-dollar-longevity-economy/?sh=294766b74965</nowiki>> [Accessed 14 December 2021].</ref>
== Is age an important for risk factor for COVID-19 mortality? ==
[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|thumb|572x572px|The risk of dying from COVID-19 increases exponentially with age. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age is the single most significant risk factor for COVID-19 mortality. The mortality rate from COVID-19 increases exponentially with age, such that the death rate for those aged over 80 years is over 1000 times higher than those below 30 years.<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref>

This increase in COVID-19 mortality with age is thought to be the result of a weakening of the immune system with age, known as immunosenescence.<ref>Bajaj, V., Gadi, N., Spihlman, A. P., Wu, S. C., Choi, C. H., & Moulton, V. R. (2021). Aging, immunity, and COVID-19: how age influences the host immune response to coronavirus infections?. ''Frontiers in Physiology'', ''11'', 1793.</ref>

The mortality rate doubling time for COVID-19 is close to the all-cause mortality rate doubling time.<ref name=":29" /> This has led several scientists to conclude that COVID-19 meets criteria for an age-related disease.<ref name=":29" /><ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

== How is aging biology research different to other fields of medical research? ==
Scientists studying the biology of aging believe that aging is a root cause of all the major diseases of aging, and that targeting aging directly would treat or reverse multiple diseases, simultaneously. This is known as the geroscience hypothesis, and has garnered traction in recent years.<ref name=":24">Austad, S. N. (2016). The geroscience hypothesis: is it possible to change the rate of aging?. In ''Advances in geroscience'' (pp. 1-36). Springer, Cham.</ref>

The approach of targeting aging directly differs from many fields in mainstream medical research such as cancer research, which seek to find cures for individual diseases. An argument in favour of targeting aging directly is that targeting single diseases leads to diminishing returns in healthy lifespan extension.<ref name=":18" /> Due to the many diseases that occur concurrently in older age, completely curing a single disease such as cancer would only add 2-3 healthy years of life on average, whereas slowing aging could add 30 or more healthy years.<ref name=":18" /> This is because another disease in line, e.g. Alzheimer's or lung disease, will subsequently result in death, a phenomenon known as the Taeuber Paradox.<ref name=":17">En.wikipedia.org. 2021. ''Taeuber Paradox - Wikipedia''. [online] Available at: <<nowiki>https://en.wikipedia.org/wiki/Taeuber_Paradox</nowiki>> [Accessed 14 December 2021].</ref>
== Do all animals age in the same way? ==
[[File:Naked mole rat graph.png|alt=Naked mole rat graph|thumb|530x530px|The naked mole-rat does not follow the same increased risk of mortality due to aging that humans and other mammals do.<ref>Ruby, J. G., Smith, M., & Buffenstein, R. (2018). Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age. ''elife'', ''7'', e31157.</ref> ]]
Many species, due to differences in their biology, age at different rates to humans. The jellyfish ''Turritopsis dohrnii'' can revert to earlier stages of its life cycle in response to stress, and is theoretically ''biologically'' immortal - though eventually dies, usually due to predation.<ref>Bavestrello, Giorgio; Christian Sommer; Michele Sarà (1992). "Bi-directional conversion in Turritopsis nutricula (Hydrozoa)".</ref>

Among mammals, the naked mole rat is an exceptionally long lived organism. It lives roughly ten times longer than similarly-sized rats, with resistance to cancer and age-related diseases.<ref name=":3">Ruby, J. G., Smith, M., & Buffenstein, R. (2018). Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age. ''elife'', ''7'', e31157.</ref><ref>Buffenstein, R., Amoroso, V., Andziak, B., Avdieiev, S., Azpurua, J., Barker, A. J., ... & Smith, E. S. J. (2021). The naked truth: a comprehensive clarification and classification of current ‘myths’ in naked mole‐rat biology. ''Biological Reviews''.</ref> Unlike other organisms, such as humans, horses and mice, the mortality rate of the naked mole rat appears steady over time. This trend does not follow the exponential increase in mortality (Gompertz-Makeham law) that humans do.<ref name=":3" />

Scientists are now studying the naked mole rat to identify key patterns in their genetics, environmental traits, and metabolism that may be responsible for their longer lifespans.<ref>Kim, E. B., Fang, X., Fushan, A. A., Huang, Z., Lobanov, A. V., Han, L., ... & Gladyshev, V. N. (2011). Genome sequencing reveals insights into physiology and longevity of the naked mole rat. ''Nature'', ''479''(7372), 223-227.</ref>

[[File:Naked mole rat.jpg|alt=Naked mole rat|center|thumb|323x323px|The naked mole-rat is unusually long-lived relative to other mice and rats.<ref name=":3" /> ]]

== Is aging considered a disease? ==
Aging is not currently classified as a disease by regulatory bodies such as the Food and Drug Administration (FDA) in the United States. However, several scientists in the aging field have publicly stated their preference for aging to be defined as, or at least thought of, as a disease, including professors David Sinclair and Nir Barzilai.<ref>TEDx Talks. (2020, June 9). ''Ageing'' ''is'' ''a'' ''treatable'' ''disease'' ''|'' ''Nir'' ''Bazilai'' ''|'' ''TEDxBeaconStreetSalon'' [Video]. YouTube. <nowiki>https://www.youtube.com/watch?v=XN7rLbCBO1c</nowiki></ref>

Recognition of aging as a treatable medical condition by the WHO comes from the new ICD-11 extension code MG2A and XT9T. MG2A refers to “Ageing associated decline in intrinsic capacity”, and is classified under "general symptoms".<ref>https://icd.who.int/dev11/l-m/en?fbclid=IwAR22C-Gx2i9mckSYLenAwLAkWuBt3s3ncQLdjs5aar1W42jAbibuD6SQ2gE#/http://id.who.int/icd/entity/835503193</ref> XT9T refers to "Ageing-related”, under the "Causality" category, and recognizes aging as a contributor to disease.<ref>https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f459275392</ref>

== What are the economic benefits of extending healthy lifespan? ==
Extending the healthy human lifespan could have significant economic benefits gobally. An economic analysis from 2021 by researchers at the University of Oxford and Harvard University estimated the benefit of a drug that slows aging by 1 year as $38 trillion.<ref name=":23">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This is mainly because slowing aging prevents age-related diseases such as cancer and Alzheimer’s disease, which are of great expense to healthcare systems, productivity, and society. The study demonstrated a larger economic benefit of slowing aging than curing the individual diseases of aging. <ref name=":23" />
== Which scientists and institutions are trying to understand and reverse aging? ==
Over [https://whoswho.senescence.info/ 300 scientists are working on understanding the biology of aging] in leading institutions that include Harvard University, Stanford University, Yale University, and the University of Oxford.<ref>''Who's Who in Gerontology: Researchers and Companies Working on Aging''. (n.d.). Who's Who in Gerontology: Researchers and Companies Working on Aging. <nowiki>https://whoswho.senescence.info/</nowiki></ref> Some of the most well-known institutes and labs include:

=== The Buck Institute for Research on Aging ===
The Buck Institute for Research on Aging is one of the largest longevity research institutes with over 250 scientists. The research covers several areas including the mechanisms of aging, neurodegeneration, senescence, stem cells and regenerative medicine, cellular stress and disease, cancer associated with aging, and mitochondrial function.<ref>''Buck Institute''. (n.d.). BUCK. <nowiki>https://www.buckinstitute.org/</nowiki></ref>

=== Professor David Sinclair - Harvard Medical School ===
Professor Sinclair’s lab focuses on understanding and reversing aging. The lab focuses on a range of areas including DNA repair, mitochondrial dysfunction, and the interactions between epigenetic and genetic instability, and tissue reprogramming.<ref>''Welcome | The Sinclair Lab''. (n.d.). Welcome | The Sinclair Lab. <nowiki>https://sinclair.hms.harvard.edu/</nowiki></ref>

=== Professor Matt Kaeberlein - University of Washington ===
Professor Kaeberlein's lab focuses on biological mechanisms of aging in order to facilitate translational interventions that promote healthspan and improve quality of life. Kaeberlein is known for his work on the longevity drug rapamycin in organisms such as mice and dogs. He is Director of the Dog Aging Project, a multi-year initiative studying the genetic and environmental factors that influence health, with over 33,000 participating dogs.<ref>''Matt Kaeberlein, PhD | Faculty | Dept. of Laboratory Medicine & Pathology | UW Medicine''. (n.d.). Dept. of Laboratory Medicine & Pathology | UW Medicine. <nowiki>https://dlmp.uw.edu/faculty/kaeberlein</nowiki></ref>

=== Professor Brian Kennedy - National University of Singapore ===
Professor Kennedy’s lab focuses on understanding the biology of aging and translating research discoveries into new ways of delaying aging in humans. The lab has identified drugs that extend the healthy lifespan of worms and mice and are seeking to understand their mechanisms.<ref>''Brian Kennedy - Department of Biochemistry – School of Medicine, National University of Singapore''. (n.d.). Department of Biochemistry – School of Medicine, National University of Singapore. <nowiki>https://medicine.nus.edu.sg/bch/fa</nowiki></ref>

=== Associate Professor Lynne Cox - University of Oxford ===
Professor Cox’s lab study the molecular and cellular basis of aging to identify specific biochemical processes and pathways that change organisms age. The lab particularly cellular senescence, which underpins many age-related diseases including cancer and neurodegeneration.<ref>''Associate Prof Lynne Cox''. (n.d.). Home | Biochemistry. <nowiki>https://www.bioch.ox.ac.uk/research/cox</nowiki></ref>

== What books have been written on this topic? ==
Several books have been written on the topic of aging and longevity. These include:

* [https://www.amazon.com/Lifespan-Why-Age_and-Dont-Have/dp/1501191977 ''Lifespan: Why We Age And Why We Don't Have To'' - David Sinclair (2019)]

* [https://www.amazon.com/Ending-Aging-Rejuvenation-Breakthroughs-Lifetime/dp/0312367074 ''Ending Aging'' - Dr. Aubrey de Grey (2007)]

* [https://www.amazon.com/Ageless-Science-Getting-Older-Without/dp/0385544928 ''Ageless'' - Dr. Andrew Steele (2020)]

* [https://www.amazon.com.au/Age-Later-Health-Science-Longevity-ebook/dp/B0818MYCRR ''Age Later'' - Professor Nir Barzilai (2021)]

* [https://www.amazon.com.au/Science-Technology-Growing-Young-Breakthroughs/dp/1950665879 ''The Science and Technology of Growing Young'' - Sergey Young (2021)]

== Which anti-aging drugs are being tested in clinical trials today? ==
There are over 50 drugs being tested in human clinical trials for aging or age-related diseases.

The largest trial is the Targeting Aging with Metformin (TAME) trial, which began in 2020. The trial is being run in the United States with a cohort of 3000 older adults. The goal of the TAME trial is to determine whether diabetes drug metformin slows the aging process in older adults. The TAME trial is a $75 million trial run by the American Federation for Aging Research.<ref name=":14" />

Another large clinical trial is the Participitory Evaluation (of) Aging (with) Rapamycin (for) Longevity (PEARL) study. The goal of this study is to determine whether rapamycin, a drug currently approved for immunosuppression during organ transplants, slows biomarkers of aging in 1000 adults. The PEARL trial is being run by AgelessRx.<ref name=":15" />
== Is aging a natural process that should be accepted? ==
Although aging is a natural process in humans, it is the driving force of many diseases such as cancer and Alzheimer's disease - which as a society we have decided are worth trying to find cures for. In the past, these conditions, as well as atherosclerosis and even infectious diseases were once thought of as natural processes to be accepted. As treatments for previously untreatable diseases started being developed, society moved to accommodate this.

Atherosclerosis, the hardening of the arteries, was once viewed as a natural process that was simply a consequence of aging. However, when treatments such as statins were later developed to prevent atherosclerosis, it became widely regarded as a disease to be cured. Statins are now one one of the most widely prescribed drugs in the world, used in preventing heart diseases. The inventor of statins, Akira Endo, describes in his historical paper: “Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented.”<ref>Endo A. (2010). A historical perspective on the discovery of statins. ''Proceedings of the Japan Academy. Series B, Physical and biological sciences'', ''86''(5), 484–493. <nowiki>https://doi.org/10.2183/pjab.86.484</nowiki></ref>

== Will anti-aging technology lead to overpopulation? ==
A common objection to the development of longevity technologies is that they may lead to an unsustainably large population size.

One study of a 2005 Swedish cohort of 9 million people modeled the effect of various anti-aging scenarios. The researchers showed that even with the most radical life-extension technology in which aging completely stopped after age 60, the population growth across 100 years was only 22%.<ref>Gavrilov, L. A., & Gavrilova, N. S. (2010). Demographic consequences of defeating aging. ''Rejuvenation research'', ''13''(2-3), 329-334.</ref> In reality, the first aging drugs will likely slow aging by a modest amount, and most likely increase healthspan as opposed to lifespan. This is partly based on evidence in animals showing that it is easier to extend median, as opposed to maximal lifespan.

Currently, the world’s population is 7.9 billion, and the WHO predicts the population will peak at 11 billion in 2100 before falling due to declining birth rates in many parts of the world. The fastest growing populations are in Africa and South-east Asia. However, several factors are thought to reduce birth rates over time, including increased access to contraceptives, female empowerment, increased education and increased employment. There is evidence that populations that move to a more advanced economy show a reduction in birth rates. This is expected to mitigate the increase in population size from longer lifespans.

== Will anti-aging drugs only be available to the rich? ==
It is unclear who will have first access to longevity drugs. Several researchers in the field have argued that several economic factors are likely to drive down the price of drugs that slow aging.

* The cost of many biotechnologies decreases substantially over time. For example, the first human genome cost $100 million to sequence, and is now available for a few hundred dollars.<ref>''The Cost of Sequencing a Human Genome''. (n.d.). Genome.gov. <nowiki>https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost</nowiki></ref>

* The price of many lifesaving pharmaceuticals has fallen significantly in price once generic drugs were produced. For example, Lipitor, a statin used to prevent heart disease has fallen in price from $85 in 2011 to less than $5 today.

* Many companies in the longevity field have stated that equity of access is part of their core ethos, and many researchers are part of an international coalition called the Academy of Health & Lifespan research which aims to ensure that breakthroughs in aging research are accessible to all. <ref>''Academy for Health & Lifespan Research''. (n.d.). Academy for Health & Lifespan Research. <nowiki>https://www.ahlresearch.org/</nowiki></ref>

== References ==
<references />

FAQ

2024-07-09T05:58:41Z

Geroscientist: /* Which billionaires are funding longevity biotechnology? */

Longevity biotechnology is a new field of medical research that aims delay, prevent or reverse age-related diseases to extend healthy human lifespan. This article provides an overview of the field through answering frequently asked questions.

== Why is aging a problem? ==
[[File:Aging graph.png|thumb|750x750px|The aging process results in the risk of age-related diseases increasing exponentially over time.]][[File:Gompertz-Makeham law of mortality.png|alt=Gompertz-Makeham law of mortality|thumb|257x257px|Gompertz-Makeham law of mortality<ref name=":0">En.wikipedia.org. 2021. ''Gompertz–Makeham law of mortality - Wikipedia''. [online] Available at: <nowiki>https://en.wikipedia.org/wiki/Gompertz%E2%80%93Makeham_law_of_mortality</nowiki> [Accessed 13 December 2021].</ref>]]Aging is the largest risk factor for the diseases that kill most people worldwide, including cancer, heart diseases and Alzheimer's disease.<ref name=":9" />

In the US in 2020, 9 of the 10 leading causes of death were strongly age-related.<ref name=":19">Ahmad, F. B., & Anderson, R. N. (2021). The leading causes of death in the US for 2020. ''JAMA'', ''325''(18), 1829-1830.https://jamanetwork.com/journals/jama/fullarticle/2778234</ref> Globally, approximately 70% of deaths annually are the result of aging.<ref name=":8" />

Aging substantially reduces quality of life. Deaths due to aging are usually preceded by many years of diseases such as arthritis, type 2 diabetes and Alzheimer’s, leading to loss of function and independence.

As a result of the aging process, the risk of an individual dying increases exponentially, notably after around 30 years old.<ref name=":26">Olshansky, S. J., & Carnes, B. A. (1997). Ever since gompertz. ''Demography'', ''34''(1), 1-15.</ref> This increase in mortality rate is known as the Gompertz-Makeham law of mortality.<ref name=":0" /><ref name=":26" />
== How many people die from aging per day? ==
Aging and its related diseases result in the deaths of 100,000 people per day; more than twice the sum of all other causes of death combined.<ref name=":8">Ritchie, H. and Roser, M., 2021. ''Causes of Death''. [online] Our World in Data. Available at: <<nowiki>https://ourworldindata.org/causes-of-death</nowiki>> [Accessed 13 December 2021].
</ref> This equates to over 37 million people dying per year of aging - a population the size of Canada. This is because aging results in the exponential increasing risk of age-related diseases such as cancer and type 2 diabetes. Aging also accounts for more than 30% of all disability-adjusted life years lost (DALYs); more than any other single cause.<ref>Vizhub.healthdata.org. 2021. ''GBD Compare | IHME Viz Hub''. [online] Available at: <<nowiki>https://vizhub.healthdata.org/gbd-compare/</nowiki>> [Accessed 13 December 2021].</ref>
[[File:Leading causes of death.png|center|thumb|713x713px|9 of the top 10 causes of death in the US in 2020 were strongly age-related.<ref name=":19" />]]

== Can healthy lifespan be extended? ==
[[File:Life extension mice.jpg|alt=Life extension mice|thumb|431x431px|Dietary manipulation, genetic manipulation, and drugs have been shown to increase the healthy lifespan of mice by up to 30%. <ref name=":1">de Magalhaes, J., 2021. ''DrugAge: Species Detail''. [online] Genomics.senescence.info. Available at: <<nowiki>https://genomics.senescence.info/drugs/species_details.php</nowiki>> [Accessed 14 December 2021].</ref>]]Clinical trials for longevity drugs in humans are in-progress, and there is not yet evidence that drugs can slow aging in humans. However, recent experimental breakthroughs over the last few decades have shown that in mice, worms and flies, healthy lifespan can be modified.<ref name=":27">Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.</ref> Many clinical trials in humans today are testing whether these results can be replicated in humans.<ref>Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.</ref>

In animal models, slowing the aging process in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs. In mice, over 100 drugs have been shown to extend healthy lifespan by up to 30%.<ref name=":1" /><ref name=":27" />

The effect of longevity drugs on mice is often significant, delaying or eliminating the burden of age-related problems such as [[frailty]], cataracts, cancer, and sarcopenia. For example, a new class of drugs called senolytics have been shown to extend healthy lifespan in mice by over 30% whilst delaying age-related dysfunction.

== Which therapies may extend healthy lifespan? ==
Several drugs are known to extend healthy lifespan in animals. While there is no conclusive data that suggests these drugs would work the same in humans, many of these drugs are now being tested in clinical trials. [[File:Unity Mice.jpg|alt=Unity Mice|thumb|723x723px|Senolytic drugs eliminate senescent cells that accumulate with age, partially reversing multiple age-related diseases and extending the healthy lifespan of mice by up to 35%.<ref name=":16" /> ]]

=== Senolytics ===
Senolytics are drugs that remove senescent cells. These are cells which accumulate in the body with age and are linked with age-related diseases such as cancer.<ref>Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., ... & Kirkland, J. L. (2018). Senolytics improve physical function and increase lifespan in old age. ''Nature medicine'', ''24''(8), 1246-1256.</ref>
[[File:Metformin2.jpg|thumb|258x258px|Metformin extends lifespan in mice by 6%, and may extend lifespan in humans.<ref name=":13">Kulkarni, A. S., Gubbi, S., & Barzilai, N. (2020). Benefits of metformin in attenuating the hallmarks of aging. ''Cell metabolism'', ''32''(1), 15-30.</ref>]]
In mice, senolytics have been shown to increase the healthy lifespan by up to 35%.<ref name=":16">Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. ''Nature'', ''530''(7589), 184-189.</ref> The first clinical trials of senolytics in humans began in 2016, demonstrating improved inflammation biomarkers and function, suggestive of benefit in humans.<ref>https://clinicaltrials.gov/ct2/show/NCT02874989</ref><ref>https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext</ref>

=== [[Metformin]] ===
Metformin is an approved drug for type 2 diabetes that extends lifespan in multiple species. In mice, Metformin extends lifespan by up to 6%.<ref>Anisimov, V. N., Berstein, L. M., Popovich, I. G., Zabezhinski, M. A., Egormin, P. A., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., Yurova, M. N., Kovalenko, I. G., & Poroshina, T. E. (2011). If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. ''Aging'', ''3''(2), 148–157. <nowiki>https://doi.org/10.18632/aging.100273</nowiki></ref> Metformin works in part by improving insulin sensitivity and may target several hallmarks of aging.<ref name=":13" /> Metformin is being tested as a longevity therapy in the largest clinical trial of its kind, the Targeting Aging with Metformin (TAME) trial in the US.<ref name=":14">''TAME - Targeting Aging with Metformin - American Federation for Aging Research''. (n.d.). American Federation for Aging Research. <nowiki>https://www.afar.org/tame-trial</nowiki></ref> This is a randomized clinical trial of 3000 elderly patients comparing metformin against placebo for the onset of age-related diseases.<ref name=":14" /> Whether it slows aging in humans is unproven; the TAME trial may provide some insight.

=== [[Rapamycin]] ===
[[File:Rapamune .jpg|alt=Rapamune |thumb|253x253px|Rapamycin, also known as Rapamune© is being tested as a drug to extend healthy lifespan in humans. <ref name=":15" />]]
Rapamycin, also known as Rapamune©, is a drug used to prevent the rejection of organ transplants by the immune system. Rapamycin has been shown to extend lifespan by up to 26% when given at middle age, and 14% when given in late life.<ref name=":20">Harrison, D., Strong, R., Sharp, Z. ''et al.'' Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''Nature'' 460, 392–395 (2009). <nowiki>https://doi.org/10.1038/nature08221</nowiki>
</ref><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., Javors, M. A., Li, X., Nadon, N. L., Nelson, J. F., Pletcher, S., Salmon, A. B., Sharp, Z. D., Van Roekel, S., Winkleman, L., & Strong, R. (2014). Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468–477. <nowiki>https://doi.org/10.1111/acel.12194</nowiki></ref>

Among the hundreds of interventions known to target aging, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref name=":25">Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref>

Rapamycin is being tested in a large-scale clinical trial called the Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study (PEARL). This is a randomized clinical trial aiming to enroll 1000 elderly patients comparing rapamycin against placebo for age-related outcomes.<ref name=":15">Clinicaltrials.gov. 2021. ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. [online] Available at: <<nowiki>https://clinicaltrials.gov/ct2/show/NCT04488601</nowiki>> [Accessed 14 December 2021].
</ref>

=== [[Epigenetic reprogramming]] ===
Epigenetic reprogramming refers to remodeling of epigenetic marks, such as methylation tags on the DNA within cells. A specific version of this technique was used in 2020 to restore vision to blind mice by fully regrowing the optic nerve.<ref>Lu, Y., Brommer, B., Tian, X. ''et al.'' Reprogramming to recover youthful epigenetic information and restore vision. ''Nature'' 588, 124–129 (2020). <nowiki>https://doi.org/10.1038/s41586-020-2975-4</nowiki></ref> The lead researcher David Sinclair at Harvard Medical School believes this approach could one day be used to regenerate other tissues of the body as a longevity strategy.<ref>''Reversing The Aging Clock With Epigenetic Reprogramming''. (n.d.). Pubs - Bio-IT World. <nowiki>https://www.bio-itworld.com/news/2021/01/13/reversing-the-aging-clock-with-epigenetic-reprogramming</nowiki></ref>

In addition, over [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap 50 other drugs] are being tested in human clinical trials for targeting aging, to prevent or reverse various diseases.<ref name=":2">Lifespan.io. 2021. ''The Rejuvenation Roadmap | Lifespan.io''. [online] Available at: <<nowiki>https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/</nowiki>> [Accessed 13 December 2021].</ref>

== What is the goal of longevity biotechnology? ==
[[File:Healthy lifespan extension.png|alt=Healthy lifespan extension|thumb|643x643px|Healthy lifespan extension involves early intervention to prevent or delay the decline associated with aging.<ref>''Longevity companies to watch in 2021 - Longevity.Technology''. (n.d.). Longevity.Technology. <nowiki>https://www.longevity.technology/longevity-companies-to-watch-in-2021/</nowiki></ref> ]]
Longevity biotechnology aims to slow or reverse the aging process to extend the healthy lifespan (‘healthspan’) of the population. Instead of treating diseases when they arise, one by one, longevity biotechnology aims to keep people healthy by slowing the aging process. The aim is to thereby prevent or reverse multiple age-related diseases at once.

The longevity biotechnology sector is rapidly growing, and there are currently over 170 private companies working on developing therapeutics to slow the aging process.<ref name=":4">Pfleger, K., 2021. ''Aging Companies''. [online] Agingbiotech.info. Available at: <<nowiki>https://agingbiotech.info/companies</nowiki>> [Accessed 13 December 2021].</ref> These companies are working on slowing or reversing the aging process by targeting one or more of the hallmarks of aging.

== Will healthy or unhealthy lifespan be extended? ==
[[File:Extending healthy lifespan.png|alt=Extending healthy lifespan|thumb|364x364px|Extending healthy versus unhealthy lifespan.<ref>''How to save Medicare: the anti-aging remedy''. (2012, March). <nowiki>https://www.researchgate.net/figure/From-longer-life-span-to-longer-health-span-and-life-span-From-A-to-B-Standard_fig1_230724035</nowiki>.</ref>]]
The stated goal of longevity biotechnology is to extend the healthy period of lifespan, particularly before age-related diseases set in. This is in contrast to many of today's medical interventions, which extend life only after diseases (e.g. cancer, Alzheimer's) have reached a clinical level.

Age-related diseases are preceded by a long period of subclinical aging, i.e. aging that has not yet progressed far enough to produce clinical symptoms. By slowing, delaying or reversing the aging process, the hypothesis is that the healthy period of life can be extended.<ref name=":24" />

Studies in mice have demonstrated that life extending drugs such as rapamycin are capable of extending the healthy, rather than unhealthy period of life.<ref name=":20" />
== Should we treat specific diseases such as cancer, or focus on aging? ==
[[File:Slowing aging versus curing cancer.jpg|alt=Slowing aging is potentially a more effective means of extending healthy lifespan than treating individual diseases due to the comorbid nature of age-related diseases. [6]|thumb|421x421px|Slowing aging is potentially a more effective means of extending healthy lifespan than treating individual diseases due to the comorbid nature of age-related diseases.<ref name=":18" /> ]]
Longevity biotechnology offers a potentially greater likelihood of extending healthy lifespan than the current approach - attempting to find cures for the individual diseases of aging. This is because biological aging is associated with many diseases of aging. These diseases develop as comorbidities, which occur in sequence. Even if a person survives one age-related disease such as cancer, another (e.g. dementia, heart disease) is likely to next kill the person, because the underlying aging process is not treated.

This phenomenon is known as the Taeuber paradox<ref name=":28">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref>, and accounts for the much smaller projected increase in healthy lifespan associated with curing the diseases of aging, such as cancer (2-3 years), versus slowing aging itself (30+ years).<ref name=":18">Matt Kaeberlein, PhD, It is Time to Embrace 21st-Century Medicine, ''Public Policy & Aging Report'', Volume 29, Issue 4, 2019, Pages 111–115, <nowiki>https://doi.org/10.1093/ppar/prz022</nowiki></ref><ref name=":28" /><ref>Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> The life expectancy estimate of the latter is based on calculations by Professor Kaeberlein at the University of Washington, using lifespan data from rapamycin-treated mice.<ref>https://twitter.com/mkaeberlein/status/1463580145126567936</ref>
== What is biological aging? ==
There are two main types of 'age': chronological age - the number of years since birth, and biological age - a measure of the physical health of a person and their position in their lifespan. Biological age is more difficult to measure, but recent technologies are now available to estimate biological age. Over time, we age biologically. This occurs due to many processes in the body, which are generally categorized into 9 processes or 'hallmarks'.<ref name=":9" />
== What are the 9 Hallmarks of Aging? ==
[[File:Hallmarks of aging.jpg|alt=Hallmarks of aging|thumb|444x444px|The nine hallmarks of aging.<ref name=":9" />]]

The hallmarks of aging framework is considered to broadly represent key biological mechanisms of the biological aging process.<ref name=":9">López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.</ref> Although there are limitations of the hallmarks framework, it has become the central framework for understanding aging biology. The nine forms of cellular and molecular ‘damage’ that comprise the hallmarks of aging are<ref name=":9" />:

* Genomic instability
* Telomere attrition
* Epigenetic alterations
* Loss of proteostasis
* Deregulated nutrient-sensing
* Mitochondrial dysfunction
* Cellular senescence
* Stem cell exhaustion
* Altered intercellular communication

These are thought to be the lowest common denominators of the aging process, on a cellular or subcellular level. All of the physiological changes associated with aging, such as greying hair, wrinkles, frailty and an increased risk of disease are thought to stem from these underlying processes.<ref name=":9" />

== How does the aging cause disease? ==
The nine hallmarks of aging have been shown to play an integral role in the development of many age-related diseases such as dementia, cancer, and a multitude of others:
=== [[Aging and Neurodegeneration|Neurodegenerative disease]] ===
[[File:Prevalence of neuro disorders.jpg|alt=Prevalence of neuro disorders|thumb|469x469px|The prevalence of neurodegenerative disorders increases exponentially with age, due to the biological aging process.<ref name=":12">Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019). Ageing as a risk factor for neurodegenerative disease. ''Nature reviews. Neurology'', ''15''(10), 565–581. <nowiki>https://doi.org/10.1038/s41582-019-0244-7</nowiki></ref> ]]
All of the hallmarks of aging are associated with an increased risk of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.<ref>Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention. ''Dialogues in clinical neuroscience'', ''11''(2), 111.</ref> For example, several types of DNA damage are associated with neurodegeneration. The shortening of telomeres occurs as part of biological aging and causes cellular senescence, and is associated with neurodegeneration and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.<ref name=":12" /> Additionally, mitochondrial dysfunction, altered metabolism, stem cell exhaustion and loss of proteostasis are also involved in the development of neurodegenerative diseases.<ref name=":12" />
=== [[Aging and Cancer|Cancer]] ===
Several of the hallmarks of aging such as cellular senescence and alterations in the extracellular matrix are responsible for increasing the likelihood of tumorigenesis.<ref name=":5">Fane, M., & Weeraratna, A. T. (2020). How the ageing microenvironment influences tumour progression. ''Nature Reviews Cancer'', ''20''(2), 89-106.</ref>

Other hallmarks of aging such as genomic instability (DNA mutations), loss of proteostasis (e.g. proteotoxic stress), altered intercellular communication (e.g. inflammation) and epigenetic alterations (e.g. aberrant DNA methylation) are also involved in cancer development.<ref name=":5" />
== How is biological age measured? ==
[[File:Epigenetic clock.png|alt=Epigenetic clock|thumb|605x605px|The epigenetic clock measures biological age based on marks on the epigenome.<ref name=":6" /> ]]
Recent technologies have helped the measure of biological age, including:

=== [[Epigenetic clock|Epigenetic clocks]] ===
The first generation of aging clocks are known as [[Epigenetic clock|epigenetic clocks or Horvath’s clock]].<ref name=":6">Horvath, S., & Raj, K. (2018). DNA methylation-based biomarkers and the epigenetic clock theory of ageing. ''Nature Reviews Genetics'', ''19''(6), 371-384.</ref> This clock is based on the finding that with aging, the body accumulates methylation tags on the DNA in a pattern that can be predicted with machine learning. These changes to the epigenome are influenced by lifestyle and environment, and can be used to measure biological age.<ref name=":6" /> Factors such as exercise frequency and a low BMI have been shown to reduce the rate of epigenetic aging, whereas obesity and smoking can accelerate this rate.<ref>Quach, A., Levine, M. E., Tanaka, T., Lu, A. T., Chen, B. H., Ferrucci, L., ... & Horvath, S. (2017). Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. ''Aging (Albany NY)'', ''9''(2), 419.</ref><ref>Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. ''Clinical Epigenetics'', ''11''(1), 183. <nowiki>https://doi.org/10.1186/s13148-019-0777-z</nowiki>

[[Epigenetic clock#cite%20ref-12|↑]]</ref><ref>Horvath, S., Erhart, W., Brosch, M., Ammerpohl, O., von Schönfels, W., Ahrens, M., Heits, N., Bell, J. T., Tsai, P.-C., Spector, T. D., Deloukas, P., Siebert, R., Sipos, B., Becker, T., Röcken, C., Schafmayer, C., & Hampe, J. (2014). Obesity accelerates epigenetic aging of human liver. ''Proceedings of the National Academy of Sciences'', ''111''(43), 15538–15543. <nowiki>https://doi.org/10.1073/pnas.1412759111</nowiki>

[[Epigenetic clock#cite%20ref-13|↑]]</ref> Horvath's clock has been used to accurately predict mortality risk among human populations.<ref>Fransquet, P. D., Wrigglesworth, J., Woods, R. L., Ernst, M. E., & Ryan, J. (2019). The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis. ''Clinical epigenetics'', ''11''(1), 1-17.</ref>

=== Multi-omic clocks ===
Epigenetic clocks are being developed that incorporate data from several sources. This may include multi-omic clocks which include metabolomics, proteomics, or non-molecular biomarkers such as body imaging and fitness tests.<ref name=":21" /> These clocks are built using machine learning to estimate biological age. These aging clocks are being developed that combine multiple biological functional tests to create a unique aging signature, which can be monitored over time.<ref name=":21">Kudryashova, K. S., Burka, K., Kulaga, A. Y., Vorobyeva, N. S., & Kennedy, B. K. (2020). Aging Biomarkers: From Functional Tests to Multi‐Omics Approaches. ''Proteomics'', ''20''(5-6), 1900408.</ref>
[[File:Multiomic aging clock.jpg|alt=Multiomic clocks|center|thumb|542x542px|Multiomic clocks integrate various data sources to create a unique biological aging signature that can be tracked over time.<ref name=":21" /> ]]
== Which companies are trying to solve aging? ==
[[File:Calico Labs.png|alt=T|thumb|Calico Labs, a subsidiary of Google, is a billion-dollar company searching for treatments for aging.<ref name=":22" /> ]]
There are over [https://agingbiotech.info/companies 170 longevity biotechnology companies] trying to create therapies to slow or reverse the aging process.<ref name=":4" /> There are over [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ 50 longevity drugs] currently in clinical trials in humans.<ref name=":2" />

Many of the longevity biotechnology companies are targeting specific hallmarks of aging. For example, [https://www.clearabiotech.com/#DiscoveryTimeline Cleara Biotech] are attempting to reduce cellular senescence by developing a drug that can eliminate senescent cells.<ref>Cleara Biotech. 2021. ''Cleara Biotech''. [online] Available at: <<nowiki>https://www.clearabiotech.com/#DiscoveryTimeline</nowiki>> [Accessed 15 December 2021].</ref>

Calico Labs is a Google-backed biotech company with the goal of combating aging and age-related diseases. In 2014, the company created a partnership with pharmaceutical giant AbbVie, which has since developed into a [https://www.cnbc.com/2018/06/26/alphabet-backed-calico-and-abbvie-chip-in-1-billion-to-cure-aging.html $2.5 billion venture] in the pursuit of improving “health, wellbeing and longevity.” <ref name=":22">2021. ''Google sister company and drug giant chip in another $1 billion to cure age-related diseases''. [online] Available at: <<nowiki>https://www.cnbc.com/2018/06/26/alphabet-backed-calico-and-abbvie-chip-in-1-billion-to-cure-aging.html</nowiki>> [Accessed 15 December 2021].</ref>

Since aging is not currently considered a disease by regulatory bodies such as the Food and Drug Administration (FDA), drug developers are currently focused on specific diseases of aging such as glaucoma and osteoarthritis.<ref>Clinicaltrialsarena.com. 2021. ''Unity's Phase II osteoarthritis study of UBX0101 misses primary goal''. [online] Available at: <<nowiki>https://www.clinicaltrialsarena.com/news/unity-ubx0101-osteoarthritis/</nowiki>> [Accessed 15 December 2021].</ref>

== Which billionaires are funding longevity biotechnology? ==
[[File:Jeff Bezos is funding longevity research.jpg|alt=Jeff Bezos is funding longevity research|thumb|Jeff Bezos is funding longevity research through financing Atlos Labs.<ref name=":7">MIT Technology Review. 2021. ''Meet Altos Labs, Silicon Valley’s latest wild bet on living forever''. [online] Available at: <<nowiki>https://www.technologyreview.com/2021/09/04/1034364/altos-labs-silicon-valleys-jeff-bezos-milner-bet-living-forever/</nowiki>> [Accessed 15 December 2021].</ref>]]
Several billionaires have funded companies or initiatives to slow or reverse human aging. These include:
* [[wikipedia:Jeff_Bezos|Jeff Bezos]], co-founder of Amazon, helped raise [https://www.technologyreview.com/2021/09/04/1034364/altos-labs-silicon-valleys-jeff-bezos-milner-bet-living-forever/ $3 billion for new anti-aging drug company Altos Labs] in 2021.<ref name=":7" />
* [[Sam Altman]], CEO of OpenAI, invested [[$180 million into RetroBiosciences|$180 million into RetroBiosciences whose goal is to add]] 10 years to healthy human lifespan.<ref>MIT Technology Review. 2023. Sam Altman invested $180 million into a company trying to delay death. [online] Available at: <https://www.technologyreview.com/2023/03/08/1069523/sam-altman-investment-180-million-retro-biosciences-longevity-death/> [Accessed 09 July 2024].</ref>
* [[wikipedia:Peter_Thiel|Peter Thiel]], co-founder of PayPal, was an [https://www.cnbc.com/2018/08/29/-jeff-bezos-is-backing-this-scientist-who-is-working-on-a-cure-for-aging.html early investor in Unity Biotechnology].<ref>CNBC. 2021. ''Why Jeff Bezos is backing this Silicon Valley scientist who is working on a cure for aging''. [online] Available at: <<nowiki>https://www.cnbc.com/2018/08/29/-jeff-bezos-is-backing-this-scientist-who-is-working-on-a-cure-for-aging.html</nowiki>> [Accessed 15 December 2021].</ref>
* [[wikipedia:Sergey_Brin|Sergey Brin]], co-founder of Google, donated [https://www.cnbc.com/2017/03/31/google-co-founders-and-silicon-valley-billionaires-try-to-live-forever.html $25 million for the National Academy of Medicine’s Grand Challenge in Health Longevity] to 'end aging forever'.<ref>Google’s co-founders and other Silicon Valley billionaires are trying to live forever. (2021). Retrieved 15 December 2021, from <nowiki>https://www.cnbc.com/2017/03/31/google-co-founders-and-silicon-valley-billionaires-try-to-live-forever.html</nowiki></ref>
* [[wikipedia:Larry_Page|Larry Page]], co-founder of Google, co-founded the [[wikipedia:Calico_(company)|billion-dollar aging research company Calico Labs.]]<ref>Contributors to Wikimedia projects. (2013, September 19). ''Calico (company) - Wikipedia''. Wikipedia, the free encyclopedia. <nowiki>https://en.wikipedia.org/wiki/Calico_(company)</nowiki>
</ref>
* [[wikipedia:Mike_Cannon-Brookes|Mike Cannon-Brookes]], billionaire cofounder of Australian software giant Atlassian, has invested [https://www.forbes.com/sites/samshead/2019/08/19/billionaire-backs-uk-startup-trying-to-extend-human-lifespans/ $10 million into longevity company Juvenescence].<ref>Shead, S. (2019, August 19). ''Billionaire Backs U.K. Startup Trying To Extend Human Life Spans''. Forbes. <nowiki>https://www.forbes.com/sites/samshead/2019/08/19/billionaire-backs-uk-startup-trying-to-extend-human-lifespans/</nowiki></ref>
* [[wikipedia:Jim_Mellon|Jim Mellon]], UK billionaire investor who co-founded longevity company [https://www.juvlabs.com/people/co-founder/jim-mellon Juvenescence].<ref>''Jim Mellon - Chairman & Co-Founder''. (n.d.). Juvenescence - Science of Healthy Aging & Extended Lifespan. <nowiki>https://www.juvlabs.com/people/co-founder/jim-mellon</nowiki></ref>
* [[wikipedia:Larry_Ellison|Larry Ellison]], founder of Oracle, has spent [https://www.townandcountrymag.com/society/money-and-power/a9202324/science-of-longevity/ $430 million on longevity research].<ref>Tullis, P. (2017, March 30). ''Are You Rich Enough To Live Forever?'' Town & Country. <nowiki>https://www.townandcountrymag.com/society/money-and-power/a9202324/science-of-longevity/</nowiki></ref>
*Michael Greve, founder of Kizoo Technology, who has pledged [https://Longevity.Technology. https://www.longevity.technology/michael-greve-commits-e300m-for-rejuvenation-start-ups/ €300m to rejuvenation biotechnology companies.]<ref>''Michael Greve commits €300m for rejuvenation start-ups''. (2021, May 6). Longevity.Technology. <nowiki>https://www.longevity.technology/michael-greve-commits-e300m-for-rejuvenation-start-ups/</nowiki></ref>
*[[wikipedia:Naveen_Jain|Naveen Jain]], billionaire entrepreneur who has raised [https://www.geekwire.com/2021/gut-health-startup-viome-raises-54m-develop-cancer-diagnostics-sell-microbiome-kits/ $54 million for his startup Viome].<ref>''Gut health startup Viome raises $54M to develop cancer diagnostics and sell microbiome kits''. (2021, November 10). Geekwire. <nowiki>https://www.geekwire.com/2021/gut-health-startup-viome-raises-54m-develop-cancer-diagnostics-sell-microbiome-kits/</nowiki></ref>
* [[wikipedia:Yuri_Milner|Yuri Milner]], billionaire tech investor who helped Altos Labs raise $3 billion, with Jeff Bezos.<ref name=":7" />
*[[wikipedia:Brian_Armstrong_(businessman)|Brian Armstrong]], CEO of CoinBase, who helped found and raise [https://www.dailymail.co.uk/sciencetech/article-10310475/Billionaire-launches-new-start-hopes-REVERSE-ageing-process.html $105 million for the epigenetic reprogramming startup NewLimit.]<ref>Liberatore, S. (2021, December 14). ''Billionaire launches new start-up to REVERSE the ageing process''. Mail Online. <nowiki>https://www.dailymail.co.uk/sciencetech/article-10310475/Billionaire-launches-new-start-hopes-REVERSE-ageing-process.html</nowiki></ref>
* [[wikipedia:Vitalik_Buterin|Vitalik Buterin]], founder of the cryptocurrency Ethereum, who has donated over $2.4 million to anti-aging research organization SENS, among various other biotech projects.<ref>Foundation, S. R. (n.d.). ''SENS Research Foundation Receives $2.4 Million Ethereum Donation From Vitalik Buterin''. GlobeNewswire News Room. <nowiki>https://www.globenewswire.com/news-release/2018/02/02/1332410/0/en/SENS-Research-Foundation-Receives-2-4-Million-Ethereum-Donation-From-Vitalik-Buterin.html</nowiki></ref>

== How large will the longevity biotechnology field be? ==
Analysts from the Bank of America have predicted that the market size of longevity biotechnology will reach $600 billion by 2025.<ref>2021. ''Human lifespan could soon pass 100 years thanks to medical tech, says BofA''. [online] Available at: <<nowiki>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</nowiki>> [Accessed 14 December 2021].</ref> Others have speculated that it is a trillion dollar industry owing to the immense savings associated with delaying or preventing chronic diseases.<ref>Colangelo, M., 2021. ''AI Will Drive The Multi-Trillion Dollar Longevity Economy''. [online] Forbes. Available at: <<nowiki>https://www.forbes.com/sites/cognitiveworld/2019/12/07/ai-will-drive-the-multi-trillion-dollar-longevity-economy/?sh=294766b74965</nowiki>> [Accessed 14 December 2021].</ref>
== Is age an important for risk factor for COVID-19 mortality? ==
[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|thumb|572x572px|The risk of dying from COVID-19 increases exponentially with age. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age is the single most significant risk factor for COVID-19 mortality. The mortality rate from COVID-19 increases exponentially with age, such that the death rate for those aged over 80 years is over 1000 times higher than those below 30 years.<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref>

This increase in COVID-19 mortality with age is thought to be the result of a weakening of the immune system with age, known as immunosenescence.<ref>Bajaj, V., Gadi, N., Spihlman, A. P., Wu, S. C., Choi, C. H., & Moulton, V. R. (2021). Aging, immunity, and COVID-19: how age influences the host immune response to coronavirus infections?. ''Frontiers in Physiology'', ''11'', 1793.</ref>

The mortality rate doubling time for COVID-19 is close to the all-cause mortality rate doubling time.<ref name=":29" /> This has led several scientists to conclude that COVID-19 meets criteria for an age-related disease.<ref name=":29" /><ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

== How is aging biology research different to other fields of medical research? ==
Scientists studying the biology of aging believe that aging is a root cause of all the major diseases of aging, and that targeting aging directly would treat or reverse multiple diseases, simultaneously. This is known as the geroscience hypothesis, and has garnered traction in recent years.<ref name=":24">Austad, S. N. (2016). The geroscience hypothesis: is it possible to change the rate of aging?. In ''Advances in geroscience'' (pp. 1-36). Springer, Cham.</ref>

The approach of targeting aging directly differs from many fields in mainstream medical research such as cancer research, which seek to find cures for individual diseases. An argument in favour of targeting aging directly is that targeting single diseases leads to diminishing returns in healthy lifespan extension.<ref name=":18" /> Due to the many diseases that occur concurrently in older age, completely curing a single disease such as cancer would only add 2-3 healthy years of life on average, whereas slowing aging could add 30 or more healthy years.<ref name=":18" /> This is because another disease in line, e.g. Alzheimer's or lung disease, will subsequently result in death, a phenomenon known as the Taeuber Paradox.<ref name=":17">En.wikipedia.org. 2021. ''Taeuber Paradox - Wikipedia''. [online] Available at: <<nowiki>https://en.wikipedia.org/wiki/Taeuber_Paradox</nowiki>> [Accessed 14 December 2021].</ref>
== Do all animals age in the same way? ==
[[File:Naked mole rat graph.png|alt=Naked mole rat graph|thumb|530x530px|The naked mole-rat does not follow the same increased risk of mortality due to aging that humans and other mammals do.<ref>Ruby, J. G., Smith, M., & Buffenstein, R. (2018). Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age. ''elife'', ''7'', e31157.</ref> ]]
Many species, due to differences in their biology, age at different rates to humans. The jellyfish ''Turritopsis dohrnii'' can revert to earlier stages of its life cycle in response to stress, and is theoretically ''biologically'' immortal - though eventually dies, usually due to predation.<ref>Bavestrello, Giorgio; Christian Sommer; Michele Sarà (1992). "Bi-directional conversion in Turritopsis nutricula (Hydrozoa)".</ref>

Among mammals, the naked mole rat is an exceptionally long lived organism. It lives roughly ten times longer than similarly-sized rats, with resistance to cancer and age-related diseases.<ref name=":3">Ruby, J. G., Smith, M., & Buffenstein, R. (2018). Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age. ''elife'', ''7'', e31157.</ref><ref>Buffenstein, R., Amoroso, V., Andziak, B., Avdieiev, S., Azpurua, J., Barker, A. J., ... & Smith, E. S. J. (2021). The naked truth: a comprehensive clarification and classification of current ‘myths’ in naked mole‐rat biology. ''Biological Reviews''.</ref> Unlike other organisms, such as humans, horses and mice, the mortality rate of the naked mole rat appears steady over time. This trend does not follow the exponential increase in mortality (Gompertz-Makeham law) that humans do.<ref name=":3" />

Scientists are now studying the naked mole rat to identify key patterns in their genetics, environmental traits, and metabolism that may be responsible for their longer lifespans.<ref>Kim, E. B., Fang, X., Fushan, A. A., Huang, Z., Lobanov, A. V., Han, L., ... & Gladyshev, V. N. (2011). Genome sequencing reveals insights into physiology and longevity of the naked mole rat. ''Nature'', ''479''(7372), 223-227.</ref>

[[File:Naked mole rat.jpg|alt=Naked mole rat|center|thumb|323x323px|The naked mole-rat is unusually long-lived relative to other mice and rats.<ref name=":3" /> ]]

== Is aging considered a disease? ==
Aging is not currently classified as a disease by regulatory bodies such as the Food and Drug Administration (FDA) in the United States. However, several scientists in the aging field have publicly stated their preference for aging to be defined as, or at least thought of, as a disease, including professors David Sinclair and Nir Barzilai.<ref>TEDx Talks. (2020, June 9). ''Ageing'' ''is'' ''a'' ''treatable'' ''disease'' ''|'' ''Nir'' ''Bazilai'' ''|'' ''TEDxBeaconStreetSalon'' [Video]. YouTube. <nowiki>https://www.youtube.com/watch?v=XN7rLbCBO1c</nowiki></ref>

Recognition of aging as a treatable medical condition by the WHO comes from the new ICD-11 extension code MG2A and XT9T. MG2A refers to “Ageing associated decline in intrinsic capacity”, and is classified under "general symptoms".<ref>https://icd.who.int/dev11/l-m/en?fbclid=IwAR22C-Gx2i9mckSYLenAwLAkWuBt3s3ncQLdjs5aar1W42jAbibuD6SQ2gE#/http://id.who.int/icd/entity/835503193</ref> XT9T refers to "Ageing-related”, under the "Causality" category, and recognizes aging as a contributor to disease.<ref>https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f459275392</ref>

== What are the economic benefits of extending healthy lifespan? ==
Extending the healthy human lifespan could have significant economic benefits gobally. An economic analysis from 2021 by researchers at the University of Oxford and Harvard University estimated the benefit of a drug that slows aging by 1 year as $38 trillion.<ref name=":23">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This is mainly because slowing aging prevents age-related diseases such as cancer and Alzheimer’s disease, which are of great expense to healthcare systems, productivity, and society. The study demonstrated a larger economic benefit of slowing aging than curing the individual diseases of aging. <ref name=":23" />
== Which scientists and institutions are trying to understand and reverse aging? ==
Over [https://whoswho.senescence.info/ 300 scientists are working on understanding the biology of aging] in leading institutions that include Harvard University, Stanford University, Yale University, and the University of Oxford.<ref>''Who's Who in Gerontology: Researchers and Companies Working on Aging''. (n.d.). Who's Who in Gerontology: Researchers and Companies Working on Aging. <nowiki>https://whoswho.senescence.info/</nowiki></ref> Some of the most well-known institutes and labs include:

=== The Buck Institute for Research on Aging ===
The Buck Institute for Research on Aging is one of the largest longevity research institutes with over 250 scientists. The research covers several areas including the mechanisms of aging, neurodegeneration, senescence, stem cells and regenerative medicine, cellular stress and disease, cancer associated with aging, and mitochondrial function.<ref>''Buck Institute''. (n.d.). BUCK. <nowiki>https://www.buckinstitute.org/</nowiki></ref>

=== Professor David Sinclair - Harvard Medical School ===
Professor Sinclair’s lab focuses on understanding and reversing aging. The lab focuses on a range of areas including DNA repair, mitochondrial dysfunction, and the interactions between epigenetic and genetic instability, and tissue reprogramming.<ref>''Welcome | The Sinclair Lab''. (n.d.). Welcome | The Sinclair Lab. <nowiki>https://sinclair.hms.harvard.edu/</nowiki></ref>

=== Professor Matt Kaeberlein - University of Washington ===
Professor Kaeberlein's lab focuses on biological mechanisms of aging in order to facilitate translational interventions that promote healthspan and improve quality of life. Kaeberlein is known for his work on the longevity drug rapamycin in organisms such as mice and dogs. He is Director of the Dog Aging Project, a multi-year initiative studying the genetic and environmental factors that influence health, with over 33,000 participating dogs.<ref>''Matt Kaeberlein, PhD | Faculty | Dept. of Laboratory Medicine & Pathology | UW Medicine''. (n.d.). Dept. of Laboratory Medicine & Pathology | UW Medicine. <nowiki>https://dlmp.uw.edu/faculty/kaeberlein</nowiki></ref>

=== Professor Brian Kennedy - National University of Singapore ===
Professor Kennedy’s lab focuses on understanding the biology of aging and translating research discoveries into new ways of delaying aging in humans. The lab has identified drugs that extend the healthy lifespan of worms and mice and are seeking to understand their mechanisms.<ref>''Brian Kennedy - Department of Biochemistry – School of Medicine, National University of Singapore''. (n.d.). Department of Biochemistry – School of Medicine, National University of Singapore. <nowiki>https://medicine.nus.edu.sg/bch/fa</nowiki></ref>

=== Associate Professor Lynne Cox - University of Oxford ===
Professor Cox’s lab study the molecular and cellular basis of aging to identify specific biochemical processes and pathways that change organisms age. The lab particularly cellular senescence, which underpins many age-related diseases including cancer and neurodegeneration.<ref>''Associate Prof Lynne Cox''. (n.d.). Home | Biochemistry. <nowiki>https://www.bioch.ox.ac.uk/research/cox</nowiki></ref>

== What books have been written on this topic? ==
Several books have been written on the topic of aging and longevity. These include:

* [https://www.amazon.com/Lifespan-Why-Age_and-Dont-Have/dp/1501191977 ''Lifespan: Why We Age And Why We Don't Have To'' - David Sinclair (2019)]

* [https://www.amazon.com/Ending-Aging-Rejuvenation-Breakthroughs-Lifetime/dp/0312367074 ''Ending Aging'' - Dr. Aubrey de Grey (2007)]

* [https://www.amazon.com/Ageless-Science-Getting-Older-Without/dp/0385544928 ''Ageless'' - Dr. Andrew Steele (2020)]

* [https://www.amazon.com.au/Age-Later-Health-Science-Longevity-ebook/dp/B0818MYCRR ''Age Later'' - Professor Nir Barzilai (2021)]

* [https://www.amazon.com.au/Science-Technology-Growing-Young-Breakthroughs/dp/1950665879 ''The Science and Technology of Growing Young'' - Sergey Young (2021)]

== Which anti-aging drugs are being tested in clinical trials today? ==
There are over 50 drugs being tested in human clinical trials for aging or age-related diseases.

The largest trial is the Targeting Aging with Metformin (TAME) trial, which began in 2020. The trial is being run in the United States with a cohort of 3000 older adults. The goal of the TAME trial is to determine whether diabetes drug metformin slows the aging process in older adults. The TAME trial is a $75 million trial run by the American Federation for Aging Research.<ref name=":14" />

Another large clinical trial is the Participitory Evaluation (of) Aging (with) Rapamycin (for) Longevity (PEARL) study. The goal of this study is to determine whether rapamycin, a drug currently approved for immunosuppression during organ transplants, slows biomarkers of aging in 1000 adults. The PEARL trial is being run by AgelessRx.<ref name=":15" />
== Is aging a natural process that should be accepted? ==
Although aging is a natural process in humans, it is the driving force of many diseases such as cancer and Alzheimer's disease - which as a society we have decided are worth trying to find cures for. In the past, these conditions, as well as atherosclerosis and even infectious diseases were once thought of as natural processes to be accepted. As treatments for previously untreatable diseases started being developed, society moved to accommodate this.

Atherosclerosis, the hardening of the arteries, was once viewed as a natural process that was simply a consequence of aging. However, when treatments such as statins were later developed to prevent atherosclerosis, it became widely regarded as a disease to be cured. Statins are now one one of the most widely prescribed drugs in the world, used in preventing heart diseases. The inventor of statins, Akira Endo, describes in his historical paper: “Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented.”<ref>Endo A. (2010). A historical perspective on the discovery of statins. ''Proceedings of the Japan Academy. Series B, Physical and biological sciences'', ''86''(5), 484–493. <nowiki>https://doi.org/10.2183/pjab.86.484</nowiki></ref>

== Will anti-aging technology lead to overpopulation? ==
A common objection to the development of longevity technologies is that they may lead to an unsustainably large population size.

One study of a 2005 Swedish cohort of 9 million people modeled the effect of various anti-aging scenarios. The researchers showed that even with the most radical life-extension technology in which aging completely stopped after age 60, the population growth across 100 years was only 22%.<ref>Gavrilov, L. A., & Gavrilova, N. S. (2010). Demographic consequences of defeating aging. ''Rejuvenation research'', ''13''(2-3), 329-334.</ref> In reality, the first aging drugs will likely slow aging by a modest amount, and most likely increase healthspan as opposed to lifespan. This is partly based on evidence in animals showing that it is easier to extend median, as opposed to maximal lifespan.

Currently, the world’s population is 7.9 billion, and the WHO predicts the population will peak at 11 billion in 2100 before falling due to declining birth rates in many parts of the world. The fastest growing populations are in Africa and South-east Asia. However, several factors are thought to reduce birth rates over time, including increased access to contraceptives, female empowerment, increased education and increased employment. There is evidence that populations that move to a more advanced economy show a reduction in birth rates. This is expected to mitigate the increase in population size from longer lifespans.

== Will anti-aging drugs only be available to the rich? ==
It is unclear who will have first access to longevity drugs. Several researchers in the field have argued that several economic factors are likely to drive down the price of drugs that slow aging.

* The cost of many biotechnologies decreases substantially over time. For example, the first human genome cost $100 million to sequence, and is now available for a few hundred dollars.<ref>''The Cost of Sequencing a Human Genome''. (n.d.). Genome.gov. <nowiki>https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost</nowiki></ref>

* The price of many lifesaving pharmaceuticals has fallen significantly in price once generic drugs were produced. For example, Lipitor, a statin used to prevent heart disease has fallen in price from $85 in 2011 to less than $5 today.

* Many companies in the longevity field have stated that equity of access is part of their core ethos, and many researchers are part of an international coalition called the Academy of Health & Lifespan research which aims to ensure that breakthroughs in aging research are accessible to all. <ref>''Academy for Health & Lifespan Research''. (n.d.). Academy for Health & Lifespan Research. <nowiki>https://www.ahlresearch.org/</nowiki></ref>

== References ==
<references />

Rapamycin

2024-06-19T07:26:52Z

Geroscientist: /* Yeast */

[[File:Rapamycin2.jpg|thumb|211x211px|The chemical structure of rapamycin.]]
Rapamycin, also known by its brand name Rapamune®, is a compound used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Easter Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.<ref>Accessdata.fda.gov. 2021. ''Drug Approval Package: Rapamune (Sirolimus) NDA# 021083''. [online] Available at: <<nowiki>https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm</nowiki>> [Accessed 27 May 2021].</ref> At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.<ref>Doggrell, S. (2006). Sirolimus- or paclitaxel-eluting stents for coronary artery revascularisation. ''Expert Opinion On Pharmacotherapy'', ''7''(2), 225-228. <nowiki>https://doi.org/10.1517/14656566.7.2.225</nowiki></ref> The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.<ref>Cancer, C. (2021). ''Everolimus - Drug Information - Chemocare''. Chemocare.com. Retrieved 27 May 2021, from <nowiki>http://chemocare.com/chemotherapy/drug-info/everolimus.aspx</nowiki>.</ref>

Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":2" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref><ref>Mannick, J. B., & Lamming, D. W. (2023). Targeting the biology of aging with mTOR inhibitors. Nature Aging, 1-19. PMID: 37142830 PMC10330278 [https://www.nature.com/articles/s43587-023-00416-y DOI: 10.1038/s43587-023-00416-y]</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":2">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref> It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

== Evidence of increased healthspan or lifespan ==

=== Non-human primates ===
Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed that rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' The extension of lifespan was associated with improved healthspan, with preserved cognitive health and a reduced burden of age-related disease in treated marmosets versus placebo. Rapamycin was delivered orally at 1 mg/kg/day.

=== Dogs ===
There is preliminary evidence that rapamycin may prevent age-related decline in dogs. One study showed statistically significant improvements in heart function in dogs receiving rapamycin, relative to those that received placebo, similar to what has been observed in older laboratory mice.<ref name=":9">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411365/ Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.]</ref> As part of the Dog Aging Project at the University of Washington, the TRIAD study is testing whether rapamycin can extend healthy lifespan in pet dogs.
=== Mice ===
In multiple studies in different breeds of mice, rapamycin demonstrates a robust effect on increasing healthy lifespan. Rapamycin significantly extends lifespan in approximately 90% of the mice models it has been tested in.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref>

In 2009, rapamycin was shown to increase the lifespan of both male and female mice when given in late life (600 days).<ref name=":5">[https://doi.org/10.1038%2Fnature08221 Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''nature'', ''460''(7253), 392-395.]</ref> Mean survival was extended by 28% for males and 38% for females, while maximal lifespan increased by 9% for males and 14% for females.<ref name=":5" /> This was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological drug. This mouse study is special because the results were obtained following the US National Institute on Aging's Interventions Testing Program (ITP) protocol. The ITP is regarded as the gold standard for testing drugs that target aging.<ref>Nadon, N. L., Strong, R., Miller, R. A., Nelson, J., Javors, M., Sharp, Z. D., ... & Harrison, D. E. (2008). Design of aging intervention studies: the NIA interventions testing program. ''Age'', ''30''(4), 187-199.</ref>

The landmark 2009 study also showed that rapamycin could increase healthy lifespan when given in old age. This has important implications for human testing, as it suggests that the drug might still exhibit healthspan and lifespan benefits even when given to the elderly. Rapamycin contrasts with calorie restriction in this regard; some evidence suggests that calorie restriction needs to be practiced from early adulthood, and may even fail to provide benefit for animals that are already old.<ref>Szafranski, K., & Mekhail, K. (2014). The fine line between lifespan extension and shortening in response to caloric restriction. ''Nucleus'', ''5''(1), 56-65.</ref>
==== Rapidly aging mice models ====
Using a mouse model that mimics the accelerated aging disease Hutchinson-Gilford progeria, rapamycin was shown to increase lifespan by over 50%. It also improved cardiac and skeletal muscle function in these mice.<ref>[https://doi.org/10.1126%2Fscitranslmed.3003802 Ramos, F. J., Chen, S. C., Garelick, M. G., Dai, D. F., Liao, C. Y., Schreiber, K. H., ... & Kennedy, B. K. (2012). Rapamycin reverses elevated mTORC1 signaling in lamin A/C–deficient mice, rescues cardiac and skeletal muscle function, and extends survival. ''Science translational medicine'', ''4''(144), 144ra103-144ra103.]
</ref> In one short-lived mutant strain of mice that mimics Leigh syndrome, rapamycin was shown to extend maximum life span nearly three-fold.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/24231806/ Johnson, S. C., Yanos, M. E., Kayser, E. B., Quintana, A., Sangesland, M., Castanza, A., ... & Kaeberlein, M. (2013). mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. ''Science'', ''342''(6165), 1524-1528.]</ref>

==== Middle-aged mice ====
Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.<ref>Bitto, A., Ito, T.K., Pineda, V.V., LeTexier, N.J., Huang, H.Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K. and Meza, D., 2016. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. ''elife'', ''5'', p.e16351.</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269 Strong, R., Miller, R. A., Bogue, M., Fernandez, E., Javors, M. A., Libert, S., ... & Harrison, D. E. (2020). Rapamycin‐mediated mouse lifespan extension: Late‐life dosage regimes with sex‐specific effects. ''Aging cell'', ''19''(11), e13269.]</ref> Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.<ref>Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. ''J Gerontol A Biol Sci Med Sci''. 2016 Jul; 71(7):876-81. doi: [https://academic.oup.com/biomedgerontology/article/71/7/876/2605199 10.1093/gerona/glw064]. Epub 2016 Apr 18. PMID: 27091134; PMCID: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906329/ PMC4906329]</ref> These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.

=== Flies ===
Rapamycin extends the lifespan of the fruitfly, ''Drosophila melanogaster.'' The extent of lifespan extension observed is beyond what is achievable by flies undergoing other pro-longevity interventions like dietary restriction, or in mutant flies with mild decrements in insulin/insulin-like growth factor signaling (IIS).<ref>Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. ''Cell metabolism'', ''11''(1), 35-46.</ref> Combining rapamycin with two other drugs that target metabolic pathways, lithium and trametinib, results in additive lifespan extension effects, substantially increasing ''Drosophila'' lifepsan by 48%.<ref>Castillo-Quan, J. I., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., ... & Partridge, L. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. ''Proceedings of the National Academy of Sciences'', ''116''(42), 20817-20819.</ref>

=== Roundworms ===
TOR inhibition by rapamycin extends lifespan in ''Caenorhabditis elegans,'' a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in ''C. elegans'' seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.<ref>Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. ''Cell metabolism'', ''15''(5), 713-724.</ref>

=== Yeast ===
Inhibition of TOR signalling by rapamycin significantly increases the lifespan of brewer's yeast, ''Saccharomyces cerevisiae.''<ref>Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. ''Genes & development'', ''20''(2), 174-184.</ref>

== Effects on age-related diseases ==
Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref>

===== Cancer =====
In the transgenic HER-2/neu mouse model, mice die prematurely due to susceptibility to cancer.<ref name=":6" /> Rapamycin was hypothesized to improve survival in this model due to its ability to slow aging, which would also address an age-related disease like cancer.<ref name=":6" /> The drug was shown to extend maximal lifespan, by delaying aging in multiple different organs and also suppressing cancer development.<ref name=":6">Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., ... & Blagosklonny, M. V. (2010). Rapamycin extends maximal lifespan in cancer-prone mice. ''The American journal of pathology'', ''176''(5), 2092-2097.</ref>

Other studies suggest that rapamycin can extend lifespan in mouse models where cancer naturally develops, such as in mice prone to cancer due to the Apc tumor suppressor gene mutation, or in mice heterozygous for the Rb1 tumor supressor gene, among others.<ref>Hasty, P., Livi, C. B., Dodds, S. G., Jones, D., Strong, R., Javors, M., ... & Sharp, Z. D. (2014). eRapa restores a normal life span in a FAP mouse model. ''Cancer Prevention Research'', ''7''(1), 169-178.</ref><ref>Livi, C. B., Hardman, R. L., Christy, B. A., Dodds, S. G., Jones, D., Williams, C., ... & Sharp, Z. D. (2013). Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. ''Aging (Albany NY)'', ''5''(2), 100.</ref><ref>Hambright, H. G., Hurez, V., & Curiel, T. J. (2020). Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging or Vice Versa?. ''Geriatric Oncology'', 111-128.</ref>

A group of investigators in Germany have argued, based on their experiment in C57BL/6J Rj inbred mice, that rapamycin extends lifespan mainly through delaying cancer incidence, instead of via slowed aging.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref> A further analysis of the paper by Johnson et al. pointed to several important limitations of the study, suggesting that such a conclusion may be premature.<ref name=":82">Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? ''Science translational medicine'', ''5''(211), 211fs40.</ref> Key limitations included the lack of dose-response profiling of rapamycin; studying only the male sex, which is known to respond less to rapamycin likely in part due to sex differences in drug metabolism; lack of reporting on tumor size and incidence, required to determine whether lifespan extension occured only via slowed cancer or from a general effect on aging; and, the cross-sectional nature of the study, which would have reduced sensitivity for detecting age-related organ/tissue changes compared to longitudinal assays.<ref name=":82" /><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.</ref>

===== Heart Disease =====
One study investigated the effects of late-life rapamycin dosing in aged female mice, observing a reversal of age-related heart dysfunction.<ref name=":16">Flynn, J. M., O'Leary, M. N., Zambataro, C. A., Academia, E. C., Presley, M. P., Garrett, B. J., ... & Melov, S. (2013). Late‐life rapamycin treatment reverses age‐related heart dysfunction. ''Aging cell'', ''12''(5), 851-862.

</ref> This included benefits to ejection fraction, cardiac hormones, and reduced inflammation, although no effect was observed for heart fibrosis.<ref name=":16" /> Additionally, improvements in behaviour and physical function were demonstrated.<ref name=":16" /> Another study in naturally aged mice showed improvements in cardiac muscle stiffness, diastolic function with rapamycin.<ref name=":7">Quarles, E., Basisty, N., Chiao, Y. A., Merrihew, G., Gu, H., Sweetwyne, M. T., ... & Rabinovitch, P. S. (2020). Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. ''Aging Cell'', ''19''(2), e13086.</ref> Improvements in heart function were shown with only a brief treatment course of 8 weeks.<ref name=":7" /> Benefits persisted even after rapamycin was stopped, which appears consistent with the hypothesis that rapamycin slows aging.<ref name=":7" />

===== Alzheimer's =====
Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which age is the greatest risk factor.<ref>https://www.science.org/doi/10.1126/scitranslmed.aar4289</ref> In an Alzheimer's model of transgenic PDAPP mice, rapamycin was shown to reduce Amyloid-β, one of the hallmarks of AD.<ref name=":8" /> This led to alleviation of AD-like symptoms, such as restored cognition and memory.<ref name=":8">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> Similarly, another major AD hallmark known as tau was mitigated by rapamycin in a tauopathy mouse model.<ref name=":14">Ozcelik, S., Fraser, G., Castets, P., Schaeffer, V., Skachokova, Z., Breu, K., ... & Winkler, D. T. (2013). Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. ''PloS one'', ''8''(5), e62459.</ref> The mechanism of clearance of these proteins was linked to autophagy, with benefits seen regardless of whether it was dosed early for prevention, or in late life as treatment.<ref name=":14" />

=== Dose response ===
Rapamycin has shown a dose-response in which higher doses produce larger lifespan extension effects. UMHET3 mice of diverse genetic background were treated with varying doses of dietary rapamycin at 4.7, 14, or 42 ppm, revealing that those fed with the highest rapamycin dose had the greatest lifespan extension.<ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":0">[[Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. Journal of genetics and genomics= Yi chuan xue bao, 41(9), 459.|Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.]]</ref> Sex differences in response to rapamycin have been hypothesized to also be related to the effective dose, due to male/female differences in drug metabolism. The optimal dose for longevity in mice remains to be seen, but determining this dose will require consideration of the side effect profile of rapamycin.<ref name=":0" />

== Mechanism ==

=== Manipulating metabolic pathways - differences to calorie restriction ===
Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.<ref name=":15">Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":4" /> This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.<ref name=":3">Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. ''Current opinion in genetics & development'', ''23''(1), 53-62.</ref> mTOR plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.<ref name=":3" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.<ref name=":15" /><ref name=":4">Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. (2020). Is rapamycin a dietary restriction mimetic?. ''The Journals of Gerontology: Series A'', ''75''(1), 4-13.</ref> For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.<ref name=":15" /> This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.<ref name=":4" />

Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/21179166/ Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. ''Nature'', ''468''(7327), 1100-1104.]</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref name=":5" /><ref>Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. ''Aging (Albany NY)'', ''11''(19), 8048.
</ref> Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.<ref>Kemnitz, J. W. (2011). Calorie restriction and aging in nonhuman primates. ''Ilar Journal'', ''52''(1), 66-77.</ref><ref>Goto, S., Takahashi, R., Radak, Z., & Sharma, R. (2007). Beneficial biochemical outcomes of late‐onset dietary restriction in rodents. ''Annals of the New York Academy of Sciences'', ''1100''(1), 431-441.</ref><ref>Kristan, D. M. (2008). Calorie restriction and susceptibility to intact pathogens. ''Age'', ''30''(2), 147-156.</ref> Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref>

=== mTORC1 and mTORC2 ===
In non-mammals the mTOR equivalent is known as the target of rapamycin (TOR), first discovered by a team led by Michael Hall in the yeast ''Saccharomyces cerevisiae''.<ref>Thomas, G., & Hall, M. N. (1997). TOR signalling and control of cell growth. ''Current opinion in cell biology'', ''9''(6), 782-787.</ref><ref>Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N. R., & Hall, M. N. (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. ''Cell'', ''73''(3), 585-596.</ref> mTOR signalling appears to be evolutionarily conserved, and this extends further to include various mammals, such as mice, rats, and dogs.

Rapamycin acts on mTOR, with multiple signaling functions subdivided across two major protein complexes known as mTORC1 and mTORC2.<ref name=":3" /> There is some evidence suggesting that the health and lifespan benefit of rapamycin is more related to inhibition of mTORC1 than mTORC2.<ref name=":19">Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.</ref><ref name=":11">Lamming, D. W., Mihaylova, M. M., Katajisto, P., Baar, E. L., Yilmaz, O. H., Hutchins, A., ... & Sabatini, D. M. (2014). Depletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan. ''Aging cell'', ''13''(5), 911-917.</ref> In mice, males exhibit weaker lifespan extension effects from rapamycin than in females. One study suggests that inhibiting mTORC2 explains why the sex difference in the response to mTOR inhibition by rapamycin.<ref name=":11" />

=== Effects on glucoregulatory control ===
A noted issue regarding rapamycin is the disruption of glucose metabolism with chronic dosing, which has been observed in both humans and mice. In mice, this side effect has been shown to be due in part to disruption of mTORC2 in the liver, leading to hepatic insulin resistance.<ref name=":19" /> This effect has previously been shown to be reversible upon stopping the drug in both lean and obese mice.<ref name=":18">Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J. A., ... & Salmon, A. B. (2014). Rapamycin-induced metabolic defects are reversible in both lean and obese mice. ''Aging (Albany NY)'', ''6''(9), 742.</ref> Whether disrupted glucose metabolism is dispensable for the lifespan extending effects of rapamycin remains controversial.<ref>Blagosklonny, M. V. (2012). Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. ''Aging (Albany NY)'', ''4''(5), 350.</ref><ref>[https://www.nature.com/articles/s41419-019-1822-8 Blagosklonny, M. V. (2019). Fasting and rapamycin: diabetes versus benevolent glucose intolerance. ''Cell death & disease'', ''10''(8), 1-10.]</ref><ref>[https://www.science.org/doi/full/10.1126/science.1215135 Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.]</ref><ref>Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., ... & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. ''Aging cell'', ''15''(5), 872-884.</ref> Rapamycin has previously been shown to increase insulin sensitivity with acute dosing, while decreasing insulin sensitivity with chronic dosing.<ref>Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M., & Baur, J. A. (2012). Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. ''Frontiers in genetics'', ''3'', 177.</ref>

=== Reducing the effects of cellular senescence ===
The accumulation of senescent cells is thought to be an important mechanism underlying aging. Rapamycin is regarded as a senomorphic that may inhibit the pro-inflammatory secretory phenotype produced by senescent cells in humans, mice, and rats.<ref>[[Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. Aging cell, 16(3), 564-574.|Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. ''Aging cell'', ''16''(3), 564-574.]]</ref><ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref> A preliminary study in humans aged 40 years or older showed that topical rapamycin reduced markers of cellular senescence in the skin and improved its physical appearance.<ref>[https://doi.org/10.1007%2Fs11357-019-00113-y Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Nadhan, K., Potnis, M., ... & Sell, C. (2019). Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. ''Geroscience'', ''41''(6), 861-869.]
</ref>

== Human clinical trials ==
[[File:Rapamycin.jpg|thumb|235x235px|Part of the rationale of the PEARL study is to determine the optimal dose of rapamycin to potentially slow aging.<ref name=":2" />]]

=== PEARL study ===
Rapamycin is currently being tested for safety and efficacy in a clinical trial called the Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity (PEARL) study. The clinical trial aims to systematically investigate the use of rapamycin to promote healthy longevity, and is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

The study will begin with 200 adults aged 50 years or older who will receive rapamycin for up to one year. The study is being conducted by AgelessRx, a new company dedicated to developing scientifically supported interventions to prevent and treat age-related diseases, in collaboration with the University of California.<ref>[https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/ ''AgelessRx and funding an IRB-approved rapamycin trial - Longevity.Technology''. Longevity.Technology. (2021). Retrieved 27 May 2021, from https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/.]</ref>

The trial aims to obtain clinical data at 6 and 12 months of treatment, such as via testing of blood, body composition DXA, fecal microbiome, immune function, inflammation, skeletal muscle, and epigenetic aging clocks.

== Dog clinical trials ==
The Dog Aging Project is a US Government NIH-funded initiative investigating dog aging.<ref>https://dogagingproject.org/</ref> The project is led by Professor Matt Kaeberlein at the University of Washington.<ref name=":10">Kaeberlein, M., Creevy, K. E., & Promislow, D. E. (2016). The dog aging project: translational geroscience in companion animals. ''Mammalian genome'', ''27''(7), 279-288.</ref>

The Test of Rapamycin In Aging Dogs (TRIAD) study is investigating rapamycin as a treatment to slow aging in dogs. The investigators hope to increase healthy canine lifespan with rapamycin by delaying the onset of age-related diseases like cancer and heart disease.<ref name=":9" /><ref name=":10" />

Aging biology scientists believe that studying dog aging might not only help improve canine healthspan, but also have implications for humans.<ref name=":10" /> Dogs may be a useful animal model because they share the same environment that humans live in, and suffer from similar chronic diseases with aging.<ref>Hoffman, J. M., Creevy, K. E., Franks, A., O'Neill, D. G., & Promislow, D. E. (2018). The companion dog as a model for human aging and mortality. ''Aging Cell'', ''17''(3), e12737.</ref>

===== Heart disease =====
One randomized-controlled trial in 24 middle-aged dogs treated with low-dose rapamycin showed suggestion of partial reversal of age-related heart dysfunction, as measured via echocardiography. The intervention was well-tolerated, with no clinically meaningful adverse events noted with a non-immunosuppressive dose of rapamycin during the 10 week period. This was a small study over a relatively short duration; further testing in larger clinical studies will be necessary to determine whether rapamycin can be used to treat age-related heart disease in dogs.

== Regulatory approval ==
Rapamycin was approved by the US Food and Drug Administration (FDA) in 1999 to prevent organ rejection in liver transplant patients, and has been marketed under the brand name Rapamune.<ref>[https://link.springer.com/article/10.1007/s11357-020-00274-1 Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.]</ref> The patent on rapamycin has expired, and chemically similar compounds called 'rapalogs' are being researched by biotechnology companies.<ref>[https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.9b00215 Abdel-Magid, A. F. (2019). Rapalogs potential as practical alternatives to rapamycin.]
</ref> It is not currently approved for use as an anti-aging medication, due to lack of human clinical data for this purpose.

== Safety ==
Rapamycin has been used to treat millions of patients over several decades since obtaining FDA approval in 1999. It is generally considered safe in humans, but only when used under clinical supervision for specific indications. Rapamycin and its analogs are immunosuppressants, and used as such in the clinic; some rapalogs have received “black-box” FDA warnings due to the risks of infection, as well as the potential risk of cancer due to suppression of tumor immune surveillance.<ref>https://www.pfizermedicalinformation.com/en-us/rapamune/boxed-warning</ref><ref>https://www.pdr.net/drug-summary/Afinitor-everolimus-416.6101</ref>

Various side effects have been reported with the dose of rapamycin used to prevent rejection in organ transplant patients, who are often concurrently treated with multiple other medications.<ref>Webster, A. C., Lee, V. W., Chapman, J. R., & Craig, J. C. (2006). Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. ''Transplantation'', ''81''(9), 1234-1248.</ref> These include pain, headache, fever, high blood pressure, glucose intolerance, new-onset diabetes, nausea, abdominal pain, constipation, diarrhea, thrombocytopenia, leukopenia, among others. However, side effects are mostly reversible (at least if therapy is rapidly discontinued) and represent worst-case scenarios, particularly because the patients sampled in clinical studies are already severely ill and taking the drug along with other medications.<ref>Bischof, E., Siow, R.C., Zhavoronkov, A. and Kaeberlein, M., 2021. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), pp.e105-e111.
</ref> In subjects taking high doses of rapamycin and analogs for severe, chronic conditions including tuberous sclerosis complex, an inherited genetic disorder of increased mTOR signaling, or for cancer, the side effects have occasionally led life-threatening adverse events or death.<ref>Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anti-cancer drugs. 2015;26(4):437-42. PMID: [https://pubmed.ncbi.nlm.nih.gov/25719621/ 25719621] DOI: [https://doi.org/10.1097/cad.0000000000000207 10.1097/CAD.0000000000000207]</ref><ref>Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010; 116(18):4256-65. PMID: [https://pubmed.ncbi.nlm.nih.gov/20549832/ 20549832] DOI: [https://doi.org/10.1002/cncr.25219 10.1002/cncr.25219] </ref>

Case studies of the safety profile of rapamycin in the context of overdosing have suggested that it may have a large margin of safety or a high median lethal dose, but only in the acute setting.<ref>Ceschi, A., Heistermann, E., Gros, S., Reichert, C., Kupferschmidt, H., Banner, N. R., ... & Taegtmeyer, A. B. (2015). Acute sirolimus overdose: a multicenter case series. ''PLoS One'', ''10''(5), e0128033.</ref> The distinction with chronic high dose mTOR inhibition must be made because resultant immunosuppression can lead to susceptibility to infection with fatal consequences. Some preclinical data suggests that the longevity benefits of rapamycin may be retained via intermittent dosing.<ref name=":2" /> In considering the known clinical data about rapamycin's controversial safety at continuous, high doses, some researchers have proposed that rapamycin should dosed intermittently to minimize side effects while sufficiently inhibiting mTOR for an effect on aging.<ref name=":2" />

From a longevity perspective, there is a lack of published clinical data demonstrating the safety of rapamycin in healthy adults. One small randomized pilot study of rapamycin in 25 older adults aged 70-95 taking 1 mg/day of rapamycin reported finding no clinically significant effects, including a lack of effect on immune function.<ref name=":13">Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., ... & Kellogg Jr, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. ''Experimental gerontology'', ''105'', 53-69.</ref> However, laboratory results from this trial suggested that the subjects experienced negative metabolic effects, including a small increase in glycated hemoglobin (within-group p=0.03) and a 40% rise in triglyceride levels (within-group p=0.05).<ref>Lamming, D. Rapamycin and Rapalogs. Preprints 2021, 2021020491 (doi: [https://www.preprints.org/manuscript/202102.0491/v1 10.20944/preprints202102.0491.v1]).</ref> This was a small study with a low dose of rapamycin, dosed over a short duration of 8 weeks. Considering the fact that, based on preclinical animal data, any potential benefit of rapamycin for aging will require long-term dosing, further testing in clinical trials is necessary to better characterize safety.<ref name=":13" />

Clinical trials such as the PEARL study are needed to provide evidence for the safety profile of rapamycin in otherwise healthy older adults.

== Rapalogs ==
Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>
However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>
Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875. https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>

Antiemetic; piperazine-derivative antihistamine '''meclizine''', which is often available over the counter, is also found to be an mTOR inhibitor that male-specificly extends median lifespan in male mice by '''8%'''.<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Rosenthal, N., Korstanje, R., Fernandez, E., ... & Miller, R. A. (2023). Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. GeroScience, 1-22. PMID: 38041783 [https://doi.org/10.1007/s11357-023-01011-0 DOI: 10.1007/s11357-023-01011-0]</ref> Meclizine also is Toll-like receptor 4 (TLR4) inhibitor. Toll like receptors role is to detect pathogen molecules and initiate an immunologic response to them especially through production of pro-inflammatory cytokines and increased levels of type I interferon production.<ref>Zali, H., Golchin, A., Farahani, M., Yazdani, M., Ranjbar, M. M., & Dabbagh, A. (2019). FDA approved drugs repurposing of Toll-like receptor4 (TLR4) candidate for neuropathy. Iranian Journal of Pharmaceutical Research: IJPR, 18(3), 1639. PMID: 32641971 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934974/ PMC6934974] DOI: 10.22037/ijpr.2019.2394</ref>

=== mTOR inhibition improves immune function in the elderly ===

In a phase 2 randomized clinical trial published in ''Science Translational Medicine'' in 2014, low-dose TORC1 inhibition with the rapalog everolimus showed improvement in immune function in the elderly. The clinical trial enrolled 218 adults aged ≥65 years, observing decreased incidence of all infections, as well as improved influenza vaccination responses and upregulation of antiviral immunity.<ref name=":17">Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref>

Everolimus enhanced the influenza vaccine response by approximately 20% at relatively well tolerated doses.<ref name=":17" /> One mechanism was related to a reduction in the percentage of CD4 and CD8 T cells expressing the programmed death-1 receptor, which has increased expression with age and a major role in inhibiting T cell signaling.<ref name=":17" /> These findings suggest that, at an appopriate dose, mTOR inhibition may improve the age-related decline in immune function in the elderly.

=== TORC1 inhibition enhances immune function and reduces infections in the elderly ===

A phase 2a trial clinical trial randomized 264 older adults to treatment with everolimus and placebo, and was published in ''Science Translational Medicine'' in 2018. The trial showed potential for reducing the effects of immune aging, with improvement in influenza vaccination response in the elderly.<ref name=":1">Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref>[[File:Rtb101 Ph2 Ph3.jpg|thumb|461x461px|A) Number of patients with laboratory-confirmed RTIs of ''any severity'' caused by specific viruses, comparing RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 RCTs B) Number of patients with laboratory-confirmed RTIs with ''severe symptoms'' caused by specific viruses in the RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 trials. RTI = respiratory tract infection]]

=== Improving immune function in older adults for respiratory tract infections, including coronaviruses ===
Low-dose mTOR inhibition with dactolisib in a Phase 2b and phase 3 trial in the elderly showed reduced coronavirus (non [[COVID-19]]) incidence, as well as reductions in severe symptoms.<ref name=":12">Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., ... & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. ''The Lancet Healthy Longevity'', ''2''(5), e250-e262.</ref> However, the data remains inconclusive as the study was powered statistically for a reduction in clinically symptomatic respiratory tract infections (RTIs), and not laboratory-confirmed RTIs.<ref name=":12" />

Following the success of two phase 2 clinical trials investigating mTOR inhibition for targeting the aging immune system, dactolisib is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial (ClinicalTrials.gov Identifier: NCT04584710, NCT04409327), exploring the potential for preventing severe disease in elderly adults with no symptoms, who have been exposed to [[COVID-19]].<ref name=":12" />

Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit.

This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.<ref name=":12" />

== See also ==
* [https://en.longevitywiki.org/wiki/Isomyosamine Isomyosamine] ('''MYMD-1®''') <ref>Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. 78(2), 227-235 PMID 35914953 doi:10.1093/gerona/glac142</ref>

== References ==
<references />
[[Category:Drugs]]
[[Category:Main list]]
[[Category:Fundamentals]]

Rapamycin

2024-06-19T06:28:06Z

Geroscientist: /* Non-human primates */

[[File:Rapamycin2.jpg|thumb|211x211px|The chemical structure of rapamycin.]]
Rapamycin, also known by its brand name Rapamune®, is a compound used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Easter Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.<ref>Accessdata.fda.gov. 2021. ''Drug Approval Package: Rapamune (Sirolimus) NDA# 021083''. [online] Available at: <<nowiki>https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm</nowiki>> [Accessed 27 May 2021].</ref> At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.<ref>Doggrell, S. (2006). Sirolimus- or paclitaxel-eluting stents for coronary artery revascularisation. ''Expert Opinion On Pharmacotherapy'', ''7''(2), 225-228. <nowiki>https://doi.org/10.1517/14656566.7.2.225</nowiki></ref> The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.<ref>Cancer, C. (2021). ''Everolimus - Drug Information - Chemocare''. Chemocare.com. Retrieved 27 May 2021, from <nowiki>http://chemocare.com/chemotherapy/drug-info/everolimus.aspx</nowiki>.</ref>

Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":2" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref><ref>Mannick, J. B., & Lamming, D. W. (2023). Targeting the biology of aging with mTOR inhibitors. Nature Aging, 1-19. PMID: 37142830 PMC10330278 [https://www.nature.com/articles/s43587-023-00416-y DOI: 10.1038/s43587-023-00416-y]</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":2">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref> It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

== Evidence of increased healthspan or lifespan ==

=== Non-human primates ===
Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed that rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' The extension of lifespan was associated with improved healthspan, with preserved cognitive health and a reduced burden of age-related disease in treated marmosets versus placebo. Rapamycin was delivered orally at 1 mg/kg/day.

=== Dogs ===
There is preliminary evidence that rapamycin may prevent age-related decline in dogs. One study showed statistically significant improvements in heart function in dogs receiving rapamycin, relative to those that received placebo, similar to what has been observed in older laboratory mice.<ref name=":9">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411365/ Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.]</ref> As part of the Dog Aging Project at the University of Washington, the TRIAD study is testing whether rapamycin can extend healthy lifespan in pet dogs.
=== Mice ===
In multiple studies in different breeds of mice, rapamycin demonstrates a robust effect on increasing healthy lifespan. Rapamycin significantly extends lifespan in approximately 90% of the mice models it has been tested in.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref>

In 2009, rapamycin was shown to increase the lifespan of both male and female mice when given in late life (600 days).<ref name=":5">[https://doi.org/10.1038%2Fnature08221 Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''nature'', ''460''(7253), 392-395.]</ref> Mean survival was extended by 28% for males and 38% for females, while maximal lifespan increased by 9% for males and 14% for females.<ref name=":5" /> This was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological drug. This mouse study is special because the results were obtained following the US National Institute on Aging's Interventions Testing Program (ITP) protocol. The ITP is regarded as the gold standard for testing drugs that target aging.<ref>Nadon, N. L., Strong, R., Miller, R. A., Nelson, J., Javors, M., Sharp, Z. D., ... & Harrison, D. E. (2008). Design of aging intervention studies: the NIA interventions testing program. ''Age'', ''30''(4), 187-199.</ref>

The landmark 2009 study also showed that rapamycin could increase healthy lifespan when given in old age. This has important implications for human testing, as it suggests that the drug might still exhibit healthspan and lifespan benefits even when given to the elderly. Rapamycin contrasts with calorie restriction in this regard; some evidence suggests that calorie restriction needs to be practiced from early adulthood, and may even fail to provide benefit for animals that are already old.<ref>Szafranski, K., & Mekhail, K. (2014). The fine line between lifespan extension and shortening in response to caloric restriction. ''Nucleus'', ''5''(1), 56-65.</ref>
==== Rapidly aging mice models ====
Using a mouse model that mimics the accelerated aging disease Hutchinson-Gilford progeria, rapamycin was shown to increase lifespan by over 50%. It also improved cardiac and skeletal muscle function in these mice.<ref>[https://doi.org/10.1126%2Fscitranslmed.3003802 Ramos, F. J., Chen, S. C., Garelick, M. G., Dai, D. F., Liao, C. Y., Schreiber, K. H., ... & Kennedy, B. K. (2012). Rapamycin reverses elevated mTORC1 signaling in lamin A/C–deficient mice, rescues cardiac and skeletal muscle function, and extends survival. ''Science translational medicine'', ''4''(144), 144ra103-144ra103.]
</ref> In one short-lived mutant strain of mice that mimics Leigh syndrome, rapamycin was shown to extend maximum life span nearly three-fold.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/24231806/ Johnson, S. C., Yanos, M. E., Kayser, E. B., Quintana, A., Sangesland, M., Castanza, A., ... & Kaeberlein, M. (2013). mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. ''Science'', ''342''(6165), 1524-1528.]</ref>

==== Middle-aged mice ====
Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.<ref>Bitto, A., Ito, T.K., Pineda, V.V., LeTexier, N.J., Huang, H.Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K. and Meza, D., 2016. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. ''elife'', ''5'', p.e16351.</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269 Strong, R., Miller, R. A., Bogue, M., Fernandez, E., Javors, M. A., Libert, S., ... & Harrison, D. E. (2020). Rapamycin‐mediated mouse lifespan extension: Late‐life dosage regimes with sex‐specific effects. ''Aging cell'', ''19''(11), e13269.]</ref> Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.<ref>Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. ''J Gerontol A Biol Sci Med Sci''. 2016 Jul; 71(7):876-81. doi: [https://academic.oup.com/biomedgerontology/article/71/7/876/2605199 10.1093/gerona/glw064]. Epub 2016 Apr 18. PMID: 27091134; PMCID: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906329/ PMC4906329]</ref> These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.

=== Yeast ===
Inhibition of TOR signalling by rapamycin significantly increases the lifespan of yeast known as ''Saccharomyces cerevisiae.''<ref>Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. ''Genes & development'', ''20''(2), 174-184.</ref>

=== Flies ===
Rapamycin extends the lifespan of the fruitfly, ''Drosophila melanogaster.'' The extent of lifespan extension observed is beyond what is achievable by flies undergoing other pro-longevity interventions like dietary restriction, or in mutant flies with mild decrements in insulin/insulin-like growth factor signaling (IIS).<ref>Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. ''Cell metabolism'', ''11''(1), 35-46.</ref> Combining rapamycin with two other drugs that target metabolic pathways, lithium and trametinib, results in additive lifespan extension effects, substantially increasing ''Drosophila'' lifepsan by 48%.<ref>Castillo-Quan, J. I., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., ... & Partridge, L. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. ''Proceedings of the National Academy of Sciences'', ''116''(42), 20817-20819.</ref>

=== Roundworms ===
TOR inhibition by rapamycin extends lifespan in ''Caenorhabditis elegans,'' a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in ''C. elegans'' seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.<ref>Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. ''Cell metabolism'', ''15''(5), 713-724.</ref>

=== Age-related diseases ===
Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref>

===== Cancer =====
In the transgenic HER-2/neu mouse model, mice die prematurely due to susceptibility to cancer.<ref name=":6" /> Rapamycin was hypothesized to improve survival in this model due to its ability to slow aging, which would also address an age-related disease like cancer.<ref name=":6" /> The drug was shown to extend maximal lifespan, by delaying aging in multiple different organs and also suppressing cancer development.<ref name=":6">Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., ... & Blagosklonny, M. V. (2010). Rapamycin extends maximal lifespan in cancer-prone mice. ''The American journal of pathology'', ''176''(5), 2092-2097.</ref>

Other studies suggest that rapamycin can extend lifespan in mouse models where cancer naturally develops, such as in mice prone to cancer due to the Apc tumor suppressor gene mutation, or in mice heterozygous for the Rb1 tumor supressor gene, among others.<ref>Hasty, P., Livi, C. B., Dodds, S. G., Jones, D., Strong, R., Javors, M., ... & Sharp, Z. D. (2014). eRapa restores a normal life span in a FAP mouse model. ''Cancer Prevention Research'', ''7''(1), 169-178.</ref><ref>Livi, C. B., Hardman, R. L., Christy, B. A., Dodds, S. G., Jones, D., Williams, C., ... & Sharp, Z. D. (2013). Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. ''Aging (Albany NY)'', ''5''(2), 100.</ref><ref>Hambright, H. G., Hurez, V., & Curiel, T. J. (2020). Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging or Vice Versa?. ''Geriatric Oncology'', 111-128.</ref>

A group of investigators in Germany have argued, based on their experiment in C57BL/6J Rj inbred mice, that rapamycin extends lifespan mainly through delaying cancer incidence, instead of via slowed aging.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref> A further analysis of the paper by Johnson et al. pointed to several important limitations of the study, suggesting that such a conclusion may be premature.<ref name=":82">Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? ''Science translational medicine'', ''5''(211), 211fs40.</ref> Key limitations included the lack of dose-response profiling of rapamycin; studying only the male sex, which is known to respond less to rapamycin likely in part due to sex differences in drug metabolism; lack of reporting on tumor size and incidence, required to determine whether lifespan extension occured only via slowed cancer or from a general effect on aging; and, the cross-sectional nature of the study, which would have reduced sensitivity for detecting age-related organ/tissue changes compared to longitudinal assays.<ref name=":82" /><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.</ref>

===== Heart Disease =====
One study investigated the effects of late-life rapamycin dosing in aged female mice, observing a reversal of age-related heart dysfunction.<ref name=":16">Flynn, J. M., O'Leary, M. N., Zambataro, C. A., Academia, E. C., Presley, M. P., Garrett, B. J., ... & Melov, S. (2013). Late‐life rapamycin treatment reverses age‐related heart dysfunction. ''Aging cell'', ''12''(5), 851-862.

</ref> This included benefits to ejection fraction, cardiac hormones, and reduced inflammation, although no effect was observed for heart fibrosis.<ref name=":16" /> Additionally, improvements in behaviour and physical function were demonstrated.<ref name=":16" /> Another study in naturally aged mice showed improvements in cardiac muscle stiffness, diastolic function with rapamycin.<ref name=":7">Quarles, E., Basisty, N., Chiao, Y. A., Merrihew, G., Gu, H., Sweetwyne, M. T., ... & Rabinovitch, P. S. (2020). Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. ''Aging Cell'', ''19''(2), e13086.</ref> Improvements in heart function were shown with only a brief treatment course of 8 weeks.<ref name=":7" /> Benefits persisted even after rapamycin was stopped, which appears consistent with the hypothesis that rapamycin slows aging.<ref name=":7" />

===== Alzheimer's =====
Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which age is the greatest risk factor.<ref>https://www.science.org/doi/10.1126/scitranslmed.aar4289</ref> In an Alzheimer's model of transgenic PDAPP mice, rapamycin was shown to reduce Amyloid-β, one of the hallmarks of AD.<ref name=":8" /> This led to alleviation of AD-like symptoms, such as restored cognition and memory.<ref name=":8">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> Similarly, another major AD hallmark known as tau was mitigated by rapamycin in a tauopathy mouse model.<ref name=":14">Ozcelik, S., Fraser, G., Castets, P., Schaeffer, V., Skachokova, Z., Breu, K., ... & Winkler, D. T. (2013). Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. ''PloS one'', ''8''(5), e62459.</ref> The mechanism of clearance of these proteins was linked to autophagy, with benefits seen regardless of whether it was dosed early for prevention, or in late life as treatment.<ref name=":14" />

=== Dose response ===
Rapamycin has shown a dose-response in which higher doses produce larger lifespan extension effects. UMHET3 mice of diverse genetic background were treated with varying doses of dietary rapamycin at 4.7, 14, or 42 ppm, revealing that those fed with the highest rapamycin dose had the greatest lifespan extension.<ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":0">[[Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. Journal of genetics and genomics= Yi chuan xue bao, 41(9), 459.|Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.]]</ref> Sex differences in response to rapamycin have been hypothesized to also be related to the effective dose, due to male/female differences in drug metabolism. The optimal dose for longevity in mice remains to be seen, but determining this dose will require consideration of the side effect profile of rapamycin.<ref name=":0" />

== Mechanism ==

=== Manipulating metabolic pathways - differences to calorie restriction ===
Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.<ref name=":15">Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":4" /> This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.<ref name=":3">Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. ''Current opinion in genetics & development'', ''23''(1), 53-62.</ref> mTOR plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.<ref name=":3" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.<ref name=":15" /><ref name=":4">Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. (2020). Is rapamycin a dietary restriction mimetic?. ''The Journals of Gerontology: Series A'', ''75''(1), 4-13.</ref> For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.<ref name=":15" /> This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.<ref name=":4" />

Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/21179166/ Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. ''Nature'', ''468''(7327), 1100-1104.]</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref name=":5" /><ref>Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. ''Aging (Albany NY)'', ''11''(19), 8048.
</ref> Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.<ref>Kemnitz, J. W. (2011). Calorie restriction and aging in nonhuman primates. ''Ilar Journal'', ''52''(1), 66-77.</ref><ref>Goto, S., Takahashi, R., Radak, Z., & Sharma, R. (2007). Beneficial biochemical outcomes of late‐onset dietary restriction in rodents. ''Annals of the New York Academy of Sciences'', ''1100''(1), 431-441.</ref><ref>Kristan, D. M. (2008). Calorie restriction and susceptibility to intact pathogens. ''Age'', ''30''(2), 147-156.</ref> Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref>

=== mTORC1 and mTORC2 ===
In non-mammals the mTOR equivalent is known as the target of rapamycin (TOR), first discovered by a team led by Michael Hall in the yeast ''Saccharomyces cerevisiae''.<ref>Thomas, G., & Hall, M. N. (1997). TOR signalling and control of cell growth. ''Current opinion in cell biology'', ''9''(6), 782-787.</ref><ref>Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N. R., & Hall, M. N. (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. ''Cell'', ''73''(3), 585-596.</ref> mTOR signalling appears to be evolutionarily conserved, and this extends further to include various mammals, such as mice, rats, and dogs.

Rapamycin acts on mTOR, with multiple signaling functions subdivided across two major protein complexes known as mTORC1 and mTORC2.<ref name=":3" /> There is some evidence suggesting that the health and lifespan benefit of rapamycin is more related to inhibition of mTORC1 than mTORC2.<ref name=":19">Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.</ref><ref name=":11">Lamming, D. W., Mihaylova, M. M., Katajisto, P., Baar, E. L., Yilmaz, O. H., Hutchins, A., ... & Sabatini, D. M. (2014). Depletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan. ''Aging cell'', ''13''(5), 911-917.</ref> In mice, males exhibit weaker lifespan extension effects from rapamycin than in females. One study suggests that inhibiting mTORC2 explains why the sex difference in the response to mTOR inhibition by rapamycin.<ref name=":11" />

=== Effects on glucoregulatory control ===
A noted issue regarding rapamycin is the disruption of glucose metabolism with chronic dosing, which has been observed in both humans and mice. In mice, this side effect has been shown to be due in part to disruption of mTORC2 in the liver, leading to hepatic insulin resistance.<ref name=":19" /> This effect has previously been shown to be reversible upon stopping the drug in both lean and obese mice.<ref name=":18">Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J. A., ... & Salmon, A. B. (2014). Rapamycin-induced metabolic defects are reversible in both lean and obese mice. ''Aging (Albany NY)'', ''6''(9), 742.</ref> Whether disrupted glucose metabolism is dispensable for the lifespan extending effects of rapamycin remains controversial.<ref>Blagosklonny, M. V. (2012). Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. ''Aging (Albany NY)'', ''4''(5), 350.</ref><ref>[https://www.nature.com/articles/s41419-019-1822-8 Blagosklonny, M. V. (2019). Fasting and rapamycin: diabetes versus benevolent glucose intolerance. ''Cell death & disease'', ''10''(8), 1-10.]</ref><ref>[https://www.science.org/doi/full/10.1126/science.1215135 Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.]</ref><ref>Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., ... & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. ''Aging cell'', ''15''(5), 872-884.</ref> Rapamycin has previously been shown to increase insulin sensitivity with acute dosing, while decreasing insulin sensitivity with chronic dosing.<ref>Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M., & Baur, J. A. (2012). Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. ''Frontiers in genetics'', ''3'', 177.</ref>

=== Reducing the effects of cellular senescence ===
The accumulation of senescent cells is thought to be an important mechanism underlying aging. Rapamycin is regarded as a senomorphic that may inhibit the pro-inflammatory secretory phenotype produced by senescent cells in humans, mice, and rats.<ref>[[Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. Aging cell, 16(3), 564-574.|Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. ''Aging cell'', ''16''(3), 564-574.]]</ref><ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref> A preliminary study in humans aged 40 years or older showed that topical rapamycin reduced markers of cellular senescence in the skin and improved its physical appearance.<ref>[https://doi.org/10.1007%2Fs11357-019-00113-y Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Nadhan, K., Potnis, M., ... & Sell, C. (2019). Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. ''Geroscience'', ''41''(6), 861-869.]
</ref>

== Human clinical trials ==
[[File:Rapamycin.jpg|thumb|235x235px|Part of the rationale of the PEARL study is to determine the optimal dose of rapamycin to potentially slow aging.<ref name=":2" />]]

=== PEARL study ===
Rapamycin is currently being tested for safety and efficacy in a clinical trial called the Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity (PEARL) study. The clinical trial aims to systematically investigate the use of rapamycin to promote healthy longevity, and is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

The study will begin with 200 adults aged 50 years or older who will receive rapamycin for up to one year. The study is being conducted by AgelessRx, a new company dedicated to developing scientifically supported interventions to prevent and treat age-related diseases, in collaboration with the University of California.<ref>[https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/ ''AgelessRx and funding an IRB-approved rapamycin trial - Longevity.Technology''. Longevity.Technology. (2021). Retrieved 27 May 2021, from https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/.]</ref>

The trial aims to obtain clinical data at 6 and 12 months of treatment, such as via testing of blood, body composition DXA, fecal microbiome, immune function, inflammation, skeletal muscle, and epigenetic aging clocks.

== Dog clinical trials ==
The Dog Aging Project is a US Government NIH-funded initiative investigating dog aging.<ref>https://dogagingproject.org/</ref> The project is led by Professor Matt Kaeberlein at the University of Washington.<ref name=":10">Kaeberlein, M., Creevy, K. E., & Promislow, D. E. (2016). The dog aging project: translational geroscience in companion animals. ''Mammalian genome'', ''27''(7), 279-288.</ref>

The Test of Rapamycin In Aging Dogs (TRIAD) study is investigating rapamycin as a treatment to slow aging in dogs. The investigators hope to increase healthy canine lifespan with rapamycin by delaying the onset of age-related diseases like cancer and heart disease.<ref name=":9" /><ref name=":10" />

Aging biology scientists believe that studying dog aging might not only help improve canine healthspan, but also have implications for humans.<ref name=":10" /> Dogs may be a useful animal model because they share the same environment that humans live in, and suffer from similar chronic diseases with aging.<ref>Hoffman, J. M., Creevy, K. E., Franks, A., O'Neill, D. G., & Promislow, D. E. (2018). The companion dog as a model for human aging and mortality. ''Aging Cell'', ''17''(3), e12737.</ref>

===== Heart disease =====
One randomized-controlled trial in 24 middle-aged dogs treated with low-dose rapamycin showed suggestion of partial reversal of age-related heart dysfunction, as measured via echocardiography. The intervention was well-tolerated, with no clinically meaningful adverse events noted with a non-immunosuppressive dose of rapamycin during the 10 week period. This was a small study over a relatively short duration; further testing in larger clinical studies will be necessary to determine whether rapamycin can be used to treat age-related heart disease in dogs.

== Regulatory approval ==
Rapamycin was approved by the US Food and Drug Administration (FDA) in 1999 to prevent organ rejection in liver transplant patients, and has been marketed under the brand name Rapamune.<ref>[https://link.springer.com/article/10.1007/s11357-020-00274-1 Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.]</ref> The patent on rapamycin has expired, and chemically similar compounds called 'rapalogs' are being researched by biotechnology companies.<ref>[https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.9b00215 Abdel-Magid, A. F. (2019). Rapalogs potential as practical alternatives to rapamycin.]
</ref> It is not currently approved for use as an anti-aging medication, due to lack of human clinical data for this purpose.

== Safety ==
Rapamycin has been used to treat millions of patients over several decades since obtaining FDA approval in 1999. It is generally considered safe in humans, but only when used under clinical supervision for specific indications. Rapamycin and its analogs are immunosuppressants, and used as such in the clinic; some rapalogs have received “black-box” FDA warnings due to the risks of infection, as well as the potential risk of cancer due to suppression of tumor immune surveillance.<ref>https://www.pfizermedicalinformation.com/en-us/rapamune/boxed-warning</ref><ref>https://www.pdr.net/drug-summary/Afinitor-everolimus-416.6101</ref>

Various side effects have been reported with the dose of rapamycin used to prevent rejection in organ transplant patients, who are often concurrently treated with multiple other medications.<ref>Webster, A. C., Lee, V. W., Chapman, J. R., & Craig, J. C. (2006). Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. ''Transplantation'', ''81''(9), 1234-1248.</ref> These include pain, headache, fever, high blood pressure, glucose intolerance, new-onset diabetes, nausea, abdominal pain, constipation, diarrhea, thrombocytopenia, leukopenia, among others. However, side effects are mostly reversible (at least if therapy is rapidly discontinued) and represent worst-case scenarios, particularly because the patients sampled in clinical studies are already severely ill and taking the drug along with other medications.<ref>Bischof, E., Siow, R.C., Zhavoronkov, A. and Kaeberlein, M., 2021. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), pp.e105-e111.
</ref> In subjects taking high doses of rapamycin and analogs for severe, chronic conditions including tuberous sclerosis complex, an inherited genetic disorder of increased mTOR signaling, or for cancer, the side effects have occasionally led life-threatening adverse events or death.<ref>Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anti-cancer drugs. 2015;26(4):437-42. PMID: [https://pubmed.ncbi.nlm.nih.gov/25719621/ 25719621] DOI: [https://doi.org/10.1097/cad.0000000000000207 10.1097/CAD.0000000000000207]</ref><ref>Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010; 116(18):4256-65. PMID: [https://pubmed.ncbi.nlm.nih.gov/20549832/ 20549832] DOI: [https://doi.org/10.1002/cncr.25219 10.1002/cncr.25219] </ref>

Case studies of the safety profile of rapamycin in the context of overdosing have suggested that it may have a large margin of safety or a high median lethal dose, but only in the acute setting.<ref>Ceschi, A., Heistermann, E., Gros, S., Reichert, C., Kupferschmidt, H., Banner, N. R., ... & Taegtmeyer, A. B. (2015). Acute sirolimus overdose: a multicenter case series. ''PLoS One'', ''10''(5), e0128033.</ref> The distinction with chronic high dose mTOR inhibition must be made because resultant immunosuppression can lead to susceptibility to infection with fatal consequences. Some preclinical data suggests that the longevity benefits of rapamycin may be retained via intermittent dosing.<ref name=":2" /> In considering the known clinical data about rapamycin's controversial safety at continuous, high doses, some researchers have proposed that rapamycin should dosed intermittently to minimize side effects while sufficiently inhibiting mTOR for an effect on aging.<ref name=":2" />

From a longevity perspective, there is a lack of published clinical data demonstrating the safety of rapamycin in healthy adults. One small randomized pilot study of rapamycin in 25 older adults aged 70-95 taking 1 mg/day of rapamycin reported finding no clinically significant effects, including a lack of effect on immune function.<ref name=":13">Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., ... & Kellogg Jr, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. ''Experimental gerontology'', ''105'', 53-69.</ref> However, laboratory results from this trial suggested that the subjects experienced negative metabolic effects, including a small increase in glycated hemoglobin (within-group p=0.03) and a 40% rise in triglyceride levels (within-group p=0.05).<ref>Lamming, D. Rapamycin and Rapalogs. Preprints 2021, 2021020491 (doi: [https://www.preprints.org/manuscript/202102.0491/v1 10.20944/preprints202102.0491.v1]).</ref> This was a small study with a low dose of rapamycin, dosed over a short duration of 8 weeks. Considering the fact that, based on preclinical animal data, any potential benefit of rapamycin for aging will require long-term dosing, further testing in clinical trials is necessary to better characterize safety.<ref name=":13" />

Clinical trials such as the PEARL study are needed to provide evidence for the safety profile of rapamycin in otherwise healthy older adults.

== Rapalogs ==
Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>
However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>
Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875. https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>

Antiemetic; piperazine-derivative antihistamine '''meclizine''', which is often available over the counter, is also found to be an mTOR inhibitor that male-specificly extends median lifespan in male mice by '''8%'''.<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Rosenthal, N., Korstanje, R., Fernandez, E., ... & Miller, R. A. (2023). Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. GeroScience, 1-22. PMID: 38041783 [https://doi.org/10.1007/s11357-023-01011-0 DOI: 10.1007/s11357-023-01011-0]</ref> Meclizine also is Toll-like receptor 4 (TLR4) inhibitor. Toll like receptors role is to detect pathogen molecules and initiate an immunologic response to them especially through production of pro-inflammatory cytokines and increased levels of type I interferon production.<ref>Zali, H., Golchin, A., Farahani, M., Yazdani, M., Ranjbar, M. M., & Dabbagh, A. (2019). FDA approved drugs repurposing of Toll-like receptor4 (TLR4) candidate for neuropathy. Iranian Journal of Pharmaceutical Research: IJPR, 18(3), 1639. PMID: 32641971 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934974/ PMC6934974] DOI: 10.22037/ijpr.2019.2394</ref>

=== mTOR inhibition improves immune function in the elderly ===

In a phase 2 randomized clinical trial published in ''Science Translational Medicine'' in 2014, low-dose TORC1 inhibition with the rapalog everolimus showed improvement in immune function in the elderly. The clinical trial enrolled 218 adults aged ≥65 years, observing decreased incidence of all infections, as well as improved influenza vaccination responses and upregulation of antiviral immunity.<ref name=":17">Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref>

Everolimus enhanced the influenza vaccine response by approximately 20% at relatively well tolerated doses.<ref name=":17" /> One mechanism was related to a reduction in the percentage of CD4 and CD8 T cells expressing the programmed death-1 receptor, which has increased expression with age and a major role in inhibiting T cell signaling.<ref name=":17" /> These findings suggest that, at an appopriate dose, mTOR inhibition may improve the age-related decline in immune function in the elderly.

=== TORC1 inhibition enhances immune function and reduces infections in the elderly ===

A phase 2a trial clinical trial randomized 264 older adults to treatment with everolimus and placebo, and was published in ''Science Translational Medicine'' in 2018. The trial showed potential for reducing the effects of immune aging, with improvement in influenza vaccination response in the elderly.<ref name=":1">Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref>[[File:Rtb101 Ph2 Ph3.jpg|thumb|461x461px|A) Number of patients with laboratory-confirmed RTIs of ''any severity'' caused by specific viruses, comparing RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 RCTs B) Number of patients with laboratory-confirmed RTIs with ''severe symptoms'' caused by specific viruses in the RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 trials. RTI = respiratory tract infection]]

=== Improving immune function in older adults for respiratory tract infections, including coronaviruses ===
Low-dose mTOR inhibition with dactolisib in a Phase 2b and phase 3 trial in the elderly showed reduced coronavirus (non [[COVID-19]]) incidence, as well as reductions in severe symptoms.<ref name=":12">Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., ... & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. ''The Lancet Healthy Longevity'', ''2''(5), e250-e262.</ref> However, the data remains inconclusive as the study was powered statistically for a reduction in clinically symptomatic respiratory tract infections (RTIs), and not laboratory-confirmed RTIs.<ref name=":12" />

Following the success of two phase 2 clinical trials investigating mTOR inhibition for targeting the aging immune system, dactolisib is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial (ClinicalTrials.gov Identifier: NCT04584710, NCT04409327), exploring the potential for preventing severe disease in elderly adults with no symptoms, who have been exposed to [[COVID-19]].<ref name=":12" />

Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit.

This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.<ref name=":12" />

== See also ==
* [https://en.longevitywiki.org/wiki/Isomyosamine Isomyosamine] ('''MYMD-1®''') <ref>Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. 78(2), 227-235 PMID 35914953 doi:10.1093/gerona/glac142</ref>

== References ==
<references />
[[Category:Drugs]]
[[Category:Main list]]
[[Category:Fundamentals]]

Rapamycin

2024-06-19T06:27:12Z

Geroscientist: /* Non-human primates */

[[File:Rapamycin2.jpg|thumb|211x211px|The chemical structure of rapamycin.]]
Rapamycin, also known by its brand name Rapamune®, is a compound used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Easter Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.<ref>Accessdata.fda.gov. 2021. ''Drug Approval Package: Rapamune (Sirolimus) NDA# 021083''. [online] Available at: <<nowiki>https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm</nowiki>> [Accessed 27 May 2021].</ref> At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.<ref>Doggrell, S. (2006). Sirolimus- or paclitaxel-eluting stents for coronary artery revascularisation. ''Expert Opinion On Pharmacotherapy'', ''7''(2), 225-228. <nowiki>https://doi.org/10.1517/14656566.7.2.225</nowiki></ref> The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.<ref>Cancer, C. (2021). ''Everolimus - Drug Information - Chemocare''. Chemocare.com. Retrieved 27 May 2021, from <nowiki>http://chemocare.com/chemotherapy/drug-info/everolimus.aspx</nowiki>.</ref>

Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":2" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref><ref>Mannick, J. B., & Lamming, D. W. (2023). Targeting the biology of aging with mTOR inhibitors. Nature Aging, 1-19. PMID: 37142830 PMC10330278 [https://www.nature.com/articles/s43587-023-00416-y DOI: 10.1038/s43587-023-00416-y]</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":2">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref> It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

== Evidence of increased healthspan or lifespan ==

=== Non-human primates ===
Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed that rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' The extension of lifespan was associated with improved healthspan, with preserved cognitive health, and reduced burden of age-related disease in treated marmosets. Rapamycin was delivered orally at 1 mg/kg/day.

=== Dogs ===
There is preliminary evidence that rapamycin may prevent age-related decline in dogs. One study showed statistically significant improvements in heart function in dogs receiving rapamycin, relative to those that received placebo, similar to what has been observed in older laboratory mice.<ref name=":9">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411365/ Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.]</ref> As part of the Dog Aging Project at the University of Washington, the TRIAD study is testing whether rapamycin can extend healthy lifespan in pet dogs.
=== Mice ===
In multiple studies in different breeds of mice, rapamycin demonstrates a robust effect on increasing healthy lifespan. Rapamycin significantly extends lifespan in approximately 90% of the mice models it has been tested in.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref>

In 2009, rapamycin was shown to increase the lifespan of both male and female mice when given in late life (600 days).<ref name=":5">[https://doi.org/10.1038%2Fnature08221 Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''nature'', ''460''(7253), 392-395.]</ref> Mean survival was extended by 28% for males and 38% for females, while maximal lifespan increased by 9% for males and 14% for females.<ref name=":5" /> This was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological drug. This mouse study is special because the results were obtained following the US National Institute on Aging's Interventions Testing Program (ITP) protocol. The ITP is regarded as the gold standard for testing drugs that target aging.<ref>Nadon, N. L., Strong, R., Miller, R. A., Nelson, J., Javors, M., Sharp, Z. D., ... & Harrison, D. E. (2008). Design of aging intervention studies: the NIA interventions testing program. ''Age'', ''30''(4), 187-199.</ref>

The landmark 2009 study also showed that rapamycin could increase healthy lifespan when given in old age. This has important implications for human testing, as it suggests that the drug might still exhibit healthspan and lifespan benefits even when given to the elderly. Rapamycin contrasts with calorie restriction in this regard; some evidence suggests that calorie restriction needs to be practiced from early adulthood, and may even fail to provide benefit for animals that are already old.<ref>Szafranski, K., & Mekhail, K. (2014). The fine line between lifespan extension and shortening in response to caloric restriction. ''Nucleus'', ''5''(1), 56-65.</ref>
==== Rapidly aging mice models ====
Using a mouse model that mimics the accelerated aging disease Hutchinson-Gilford progeria, rapamycin was shown to increase lifespan by over 50%. It also improved cardiac and skeletal muscle function in these mice.<ref>[https://doi.org/10.1126%2Fscitranslmed.3003802 Ramos, F. J., Chen, S. C., Garelick, M. G., Dai, D. F., Liao, C. Y., Schreiber, K. H., ... & Kennedy, B. K. (2012). Rapamycin reverses elevated mTORC1 signaling in lamin A/C–deficient mice, rescues cardiac and skeletal muscle function, and extends survival. ''Science translational medicine'', ''4''(144), 144ra103-144ra103.]
</ref> In one short-lived mutant strain of mice that mimics Leigh syndrome, rapamycin was shown to extend maximum life span nearly three-fold.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/24231806/ Johnson, S. C., Yanos, M. E., Kayser, E. B., Quintana, A., Sangesland, M., Castanza, A., ... & Kaeberlein, M. (2013). mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. ''Science'', ''342''(6165), 1524-1528.]</ref>

==== Middle-aged mice ====
Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.<ref>Bitto, A., Ito, T.K., Pineda, V.V., LeTexier, N.J., Huang, H.Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K. and Meza, D., 2016. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. ''elife'', ''5'', p.e16351.</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269 Strong, R., Miller, R. A., Bogue, M., Fernandez, E., Javors, M. A., Libert, S., ... & Harrison, D. E. (2020). Rapamycin‐mediated mouse lifespan extension: Late‐life dosage regimes with sex‐specific effects. ''Aging cell'', ''19''(11), e13269.]</ref> Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.<ref>Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. ''J Gerontol A Biol Sci Med Sci''. 2016 Jul; 71(7):876-81. doi: [https://academic.oup.com/biomedgerontology/article/71/7/876/2605199 10.1093/gerona/glw064]. Epub 2016 Apr 18. PMID: 27091134; PMCID: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906329/ PMC4906329]</ref> These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.

=== Yeast ===
Inhibition of TOR signalling by rapamycin significantly increases the lifespan of yeast known as ''Saccharomyces cerevisiae.''<ref>Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. ''Genes & development'', ''20''(2), 174-184.</ref>

=== Flies ===
Rapamycin extends the lifespan of the fruitfly, ''Drosophila melanogaster.'' The extent of lifespan extension observed is beyond what is achievable by flies undergoing other pro-longevity interventions like dietary restriction, or in mutant flies with mild decrements in insulin/insulin-like growth factor signaling (IIS).<ref>Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. ''Cell metabolism'', ''11''(1), 35-46.</ref> Combining rapamycin with two other drugs that target metabolic pathways, lithium and trametinib, results in additive lifespan extension effects, substantially increasing ''Drosophila'' lifepsan by 48%.<ref>Castillo-Quan, J. I., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., ... & Partridge, L. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. ''Proceedings of the National Academy of Sciences'', ''116''(42), 20817-20819.</ref>

=== Roundworms ===
TOR inhibition by rapamycin extends lifespan in ''Caenorhabditis elegans,'' a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in ''C. elegans'' seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.<ref>Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. ''Cell metabolism'', ''15''(5), 713-724.</ref>

=== Age-related diseases ===
Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref>

===== Cancer =====
In the transgenic HER-2/neu mouse model, mice die prematurely due to susceptibility to cancer.<ref name=":6" /> Rapamycin was hypothesized to improve survival in this model due to its ability to slow aging, which would also address an age-related disease like cancer.<ref name=":6" /> The drug was shown to extend maximal lifespan, by delaying aging in multiple different organs and also suppressing cancer development.<ref name=":6">Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., ... & Blagosklonny, M. V. (2010). Rapamycin extends maximal lifespan in cancer-prone mice. ''The American journal of pathology'', ''176''(5), 2092-2097.</ref>

Other studies suggest that rapamycin can extend lifespan in mouse models where cancer naturally develops, such as in mice prone to cancer due to the Apc tumor suppressor gene mutation, or in mice heterozygous for the Rb1 tumor supressor gene, among others.<ref>Hasty, P., Livi, C. B., Dodds, S. G., Jones, D., Strong, R., Javors, M., ... & Sharp, Z. D. (2014). eRapa restores a normal life span in a FAP mouse model. ''Cancer Prevention Research'', ''7''(1), 169-178.</ref><ref>Livi, C. B., Hardman, R. L., Christy, B. A., Dodds, S. G., Jones, D., Williams, C., ... & Sharp, Z. D. (2013). Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. ''Aging (Albany NY)'', ''5''(2), 100.</ref><ref>Hambright, H. G., Hurez, V., & Curiel, T. J. (2020). Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging or Vice Versa?. ''Geriatric Oncology'', 111-128.</ref>

A group of investigators in Germany have argued, based on their experiment in C57BL/6J Rj inbred mice, that rapamycin extends lifespan mainly through delaying cancer incidence, instead of via slowed aging.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref> A further analysis of the paper by Johnson et al. pointed to several important limitations of the study, suggesting that such a conclusion may be premature.<ref name=":82">Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? ''Science translational medicine'', ''5''(211), 211fs40.</ref> Key limitations included the lack of dose-response profiling of rapamycin; studying only the male sex, which is known to respond less to rapamycin likely in part due to sex differences in drug metabolism; lack of reporting on tumor size and incidence, required to determine whether lifespan extension occured only via slowed cancer or from a general effect on aging; and, the cross-sectional nature of the study, which would have reduced sensitivity for detecting age-related organ/tissue changes compared to longitudinal assays.<ref name=":82" /><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.</ref>

===== Heart Disease =====
One study investigated the effects of late-life rapamycin dosing in aged female mice, observing a reversal of age-related heart dysfunction.<ref name=":16">Flynn, J. M., O'Leary, M. N., Zambataro, C. A., Academia, E. C., Presley, M. P., Garrett, B. J., ... & Melov, S. (2013). Late‐life rapamycin treatment reverses age‐related heart dysfunction. ''Aging cell'', ''12''(5), 851-862.

</ref> This included benefits to ejection fraction, cardiac hormones, and reduced inflammation, although no effect was observed for heart fibrosis.<ref name=":16" /> Additionally, improvements in behaviour and physical function were demonstrated.<ref name=":16" /> Another study in naturally aged mice showed improvements in cardiac muscle stiffness, diastolic function with rapamycin.<ref name=":7">Quarles, E., Basisty, N., Chiao, Y. A., Merrihew, G., Gu, H., Sweetwyne, M. T., ... & Rabinovitch, P. S. (2020). Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. ''Aging Cell'', ''19''(2), e13086.</ref> Improvements in heart function were shown with only a brief treatment course of 8 weeks.<ref name=":7" /> Benefits persisted even after rapamycin was stopped, which appears consistent with the hypothesis that rapamycin slows aging.<ref name=":7" />

===== Alzheimer's =====
Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which age is the greatest risk factor.<ref>https://www.science.org/doi/10.1126/scitranslmed.aar4289</ref> In an Alzheimer's model of transgenic PDAPP mice, rapamycin was shown to reduce Amyloid-β, one of the hallmarks of AD.<ref name=":8" /> This led to alleviation of AD-like symptoms, such as restored cognition and memory.<ref name=":8">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> Similarly, another major AD hallmark known as tau was mitigated by rapamycin in a tauopathy mouse model.<ref name=":14">Ozcelik, S., Fraser, G., Castets, P., Schaeffer, V., Skachokova, Z., Breu, K., ... & Winkler, D. T. (2013). Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. ''PloS one'', ''8''(5), e62459.</ref> The mechanism of clearance of these proteins was linked to autophagy, with benefits seen regardless of whether it was dosed early for prevention, or in late life as treatment.<ref name=":14" />

=== Dose response ===
Rapamycin has shown a dose-response in which higher doses produce larger lifespan extension effects. UMHET3 mice of diverse genetic background were treated with varying doses of dietary rapamycin at 4.7, 14, or 42 ppm, revealing that those fed with the highest rapamycin dose had the greatest lifespan extension.<ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":0">[[Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. Journal of genetics and genomics= Yi chuan xue bao, 41(9), 459.|Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.]]</ref> Sex differences in response to rapamycin have been hypothesized to also be related to the effective dose, due to male/female differences in drug metabolism. The optimal dose for longevity in mice remains to be seen, but determining this dose will require consideration of the side effect profile of rapamycin.<ref name=":0" />

== Mechanism ==

=== Manipulating metabolic pathways - differences to calorie restriction ===
Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.<ref name=":15">Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":4" /> This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.<ref name=":3">Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. ''Current opinion in genetics & development'', ''23''(1), 53-62.</ref> mTOR plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.<ref name=":3" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.<ref name=":15" /><ref name=":4">Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. (2020). Is rapamycin a dietary restriction mimetic?. ''The Journals of Gerontology: Series A'', ''75''(1), 4-13.</ref> For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.<ref name=":15" /> This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.<ref name=":4" />

Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/21179166/ Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. ''Nature'', ''468''(7327), 1100-1104.]</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref name=":5" /><ref>Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. ''Aging (Albany NY)'', ''11''(19), 8048.
</ref> Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.<ref>Kemnitz, J. W. (2011). Calorie restriction and aging in nonhuman primates. ''Ilar Journal'', ''52''(1), 66-77.</ref><ref>Goto, S., Takahashi, R., Radak, Z., & Sharma, R. (2007). Beneficial biochemical outcomes of late‐onset dietary restriction in rodents. ''Annals of the New York Academy of Sciences'', ''1100''(1), 431-441.</ref><ref>Kristan, D. M. (2008). Calorie restriction and susceptibility to intact pathogens. ''Age'', ''30''(2), 147-156.</ref> Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref>

=== mTORC1 and mTORC2 ===
In non-mammals the mTOR equivalent is known as the target of rapamycin (TOR), first discovered by a team led by Michael Hall in the yeast ''Saccharomyces cerevisiae''.<ref>Thomas, G., & Hall, M. N. (1997). TOR signalling and control of cell growth. ''Current opinion in cell biology'', ''9''(6), 782-787.</ref><ref>Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N. R., & Hall, M. N. (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. ''Cell'', ''73''(3), 585-596.</ref> mTOR signalling appears to be evolutionarily conserved, and this extends further to include various mammals, such as mice, rats, and dogs.

Rapamycin acts on mTOR, with multiple signaling functions subdivided across two major protein complexes known as mTORC1 and mTORC2.<ref name=":3" /> There is some evidence suggesting that the health and lifespan benefit of rapamycin is more related to inhibition of mTORC1 than mTORC2.<ref name=":19">Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.</ref><ref name=":11">Lamming, D. W., Mihaylova, M. M., Katajisto, P., Baar, E. L., Yilmaz, O. H., Hutchins, A., ... & Sabatini, D. M. (2014). Depletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan. ''Aging cell'', ''13''(5), 911-917.</ref> In mice, males exhibit weaker lifespan extension effects from rapamycin than in females. One study suggests that inhibiting mTORC2 explains why the sex difference in the response to mTOR inhibition by rapamycin.<ref name=":11" />

=== Effects on glucoregulatory control ===
A noted issue regarding rapamycin is the disruption of glucose metabolism with chronic dosing, which has been observed in both humans and mice. In mice, this side effect has been shown to be due in part to disruption of mTORC2 in the liver, leading to hepatic insulin resistance.<ref name=":19" /> This effect has previously been shown to be reversible upon stopping the drug in both lean and obese mice.<ref name=":18">Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J. A., ... & Salmon, A. B. (2014). Rapamycin-induced metabolic defects are reversible in both lean and obese mice. ''Aging (Albany NY)'', ''6''(9), 742.</ref> Whether disrupted glucose metabolism is dispensable for the lifespan extending effects of rapamycin remains controversial.<ref>Blagosklonny, M. V. (2012). Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. ''Aging (Albany NY)'', ''4''(5), 350.</ref><ref>[https://www.nature.com/articles/s41419-019-1822-8 Blagosklonny, M. V. (2019). Fasting and rapamycin: diabetes versus benevolent glucose intolerance. ''Cell death & disease'', ''10''(8), 1-10.]</ref><ref>[https://www.science.org/doi/full/10.1126/science.1215135 Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.]</ref><ref>Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., ... & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. ''Aging cell'', ''15''(5), 872-884.</ref> Rapamycin has previously been shown to increase insulin sensitivity with acute dosing, while decreasing insulin sensitivity with chronic dosing.<ref>Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M., & Baur, J. A. (2012). Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. ''Frontiers in genetics'', ''3'', 177.</ref>

=== Reducing the effects of cellular senescence ===
The accumulation of senescent cells is thought to be an important mechanism underlying aging. Rapamycin is regarded as a senomorphic that may inhibit the pro-inflammatory secretory phenotype produced by senescent cells in humans, mice, and rats.<ref>[[Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. Aging cell, 16(3), 564-574.|Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. ''Aging cell'', ''16''(3), 564-574.]]</ref><ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref> A preliminary study in humans aged 40 years or older showed that topical rapamycin reduced markers of cellular senescence in the skin and improved its physical appearance.<ref>[https://doi.org/10.1007%2Fs11357-019-00113-y Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Nadhan, K., Potnis, M., ... & Sell, C. (2019). Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. ''Geroscience'', ''41''(6), 861-869.]
</ref>

== Human clinical trials ==
[[File:Rapamycin.jpg|thumb|235x235px|Part of the rationale of the PEARL study is to determine the optimal dose of rapamycin to potentially slow aging.<ref name=":2" />]]

=== PEARL study ===
Rapamycin is currently being tested for safety and efficacy in a clinical trial called the Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity (PEARL) study. The clinical trial aims to systematically investigate the use of rapamycin to promote healthy longevity, and is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

The study will begin with 200 adults aged 50 years or older who will receive rapamycin for up to one year. The study is being conducted by AgelessRx, a new company dedicated to developing scientifically supported interventions to prevent and treat age-related diseases, in collaboration with the University of California.<ref>[https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/ ''AgelessRx and funding an IRB-approved rapamycin trial - Longevity.Technology''. Longevity.Technology. (2021). Retrieved 27 May 2021, from https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/.]</ref>

The trial aims to obtain clinical data at 6 and 12 months of treatment, such as via testing of blood, body composition DXA, fecal microbiome, immune function, inflammation, skeletal muscle, and epigenetic aging clocks.

== Dog clinical trials ==
The Dog Aging Project is a US Government NIH-funded initiative investigating dog aging.<ref>https://dogagingproject.org/</ref> The project is led by Professor Matt Kaeberlein at the University of Washington.<ref name=":10">Kaeberlein, M., Creevy, K. E., & Promislow, D. E. (2016). The dog aging project: translational geroscience in companion animals. ''Mammalian genome'', ''27''(7), 279-288.</ref>

The Test of Rapamycin In Aging Dogs (TRIAD) study is investigating rapamycin as a treatment to slow aging in dogs. The investigators hope to increase healthy canine lifespan with rapamycin by delaying the onset of age-related diseases like cancer and heart disease.<ref name=":9" /><ref name=":10" />

Aging biology scientists believe that studying dog aging might not only help improve canine healthspan, but also have implications for humans.<ref name=":10" /> Dogs may be a useful animal model because they share the same environment that humans live in, and suffer from similar chronic diseases with aging.<ref>Hoffman, J. M., Creevy, K. E., Franks, A., O'Neill, D. G., & Promislow, D. E. (2018). The companion dog as a model for human aging and mortality. ''Aging Cell'', ''17''(3), e12737.</ref>

===== Heart disease =====
One randomized-controlled trial in 24 middle-aged dogs treated with low-dose rapamycin showed suggestion of partial reversal of age-related heart dysfunction, as measured via echocardiography. The intervention was well-tolerated, with no clinically meaningful adverse events noted with a non-immunosuppressive dose of rapamycin during the 10 week period. This was a small study over a relatively short duration; further testing in larger clinical studies will be necessary to determine whether rapamycin can be used to treat age-related heart disease in dogs.

== Regulatory approval ==
Rapamycin was approved by the US Food and Drug Administration (FDA) in 1999 to prevent organ rejection in liver transplant patients, and has been marketed under the brand name Rapamune.<ref>[https://link.springer.com/article/10.1007/s11357-020-00274-1 Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.]</ref> The patent on rapamycin has expired, and chemically similar compounds called 'rapalogs' are being researched by biotechnology companies.<ref>[https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.9b00215 Abdel-Magid, A. F. (2019). Rapalogs potential as practical alternatives to rapamycin.]
</ref> It is not currently approved for use as an anti-aging medication, due to lack of human clinical data for this purpose.

== Safety ==
Rapamycin has been used to treat millions of patients over several decades since obtaining FDA approval in 1999. It is generally considered safe in humans, but only when used under clinical supervision for specific indications. Rapamycin and its analogs are immunosuppressants, and used as such in the clinic; some rapalogs have received “black-box” FDA warnings due to the risks of infection, as well as the potential risk of cancer due to suppression of tumor immune surveillance.<ref>https://www.pfizermedicalinformation.com/en-us/rapamune/boxed-warning</ref><ref>https://www.pdr.net/drug-summary/Afinitor-everolimus-416.6101</ref>

Various side effects have been reported with the dose of rapamycin used to prevent rejection in organ transplant patients, who are often concurrently treated with multiple other medications.<ref>Webster, A. C., Lee, V. W., Chapman, J. R., & Craig, J. C. (2006). Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. ''Transplantation'', ''81''(9), 1234-1248.</ref> These include pain, headache, fever, high blood pressure, glucose intolerance, new-onset diabetes, nausea, abdominal pain, constipation, diarrhea, thrombocytopenia, leukopenia, among others. However, side effects are mostly reversible (at least if therapy is rapidly discontinued) and represent worst-case scenarios, particularly because the patients sampled in clinical studies are already severely ill and taking the drug along with other medications.<ref>Bischof, E., Siow, R.C., Zhavoronkov, A. and Kaeberlein, M., 2021. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), pp.e105-e111.
</ref> In subjects taking high doses of rapamycin and analogs for severe, chronic conditions including tuberous sclerosis complex, an inherited genetic disorder of increased mTOR signaling, or for cancer, the side effects have occasionally led life-threatening adverse events or death.<ref>Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anti-cancer drugs. 2015;26(4):437-42. PMID: [https://pubmed.ncbi.nlm.nih.gov/25719621/ 25719621] DOI: [https://doi.org/10.1097/cad.0000000000000207 10.1097/CAD.0000000000000207]</ref><ref>Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010; 116(18):4256-65. PMID: [https://pubmed.ncbi.nlm.nih.gov/20549832/ 20549832] DOI: [https://doi.org/10.1002/cncr.25219 10.1002/cncr.25219] </ref>

Case studies of the safety profile of rapamycin in the context of overdosing have suggested that it may have a large margin of safety or a high median lethal dose, but only in the acute setting.<ref>Ceschi, A., Heistermann, E., Gros, S., Reichert, C., Kupferschmidt, H., Banner, N. R., ... & Taegtmeyer, A. B. (2015). Acute sirolimus overdose: a multicenter case series. ''PLoS One'', ''10''(5), e0128033.</ref> The distinction with chronic high dose mTOR inhibition must be made because resultant immunosuppression can lead to susceptibility to infection with fatal consequences. Some preclinical data suggests that the longevity benefits of rapamycin may be retained via intermittent dosing.<ref name=":2" /> In considering the known clinical data about rapamycin's controversial safety at continuous, high doses, some researchers have proposed that rapamycin should dosed intermittently to minimize side effects while sufficiently inhibiting mTOR for an effect on aging.<ref name=":2" />

From a longevity perspective, there is a lack of published clinical data demonstrating the safety of rapamycin in healthy adults. One small randomized pilot study of rapamycin in 25 older adults aged 70-95 taking 1 mg/day of rapamycin reported finding no clinically significant effects, including a lack of effect on immune function.<ref name=":13">Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., ... & Kellogg Jr, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. ''Experimental gerontology'', ''105'', 53-69.</ref> However, laboratory results from this trial suggested that the subjects experienced negative metabolic effects, including a small increase in glycated hemoglobin (within-group p=0.03) and a 40% rise in triglyceride levels (within-group p=0.05).<ref>Lamming, D. Rapamycin and Rapalogs. Preprints 2021, 2021020491 (doi: [https://www.preprints.org/manuscript/202102.0491/v1 10.20944/preprints202102.0491.v1]).</ref> This was a small study with a low dose of rapamycin, dosed over a short duration of 8 weeks. Considering the fact that, based on preclinical animal data, any potential benefit of rapamycin for aging will require long-term dosing, further testing in clinical trials is necessary to better characterize safety.<ref name=":13" />

Clinical trials such as the PEARL study are needed to provide evidence for the safety profile of rapamycin in otherwise healthy older adults.

== Rapalogs ==
Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>
However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>
Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875. https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>

Antiemetic; piperazine-derivative antihistamine '''meclizine''', which is often available over the counter, is also found to be an mTOR inhibitor that male-specificly extends median lifespan in male mice by '''8%'''.<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Rosenthal, N., Korstanje, R., Fernandez, E., ... & Miller, R. A. (2023). Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. GeroScience, 1-22. PMID: 38041783 [https://doi.org/10.1007/s11357-023-01011-0 DOI: 10.1007/s11357-023-01011-0]</ref> Meclizine also is Toll-like receptor 4 (TLR4) inhibitor. Toll like receptors role is to detect pathogen molecules and initiate an immunologic response to them especially through production of pro-inflammatory cytokines and increased levels of type I interferon production.<ref>Zali, H., Golchin, A., Farahani, M., Yazdani, M., Ranjbar, M. M., & Dabbagh, A. (2019). FDA approved drugs repurposing of Toll-like receptor4 (TLR4) candidate for neuropathy. Iranian Journal of Pharmaceutical Research: IJPR, 18(3), 1639. PMID: 32641971 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934974/ PMC6934974] DOI: 10.22037/ijpr.2019.2394</ref>

=== mTOR inhibition improves immune function in the elderly ===

In a phase 2 randomized clinical trial published in ''Science Translational Medicine'' in 2014, low-dose TORC1 inhibition with the rapalog everolimus showed improvement in immune function in the elderly. The clinical trial enrolled 218 adults aged ≥65 years, observing decreased incidence of all infections, as well as improved influenza vaccination responses and upregulation of antiviral immunity.<ref name=":17">Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref>

Everolimus enhanced the influenza vaccine response by approximately 20% at relatively well tolerated doses.<ref name=":17" /> One mechanism was related to a reduction in the percentage of CD4 and CD8 T cells expressing the programmed death-1 receptor, which has increased expression with age and a major role in inhibiting T cell signaling.<ref name=":17" /> These findings suggest that, at an appopriate dose, mTOR inhibition may improve the age-related decline in immune function in the elderly.

=== TORC1 inhibition enhances immune function and reduces infections in the elderly ===

A phase 2a trial clinical trial randomized 264 older adults to treatment with everolimus and placebo, and was published in ''Science Translational Medicine'' in 2018. The trial showed potential for reducing the effects of immune aging, with improvement in influenza vaccination response in the elderly.<ref name=":1">Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref>[[File:Rtb101 Ph2 Ph3.jpg|thumb|461x461px|A) Number of patients with laboratory-confirmed RTIs of ''any severity'' caused by specific viruses, comparing RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 RCTs B) Number of patients with laboratory-confirmed RTIs with ''severe symptoms'' caused by specific viruses in the RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 trials. RTI = respiratory tract infection]]

=== Improving immune function in older adults for respiratory tract infections, including coronaviruses ===
Low-dose mTOR inhibition with dactolisib in a Phase 2b and phase 3 trial in the elderly showed reduced coronavirus (non [[COVID-19]]) incidence, as well as reductions in severe symptoms.<ref name=":12">Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., ... & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. ''The Lancet Healthy Longevity'', ''2''(5), e250-e262.</ref> However, the data remains inconclusive as the study was powered statistically for a reduction in clinically symptomatic respiratory tract infections (RTIs), and not laboratory-confirmed RTIs.<ref name=":12" />

Following the success of two phase 2 clinical trials investigating mTOR inhibition for targeting the aging immune system, dactolisib is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial (ClinicalTrials.gov Identifier: NCT04584710, NCT04409327), exploring the potential for preventing severe disease in elderly adults with no symptoms, who have been exposed to [[COVID-19]].<ref name=":12" />

Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit.

This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.<ref name=":12" />

== See also ==
* [https://en.longevitywiki.org/wiki/Isomyosamine Isomyosamine] ('''MYMD-1®''') <ref>Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. 78(2), 227-235 PMID 35914953 doi:10.1093/gerona/glac142</ref>

== References ==
<references />
[[Category:Drugs]]
[[Category:Main list]]
[[Category:Fundamentals]]

Rapamycin

2024-06-19T06:25:18Z

Geroscientist: /* Non-human primates */

[[File:Rapamycin2.jpg|thumb|211x211px|The chemical structure of rapamycin.]]
Rapamycin, also known by its brand name Rapamune®, is a compound used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Easter Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.<ref>Accessdata.fda.gov. 2021. ''Drug Approval Package: Rapamune (Sirolimus) NDA# 021083''. [online] Available at: <<nowiki>https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm</nowiki>> [Accessed 27 May 2021].</ref> At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.<ref>Doggrell, S. (2006). Sirolimus- or paclitaxel-eluting stents for coronary artery revascularisation. ''Expert Opinion On Pharmacotherapy'', ''7''(2), 225-228. <nowiki>https://doi.org/10.1517/14656566.7.2.225</nowiki></ref> The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.<ref>Cancer, C. (2021). ''Everolimus - Drug Information - Chemocare''. Chemocare.com. Retrieved 27 May 2021, from <nowiki>http://chemocare.com/chemotherapy/drug-info/everolimus.aspx</nowiki>.</ref>

Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":2" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref><ref>Mannick, J. B., & Lamming, D. W. (2023). Targeting the biology of aging with mTOR inhibitors. Nature Aging, 1-19. PMID: 37142830 PMC10330278 [https://www.nature.com/articles/s43587-023-00416-y DOI: 10.1038/s43587-023-00416-y]</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":2">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref> It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

== Evidence of increased healthspan or lifespan ==

=== Non-human primates ===
Unpublished and preliminary data presented by Dr Adam Salmon at the American Aging Association annual meeting (June, 2024) showed the rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' Rapamycin was delivered orally at 1 mg/kg/day.

=== Dogs ===
There is preliminary evidence that rapamycin may prevent age-related decline in dogs. One study showed statistically significant improvements in heart function in dogs receiving rapamycin, relative to those that received placebo, similar to what has been observed in older laboratory mice.<ref name=":9">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411365/ Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.]</ref> As part of the Dog Aging Project at the University of Washington, the TRIAD study is testing whether rapamycin can extend healthy lifespan in pet dogs.
=== Mice ===
In multiple studies in different breeds of mice, rapamycin demonstrates a robust effect on increasing healthy lifespan. Rapamycin significantly extends lifespan in approximately 90% of the mice models it has been tested in.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref>

In 2009, rapamycin was shown to increase the lifespan of both male and female mice when given in late life (600 days).<ref name=":5">[https://doi.org/10.1038%2Fnature08221 Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''nature'', ''460''(7253), 392-395.]</ref> Mean survival was extended by 28% for males and 38% for females, while maximal lifespan increased by 9% for males and 14% for females.<ref name=":5" /> This was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological drug. This mouse study is special because the results were obtained following the US National Institute on Aging's Interventions Testing Program (ITP) protocol. The ITP is regarded as the gold standard for testing drugs that target aging.<ref>Nadon, N. L., Strong, R., Miller, R. A., Nelson, J., Javors, M., Sharp, Z. D., ... & Harrison, D. E. (2008). Design of aging intervention studies: the NIA interventions testing program. ''Age'', ''30''(4), 187-199.</ref>

The landmark 2009 study also showed that rapamycin could increase healthy lifespan when given in old age. This has important implications for human testing, as it suggests that the drug might still exhibit healthspan and lifespan benefits even when given to the elderly. Rapamycin contrasts with calorie restriction in this regard; some evidence suggests that calorie restriction needs to be practiced from early adulthood, and may even fail to provide benefit for animals that are already old.<ref>Szafranski, K., & Mekhail, K. (2014). The fine line between lifespan extension and shortening in response to caloric restriction. ''Nucleus'', ''5''(1), 56-65.</ref>
==== Rapidly aging mice models ====
Using a mouse model that mimics the accelerated aging disease Hutchinson-Gilford progeria, rapamycin was shown to increase lifespan by over 50%. It also improved cardiac and skeletal muscle function in these mice.<ref>[https://doi.org/10.1126%2Fscitranslmed.3003802 Ramos, F. J., Chen, S. C., Garelick, M. G., Dai, D. F., Liao, C. Y., Schreiber, K. H., ... & Kennedy, B. K. (2012). Rapamycin reverses elevated mTORC1 signaling in lamin A/C–deficient mice, rescues cardiac and skeletal muscle function, and extends survival. ''Science translational medicine'', ''4''(144), 144ra103-144ra103.]
</ref> In one short-lived mutant strain of mice that mimics Leigh syndrome, rapamycin was shown to extend maximum life span nearly three-fold.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/24231806/ Johnson, S. C., Yanos, M. E., Kayser, E. B., Quintana, A., Sangesland, M., Castanza, A., ... & Kaeberlein, M. (2013). mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. ''Science'', ''342''(6165), 1524-1528.]</ref>

==== Middle-aged mice ====
Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.<ref>Bitto, A., Ito, T.K., Pineda, V.V., LeTexier, N.J., Huang, H.Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K. and Meza, D., 2016. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. ''elife'', ''5'', p.e16351.</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269 Strong, R., Miller, R. A., Bogue, M., Fernandez, E., Javors, M. A., Libert, S., ... & Harrison, D. E. (2020). Rapamycin‐mediated mouse lifespan extension: Late‐life dosage regimes with sex‐specific effects. ''Aging cell'', ''19''(11), e13269.]</ref> Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.<ref>Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. ''J Gerontol A Biol Sci Med Sci''. 2016 Jul; 71(7):876-81. doi: [https://academic.oup.com/biomedgerontology/article/71/7/876/2605199 10.1093/gerona/glw064]. Epub 2016 Apr 18. PMID: 27091134; PMCID: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906329/ PMC4906329]</ref> These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.

=== Yeast ===
Inhibition of TOR signalling by rapamycin significantly increases the lifespan of yeast known as ''Saccharomyces cerevisiae.''<ref>Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. ''Genes & development'', ''20''(2), 174-184.</ref>

=== Flies ===
Rapamycin extends the lifespan of the fruitfly, ''Drosophila melanogaster.'' The extent of lifespan extension observed is beyond what is achievable by flies undergoing other pro-longevity interventions like dietary restriction, or in mutant flies with mild decrements in insulin/insulin-like growth factor signaling (IIS).<ref>Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. ''Cell metabolism'', ''11''(1), 35-46.</ref> Combining rapamycin with two other drugs that target metabolic pathways, lithium and trametinib, results in additive lifespan extension effects, substantially increasing ''Drosophila'' lifepsan by 48%.<ref>Castillo-Quan, J. I., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., ... & Partridge, L. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. ''Proceedings of the National Academy of Sciences'', ''116''(42), 20817-20819.</ref>

=== Roundworms ===
TOR inhibition by rapamycin extends lifespan in ''Caenorhabditis elegans,'' a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in ''C. elegans'' seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.<ref>Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. ''Cell metabolism'', ''15''(5), 713-724.</ref>

=== Age-related diseases ===
Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref>

===== Cancer =====
In the transgenic HER-2/neu mouse model, mice die prematurely due to susceptibility to cancer.<ref name=":6" /> Rapamycin was hypothesized to improve survival in this model due to its ability to slow aging, which would also address an age-related disease like cancer.<ref name=":6" /> The drug was shown to extend maximal lifespan, by delaying aging in multiple different organs and also suppressing cancer development.<ref name=":6">Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., ... & Blagosklonny, M. V. (2010). Rapamycin extends maximal lifespan in cancer-prone mice. ''The American journal of pathology'', ''176''(5), 2092-2097.</ref>

Other studies suggest that rapamycin can extend lifespan in mouse models where cancer naturally develops, such as in mice prone to cancer due to the Apc tumor suppressor gene mutation, or in mice heterozygous for the Rb1 tumor supressor gene, among others.<ref>Hasty, P., Livi, C. B., Dodds, S. G., Jones, D., Strong, R., Javors, M., ... & Sharp, Z. D. (2014). eRapa restores a normal life span in a FAP mouse model. ''Cancer Prevention Research'', ''7''(1), 169-178.</ref><ref>Livi, C. B., Hardman, R. L., Christy, B. A., Dodds, S. G., Jones, D., Williams, C., ... & Sharp, Z. D. (2013). Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. ''Aging (Albany NY)'', ''5''(2), 100.</ref><ref>Hambright, H. G., Hurez, V., & Curiel, T. J. (2020). Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging or Vice Versa?. ''Geriatric Oncology'', 111-128.</ref>

A group of investigators in Germany have argued, based on their experiment in C57BL/6J Rj inbred mice, that rapamycin extends lifespan mainly through delaying cancer incidence, instead of via slowed aging.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref> A further analysis of the paper by Johnson et al. pointed to several important limitations of the study, suggesting that such a conclusion may be premature.<ref name=":82">Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? ''Science translational medicine'', ''5''(211), 211fs40.</ref> Key limitations included the lack of dose-response profiling of rapamycin; studying only the male sex, which is known to respond less to rapamycin likely in part due to sex differences in drug metabolism; lack of reporting on tumor size and incidence, required to determine whether lifespan extension occured only via slowed cancer or from a general effect on aging; and, the cross-sectional nature of the study, which would have reduced sensitivity for detecting age-related organ/tissue changes compared to longitudinal assays.<ref name=":82" /><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.</ref>

===== Heart Disease =====
One study investigated the effects of late-life rapamycin dosing in aged female mice, observing a reversal of age-related heart dysfunction.<ref name=":16">Flynn, J. M., O'Leary, M. N., Zambataro, C. A., Academia, E. C., Presley, M. P., Garrett, B. J., ... & Melov, S. (2013). Late‐life rapamycin treatment reverses age‐related heart dysfunction. ''Aging cell'', ''12''(5), 851-862.

</ref> This included benefits to ejection fraction, cardiac hormones, and reduced inflammation, although no effect was observed for heart fibrosis.<ref name=":16" /> Additionally, improvements in behaviour and physical function were demonstrated.<ref name=":16" /> Another study in naturally aged mice showed improvements in cardiac muscle stiffness, diastolic function with rapamycin.<ref name=":7">Quarles, E., Basisty, N., Chiao, Y. A., Merrihew, G., Gu, H., Sweetwyne, M. T., ... & Rabinovitch, P. S. (2020). Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. ''Aging Cell'', ''19''(2), e13086.</ref> Improvements in heart function were shown with only a brief treatment course of 8 weeks.<ref name=":7" /> Benefits persisted even after rapamycin was stopped, which appears consistent with the hypothesis that rapamycin slows aging.<ref name=":7" />

===== Alzheimer's =====
Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which age is the greatest risk factor.<ref>https://www.science.org/doi/10.1126/scitranslmed.aar4289</ref> In an Alzheimer's model of transgenic PDAPP mice, rapamycin was shown to reduce Amyloid-β, one of the hallmarks of AD.<ref name=":8" /> This led to alleviation of AD-like symptoms, such as restored cognition and memory.<ref name=":8">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> Similarly, another major AD hallmark known as tau was mitigated by rapamycin in a tauopathy mouse model.<ref name=":14">Ozcelik, S., Fraser, G., Castets, P., Schaeffer, V., Skachokova, Z., Breu, K., ... & Winkler, D. T. (2013). Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. ''PloS one'', ''8''(5), e62459.</ref> The mechanism of clearance of these proteins was linked to autophagy, with benefits seen regardless of whether it was dosed early for prevention, or in late life as treatment.<ref name=":14" />

=== Dose response ===
Rapamycin has shown a dose-response in which higher doses produce larger lifespan extension effects. UMHET3 mice of diverse genetic background were treated with varying doses of dietary rapamycin at 4.7, 14, or 42 ppm, revealing that those fed with the highest rapamycin dose had the greatest lifespan extension.<ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":0">[[Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. Journal of genetics and genomics= Yi chuan xue bao, 41(9), 459.|Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.]]</ref> Sex differences in response to rapamycin have been hypothesized to also be related to the effective dose, due to male/female differences in drug metabolism. The optimal dose for longevity in mice remains to be seen, but determining this dose will require consideration of the side effect profile of rapamycin.<ref name=":0" />

== Mechanism ==

=== Manipulating metabolic pathways - differences to calorie restriction ===
Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.<ref name=":15">Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":4" /> This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.<ref name=":3">Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. ''Current opinion in genetics & development'', ''23''(1), 53-62.</ref> mTOR plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.<ref name=":3" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.<ref name=":15" /><ref name=":4">Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. (2020). Is rapamycin a dietary restriction mimetic?. ''The Journals of Gerontology: Series A'', ''75''(1), 4-13.</ref> For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.<ref name=":15" /> This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.<ref name=":4" />

Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/21179166/ Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. ''Nature'', ''468''(7327), 1100-1104.]</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref name=":5" /><ref>Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. ''Aging (Albany NY)'', ''11''(19), 8048.
</ref> Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.<ref>Kemnitz, J. W. (2011). Calorie restriction and aging in nonhuman primates. ''Ilar Journal'', ''52''(1), 66-77.</ref><ref>Goto, S., Takahashi, R., Radak, Z., & Sharma, R. (2007). Beneficial biochemical outcomes of late‐onset dietary restriction in rodents. ''Annals of the New York Academy of Sciences'', ''1100''(1), 431-441.</ref><ref>Kristan, D. M. (2008). Calorie restriction and susceptibility to intact pathogens. ''Age'', ''30''(2), 147-156.</ref> Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref>

=== mTORC1 and mTORC2 ===
In non-mammals the mTOR equivalent is known as the target of rapamycin (TOR), first discovered by a team led by Michael Hall in the yeast ''Saccharomyces cerevisiae''.<ref>Thomas, G., & Hall, M. N. (1997). TOR signalling and control of cell growth. ''Current opinion in cell biology'', ''9''(6), 782-787.</ref><ref>Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N. R., & Hall, M. N. (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. ''Cell'', ''73''(3), 585-596.</ref> mTOR signalling appears to be evolutionarily conserved, and this extends further to include various mammals, such as mice, rats, and dogs.

Rapamycin acts on mTOR, with multiple signaling functions subdivided across two major protein complexes known as mTORC1 and mTORC2.<ref name=":3" /> There is some evidence suggesting that the health and lifespan benefit of rapamycin is more related to inhibition of mTORC1 than mTORC2.<ref name=":19">Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.</ref><ref name=":11">Lamming, D. W., Mihaylova, M. M., Katajisto, P., Baar, E. L., Yilmaz, O. H., Hutchins, A., ... & Sabatini, D. M. (2014). Depletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan. ''Aging cell'', ''13''(5), 911-917.</ref> In mice, males exhibit weaker lifespan extension effects from rapamycin than in females. One study suggests that inhibiting mTORC2 explains why the sex difference in the response to mTOR inhibition by rapamycin.<ref name=":11" />

=== Effects on glucoregulatory control ===
A noted issue regarding rapamycin is the disruption of glucose metabolism with chronic dosing, which has been observed in both humans and mice. In mice, this side effect has been shown to be due in part to disruption of mTORC2 in the liver, leading to hepatic insulin resistance.<ref name=":19" /> This effect has previously been shown to be reversible upon stopping the drug in both lean and obese mice.<ref name=":18">Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J. A., ... & Salmon, A. B. (2014). Rapamycin-induced metabolic defects are reversible in both lean and obese mice. ''Aging (Albany NY)'', ''6''(9), 742.</ref> Whether disrupted glucose metabolism is dispensable for the lifespan extending effects of rapamycin remains controversial.<ref>Blagosklonny, M. V. (2012). Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. ''Aging (Albany NY)'', ''4''(5), 350.</ref><ref>[https://www.nature.com/articles/s41419-019-1822-8 Blagosklonny, M. V. (2019). Fasting and rapamycin: diabetes versus benevolent glucose intolerance. ''Cell death & disease'', ''10''(8), 1-10.]</ref><ref>[https://www.science.org/doi/full/10.1126/science.1215135 Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.]</ref><ref>Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., ... & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. ''Aging cell'', ''15''(5), 872-884.</ref> Rapamycin has previously been shown to increase insulin sensitivity with acute dosing, while decreasing insulin sensitivity with chronic dosing.<ref>Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M., & Baur, J. A. (2012). Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. ''Frontiers in genetics'', ''3'', 177.</ref>

=== Reducing the effects of cellular senescence ===
The accumulation of senescent cells is thought to be an important mechanism underlying aging. Rapamycin is regarded as a senomorphic that may inhibit the pro-inflammatory secretory phenotype produced by senescent cells in humans, mice, and rats.<ref>[[Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. Aging cell, 16(3), 564-574.|Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. ''Aging cell'', ''16''(3), 564-574.]]</ref><ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref> A preliminary study in humans aged 40 years or older showed that topical rapamycin reduced markers of cellular senescence in the skin and improved its physical appearance.<ref>[https://doi.org/10.1007%2Fs11357-019-00113-y Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Nadhan, K., Potnis, M., ... & Sell, C. (2019). Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. ''Geroscience'', ''41''(6), 861-869.]
</ref>

== Human clinical trials ==
[[File:Rapamycin.jpg|thumb|235x235px|Part of the rationale of the PEARL study is to determine the optimal dose of rapamycin to potentially slow aging.<ref name=":2" />]]

=== PEARL study ===
Rapamycin is currently being tested for safety and efficacy in a clinical trial called the Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity (PEARL) study. The clinical trial aims to systematically investigate the use of rapamycin to promote healthy longevity, and is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

The study will begin with 200 adults aged 50 years or older who will receive rapamycin for up to one year. The study is being conducted by AgelessRx, a new company dedicated to developing scientifically supported interventions to prevent and treat age-related diseases, in collaboration with the University of California.<ref>[https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/ ''AgelessRx and funding an IRB-approved rapamycin trial - Longevity.Technology''. Longevity.Technology. (2021). Retrieved 27 May 2021, from https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/.]</ref>

The trial aims to obtain clinical data at 6 and 12 months of treatment, such as via testing of blood, body composition DXA, fecal microbiome, immune function, inflammation, skeletal muscle, and epigenetic aging clocks.

== Dog clinical trials ==
The Dog Aging Project is a US Government NIH-funded initiative investigating dog aging.<ref>https://dogagingproject.org/</ref> The project is led by Professor Matt Kaeberlein at the University of Washington.<ref name=":10">Kaeberlein, M., Creevy, K. E., & Promislow, D. E. (2016). The dog aging project: translational geroscience in companion animals. ''Mammalian genome'', ''27''(7), 279-288.</ref>

The Test of Rapamycin In Aging Dogs (TRIAD) study is investigating rapamycin as a treatment to slow aging in dogs. The investigators hope to increase healthy canine lifespan with rapamycin by delaying the onset of age-related diseases like cancer and heart disease.<ref name=":9" /><ref name=":10" />

Aging biology scientists believe that studying dog aging might not only help improve canine healthspan, but also have implications for humans.<ref name=":10" /> Dogs may be a useful animal model because they share the same environment that humans live in, and suffer from similar chronic diseases with aging.<ref>Hoffman, J. M., Creevy, K. E., Franks, A., O'Neill, D. G., & Promislow, D. E. (2018). The companion dog as a model for human aging and mortality. ''Aging Cell'', ''17''(3), e12737.</ref>

===== Heart disease =====
One randomized-controlled trial in 24 middle-aged dogs treated with low-dose rapamycin showed suggestion of partial reversal of age-related heart dysfunction, as measured via echocardiography. The intervention was well-tolerated, with no clinically meaningful adverse events noted with a non-immunosuppressive dose of rapamycin during the 10 week period. This was a small study over a relatively short duration; further testing in larger clinical studies will be necessary to determine whether rapamycin can be used to treat age-related heart disease in dogs.

== Regulatory approval ==
Rapamycin was approved by the US Food and Drug Administration (FDA) in 1999 to prevent organ rejection in liver transplant patients, and has been marketed under the brand name Rapamune.<ref>[https://link.springer.com/article/10.1007/s11357-020-00274-1 Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.]</ref> The patent on rapamycin has expired, and chemically similar compounds called 'rapalogs' are being researched by biotechnology companies.<ref>[https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.9b00215 Abdel-Magid, A. F. (2019). Rapalogs potential as practical alternatives to rapamycin.]
</ref> It is not currently approved for use as an anti-aging medication, due to lack of human clinical data for this purpose.

== Safety ==
Rapamycin has been used to treat millions of patients over several decades since obtaining FDA approval in 1999. It is generally considered safe in humans, but only when used under clinical supervision for specific indications. Rapamycin and its analogs are immunosuppressants, and used as such in the clinic; some rapalogs have received “black-box” FDA warnings due to the risks of infection, as well as the potential risk of cancer due to suppression of tumor immune surveillance.<ref>https://www.pfizermedicalinformation.com/en-us/rapamune/boxed-warning</ref><ref>https://www.pdr.net/drug-summary/Afinitor-everolimus-416.6101</ref>

Various side effects have been reported with the dose of rapamycin used to prevent rejection in organ transplant patients, who are often concurrently treated with multiple other medications.<ref>Webster, A. C., Lee, V. W., Chapman, J. R., & Craig, J. C. (2006). Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. ''Transplantation'', ''81''(9), 1234-1248.</ref> These include pain, headache, fever, high blood pressure, glucose intolerance, new-onset diabetes, nausea, abdominal pain, constipation, diarrhea, thrombocytopenia, leukopenia, among others. However, side effects are mostly reversible (at least if therapy is rapidly discontinued) and represent worst-case scenarios, particularly because the patients sampled in clinical studies are already severely ill and taking the drug along with other medications.<ref>Bischof, E., Siow, R.C., Zhavoronkov, A. and Kaeberlein, M., 2021. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), pp.e105-e111.
</ref> In subjects taking high doses of rapamycin and analogs for severe, chronic conditions including tuberous sclerosis complex, an inherited genetic disorder of increased mTOR signaling, or for cancer, the side effects have occasionally led life-threatening adverse events or death.<ref>Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anti-cancer drugs. 2015;26(4):437-42. PMID: [https://pubmed.ncbi.nlm.nih.gov/25719621/ 25719621] DOI: [https://doi.org/10.1097/cad.0000000000000207 10.1097/CAD.0000000000000207]</ref><ref>Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010; 116(18):4256-65. PMID: [https://pubmed.ncbi.nlm.nih.gov/20549832/ 20549832] DOI: [https://doi.org/10.1002/cncr.25219 10.1002/cncr.25219] </ref>

Case studies of the safety profile of rapamycin in the context of overdosing have suggested that it may have a large margin of safety or a high median lethal dose, but only in the acute setting.<ref>Ceschi, A., Heistermann, E., Gros, S., Reichert, C., Kupferschmidt, H., Banner, N. R., ... & Taegtmeyer, A. B. (2015). Acute sirolimus overdose: a multicenter case series. ''PLoS One'', ''10''(5), e0128033.</ref> The distinction with chronic high dose mTOR inhibition must be made because resultant immunosuppression can lead to susceptibility to infection with fatal consequences. Some preclinical data suggests that the longevity benefits of rapamycin may be retained via intermittent dosing.<ref name=":2" /> In considering the known clinical data about rapamycin's controversial safety at continuous, high doses, some researchers have proposed that rapamycin should dosed intermittently to minimize side effects while sufficiently inhibiting mTOR for an effect on aging.<ref name=":2" />

From a longevity perspective, there is a lack of published clinical data demonstrating the safety of rapamycin in healthy adults. One small randomized pilot study of rapamycin in 25 older adults aged 70-95 taking 1 mg/day of rapamycin reported finding no clinically significant effects, including a lack of effect on immune function.<ref name=":13">Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., ... & Kellogg Jr, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. ''Experimental gerontology'', ''105'', 53-69.</ref> However, laboratory results from this trial suggested that the subjects experienced negative metabolic effects, including a small increase in glycated hemoglobin (within-group p=0.03) and a 40% rise in triglyceride levels (within-group p=0.05).<ref>Lamming, D. Rapamycin and Rapalogs. Preprints 2021, 2021020491 (doi: [https://www.preprints.org/manuscript/202102.0491/v1 10.20944/preprints202102.0491.v1]).</ref> This was a small study with a low dose of rapamycin, dosed over a short duration of 8 weeks. Considering the fact that, based on preclinical animal data, any potential benefit of rapamycin for aging will require long-term dosing, further testing in clinical trials is necessary to better characterize safety.<ref name=":13" />

Clinical trials such as the PEARL study are needed to provide evidence for the safety profile of rapamycin in otherwise healthy older adults.

== Rapalogs ==
Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>
However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>
Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875. https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>

Antiemetic; piperazine-derivative antihistamine '''meclizine''', which is often available over the counter, is also found to be an mTOR inhibitor that male-specificly extends median lifespan in male mice by '''8%'''.<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Rosenthal, N., Korstanje, R., Fernandez, E., ... & Miller, R. A. (2023). Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. GeroScience, 1-22. PMID: 38041783 [https://doi.org/10.1007/s11357-023-01011-0 DOI: 10.1007/s11357-023-01011-0]</ref> Meclizine also is Toll-like receptor 4 (TLR4) inhibitor. Toll like receptors role is to detect pathogen molecules and initiate an immunologic response to them especially through production of pro-inflammatory cytokines and increased levels of type I interferon production.<ref>Zali, H., Golchin, A., Farahani, M., Yazdani, M., Ranjbar, M. M., & Dabbagh, A. (2019). FDA approved drugs repurposing of Toll-like receptor4 (TLR4) candidate for neuropathy. Iranian Journal of Pharmaceutical Research: IJPR, 18(3), 1639. PMID: 32641971 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934974/ PMC6934974] DOI: 10.22037/ijpr.2019.2394</ref>

=== mTOR inhibition improves immune function in the elderly ===

In a phase 2 randomized clinical trial published in ''Science Translational Medicine'' in 2014, low-dose TORC1 inhibition with the rapalog everolimus showed improvement in immune function in the elderly. The clinical trial enrolled 218 adults aged ≥65 years, observing decreased incidence of all infections, as well as improved influenza vaccination responses and upregulation of antiviral immunity.<ref name=":17">Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref>

Everolimus enhanced the influenza vaccine response by approximately 20% at relatively well tolerated doses.<ref name=":17" /> One mechanism was related to a reduction in the percentage of CD4 and CD8 T cells expressing the programmed death-1 receptor, which has increased expression with age and a major role in inhibiting T cell signaling.<ref name=":17" /> These findings suggest that, at an appopriate dose, mTOR inhibition may improve the age-related decline in immune function in the elderly.

=== TORC1 inhibition enhances immune function and reduces infections in the elderly ===

A phase 2a trial clinical trial randomized 264 older adults to treatment with everolimus and placebo, and was published in ''Science Translational Medicine'' in 2018. The trial showed potential for reducing the effects of immune aging, with improvement in influenza vaccination response in the elderly.<ref name=":1">Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref>[[File:Rtb101 Ph2 Ph3.jpg|thumb|461x461px|A) Number of patients with laboratory-confirmed RTIs of ''any severity'' caused by specific viruses, comparing RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 RCTs B) Number of patients with laboratory-confirmed RTIs with ''severe symptoms'' caused by specific viruses in the RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 trials. RTI = respiratory tract infection]]

=== Improving immune function in older adults for respiratory tract infections, including coronaviruses ===
Low-dose mTOR inhibition with dactolisib in a Phase 2b and phase 3 trial in the elderly showed reduced coronavirus (non [[COVID-19]]) incidence, as well as reductions in severe symptoms.<ref name=":12">Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., ... & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. ''The Lancet Healthy Longevity'', ''2''(5), e250-e262.</ref> However, the data remains inconclusive as the study was powered statistically for a reduction in clinically symptomatic respiratory tract infections (RTIs), and not laboratory-confirmed RTIs.<ref name=":12" />

Following the success of two phase 2 clinical trials investigating mTOR inhibition for targeting the aging immune system, dactolisib is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial (ClinicalTrials.gov Identifier: NCT04584710, NCT04409327), exploring the potential for preventing severe disease in elderly adults with no symptoms, who have been exposed to [[COVID-19]].<ref name=":12" />

Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit.

This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.<ref name=":12" />

== See also ==
* [https://en.longevitywiki.org/wiki/Isomyosamine Isomyosamine] ('''MYMD-1®''') <ref>Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. 78(2), 227-235 PMID 35914953 doi:10.1093/gerona/glac142</ref>

== References ==
<references />
[[Category:Drugs]]
[[Category:Main list]]
[[Category:Fundamentals]]

Rapamycin

2024-06-19T06:24:51Z

Geroscientist: /* Dogs */

[[File:Rapamycin2.jpg|thumb|211x211px|The chemical structure of rapamycin.]]
Rapamycin, also known by its brand name Rapamune®, is a compound used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Easter Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Rapamycin was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name Rapamune® by Pfizer.<ref>Accessdata.fda.gov. 2021. ''Drug Approval Package: Rapamune (Sirolimus) NDA# 021083''. [online] Available at: <<nowiki>https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm</nowiki>> [Accessed 27 May 2021].</ref> At a high dose, rapamycin has an immunosuppressant function that is used in preventing rejection of kidney transplants by the immune system. It is also used to coat coronary stents, and to treat rare lung diseases.<ref>Doggrell, S. (2006). Sirolimus- or paclitaxel-eluting stents for coronary artery revascularisation. ''Expert Opinion On Pharmacotherapy'', ''7''(2), 225-228. <nowiki>https://doi.org/10.1517/14656566.7.2.225</nowiki></ref> The patent on rapamycin has expired, and pharmacological companies have developed similar drugs such as everolimus.<ref>Cancer, C. (2021). ''Everolimus - Drug Information - Chemocare''. Chemocare.com. Retrieved 27 May 2021, from <nowiki>http://chemocare.com/chemotherapy/drug-info/everolimus.aspx</nowiki>.</ref>

Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":2" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref><ref>Mannick, J. B., & Lamming, D. W. (2023). Targeting the biology of aging with mTOR inhibitors. Nature Aging, 1-19. PMID: 37142830 PMC10330278 [https://www.nature.com/articles/s43587-023-00416-y DOI: 10.1038/s43587-023-00416-y]</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":2">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref> It is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

== Evidence of increased healthspan or lifespan ==

=== Non-human primates ===
Unpublished data presented by Dr Adam Salmon at the American Aging Association annual meeting (2024) showed the rapamycin extends median lifepsan by 15% in the common marmoset ''Callithrix jacchus.'' Rapamycin was delivered orally at 1 mg/kg/day.

=== Dogs ===
There is preliminary evidence that rapamycin may prevent age-related decline in dogs. One study showed statistically significant improvements in heart function in dogs receiving rapamycin, relative to those that received placebo, similar to what has been observed in older laboratory mice.<ref name=":9">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411365/ Urfer, S. R., Kaeberlein, T. L., Mailheau, S., Bergman, P. J., Creevy, K. E., Promislow, D. E., & Kaeberlein, M. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. ''Geroscience'', ''39''(2), 117-127.]</ref> As part of the Dog Aging Project at the University of Washington, the TRIAD study is testing whether rapamycin can extend healthy lifespan in pet dogs.
=== Mice ===
In multiple studies in different breeds of mice, rapamycin demonstrates a robust effect on increasing healthy lifespan. Rapamycin significantly extends lifespan in approximately 90% of the mice models it has been tested in.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.</ref>

In 2009, rapamycin was shown to increase the lifespan of both male and female mice when given in late life (600 days).<ref name=":5">[https://doi.org/10.1038%2Fnature08221 Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., ... & Miller, R. A. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. ''nature'', ''460''(7253), 392-395.]</ref> Mean survival was extended by 28% for males and 38% for females, while maximal lifespan increased by 9% for males and 14% for females.<ref name=":5" /> This was the first evidence that the lifespan of a mammal could be significantly increased by a pharmacological drug. This mouse study is special because the results were obtained following the US National Institute on Aging's Interventions Testing Program (ITP) protocol. The ITP is regarded as the gold standard for testing drugs that target aging.<ref>Nadon, N. L., Strong, R., Miller, R. A., Nelson, J., Javors, M., Sharp, Z. D., ... & Harrison, D. E. (2008). Design of aging intervention studies: the NIA interventions testing program. ''Age'', ''30''(4), 187-199.</ref>

The landmark 2009 study also showed that rapamycin could increase healthy lifespan when given in old age. This has important implications for human testing, as it suggests that the drug might still exhibit healthspan and lifespan benefits even when given to the elderly. Rapamycin contrasts with calorie restriction in this regard; some evidence suggests that calorie restriction needs to be practiced from early adulthood, and may even fail to provide benefit for animals that are already old.<ref>Szafranski, K., & Mekhail, K. (2014). The fine line between lifespan extension and shortening in response to caloric restriction. ''Nucleus'', ''5''(1), 56-65.</ref>
==== Rapidly aging mice models ====
Using a mouse model that mimics the accelerated aging disease Hutchinson-Gilford progeria, rapamycin was shown to increase lifespan by over 50%. It also improved cardiac and skeletal muscle function in these mice.<ref>[https://doi.org/10.1126%2Fscitranslmed.3003802 Ramos, F. J., Chen, S. C., Garelick, M. G., Dai, D. F., Liao, C. Y., Schreiber, K. H., ... & Kennedy, B. K. (2012). Rapamycin reverses elevated mTORC1 signaling in lamin A/C–deficient mice, rescues cardiac and skeletal muscle function, and extends survival. ''Science translational medicine'', ''4''(144), 144ra103-144ra103.]
</ref> In one short-lived mutant strain of mice that mimics Leigh syndrome, rapamycin was shown to extend maximum life span nearly three-fold.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/24231806/ Johnson, S. C., Yanos, M. E., Kayser, E. B., Quintana, A., Sangesland, M., Castanza, A., ... & Kaeberlein, M. (2013). mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. ''Science'', ''342''(6165), 1524-1528.]</ref>

==== Middle-aged mice ====
Several recent studies have shown that rapamycin can extend the lifespan of middle-aged or aged mice. One study showed that treating 20-month-old mice (the equivalent of 56–69 years in humans) with rapamycin for only 3 months resulted in a dramatic increase in median lifespan of up to 60%.<ref>Bitto, A., Ito, T.K., Pineda, V.V., LeTexier, N.J., Huang, H.Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K. and Meza, D., 2016. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. ''elife'', ''5'', p.e16351.</ref> A study from 2020 showed that administering rapamycin in late life enhanced the lifespan of male but not female mice, providing evidence for sex differences in rapamycin response.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13269 Strong, R., Miller, R. A., Bogue, M., Fernandez, E., Javors, M. A., Libert, S., ... & Harrison, D. E. (2020). Rapamycin‐mediated mouse lifespan extension: Late‐life dosage regimes with sex‐specific effects. ''Aging cell'', ''19''(11), e13269.]</ref> Aged female mice administered rapamycin once every 5 days starting at 20 months of age also extended lifespan.<ref>Arriola Apelo SI, Pumper CP, Baar EL, Cummings NE, Lamming DW. Intermittent administration of rapamycin extends the lifespan of female C57BL/6J mice. ''J Gerontol A Biol Sci Med Sci''. 2016 Jul; 71(7):876-81. doi: [https://academic.oup.com/biomedgerontology/article/71/7/876/2605199 10.1093/gerona/glw064]. Epub 2016 Apr 18. PMID: 27091134; PMCID: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906329/ PMC4906329]</ref> These studies were important as they suggest that much of the health and longevity benefits of rapamycin could be achieved even when dosed in late life or intermittently, as opposed to only being effective with continual dosing in early life.

=== Yeast ===
Inhibition of TOR signalling by rapamycin significantly increases the lifespan of yeast known as ''Saccharomyces cerevisiae.''<ref>Powers, R. W., Kaeberlein, M., Caldwell, S. D., Kennedy, B. K., & Fields, S. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. ''Genes & development'', ''20''(2), 174-184.</ref>

=== Flies ===
Rapamycin extends the lifespan of the fruitfly, ''Drosophila melanogaster.'' The extent of lifespan extension observed is beyond what is achievable by flies undergoing other pro-longevity interventions like dietary restriction, or in mutant flies with mild decrements in insulin/insulin-like growth factor signaling (IIS).<ref>Bjedov, I., Toivonen, J. M., Kerr, F., Slack, C., Jacobson, J., Foley, A., & Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. ''Cell metabolism'', ''11''(1), 35-46.</ref> Combining rapamycin with two other drugs that target metabolic pathways, lithium and trametinib, results in additive lifespan extension effects, substantially increasing ''Drosophila'' lifepsan by 48%.<ref>Castillo-Quan, J. I., Tain, L. S., Kinghorn, K. J., Li, L., Grönke, S., Hinze, Y., ... & Partridge, L. (2019). A triple drug combination targeting components of the nutrient-sensing network maximizes longevity. ''Proceedings of the National Academy of Sciences'', ''116''(42), 20817-20819.</ref>

=== Roundworms ===
TOR inhibition by rapamycin extends lifespan in ''Caenorhabditis elegans,'' a roundworm nematode widely used in research areas of the biology of aging. The beneficial effects of rapamycin in ''C. elegans'' seem to be mediated via the SKN-1/Nrf and DAF-16/FoxO pathways.<ref>Robida-Stubbs, S., Glover-Cutter, K., Lamming, D. W., Mizunuma, M., Narasimhan, S. D., Neumann-Haefelin, E., ... & Blackwell, T. K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. ''Cell metabolism'', ''15''(5), 713-724.</ref>

=== Age-related diseases ===
Rapamycin has been investigated in specific diseases, showing major impacts on reducing mouse cancer risk, cardiac diseases, neurodegenerative-like processes, and many other pathologies.<ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref>

===== Cancer =====
In the transgenic HER-2/neu mouse model, mice die prematurely due to susceptibility to cancer.<ref name=":6" /> Rapamycin was hypothesized to improve survival in this model due to its ability to slow aging, which would also address an age-related disease like cancer.<ref name=":6" /> The drug was shown to extend maximal lifespan, by delaying aging in multiple different organs and also suppressing cancer development.<ref name=":6">Anisimov, V. N., Zabezhinski, M. A., Popovich, I. G., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., ... & Blagosklonny, M. V. (2010). Rapamycin extends maximal lifespan in cancer-prone mice. ''The American journal of pathology'', ''176''(5), 2092-2097.</ref>

Other studies suggest that rapamycin can extend lifespan in mouse models where cancer naturally develops, such as in mice prone to cancer due to the Apc tumor suppressor gene mutation, or in mice heterozygous for the Rb1 tumor supressor gene, among others.<ref>Hasty, P., Livi, C. B., Dodds, S. G., Jones, D., Strong, R., Javors, M., ... & Sharp, Z. D. (2014). eRapa restores a normal life span in a FAP mouse model. ''Cancer Prevention Research'', ''7''(1), 169-178.</ref><ref>Livi, C. B., Hardman, R. L., Christy, B. A., Dodds, S. G., Jones, D., Williams, C., ... & Sharp, Z. D. (2013). Rapamycin extends life span of Rb1+/− mice by inhibiting neuroendocrine tumors. ''Aging (Albany NY)'', ''5''(2), 100.</ref><ref>Hambright, H. G., Hurez, V., & Curiel, T. J. (2020). Chronic Mechanistic Target of Rapamycin Inhibition: Preventing Cancer to Delay Aging or Vice Versa?. ''Geriatric Oncology'', 111-128.</ref>

A group of investigators in Germany have argued, based on their experiment in C57BL/6J Rj inbred mice, that rapamycin extends lifespan mainly through delaying cancer incidence, instead of via slowed aging.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref> A further analysis of the paper by Johnson et al. pointed to several important limitations of the study, suggesting that such a conclusion may be premature.<ref name=":82">Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver? ''Science translational medicine'', ''5''(211), 211fs40.</ref> Key limitations included the lack of dose-response profiling of rapamycin; studying only the male sex, which is known to respond less to rapamycin likely in part due to sex differences in drug metabolism; lack of reporting on tumor size and incidence, required to determine whether lifespan extension occured only via slowed cancer or from a general effect on aging; and, the cross-sectional nature of the study, which would have reduced sensitivity for detecting age-related organ/tissue changes compared to longitudinal assays.<ref name=":82" /><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.</ref>

===== Heart Disease =====
One study investigated the effects of late-life rapamycin dosing in aged female mice, observing a reversal of age-related heart dysfunction.<ref name=":16">Flynn, J. M., O'Leary, M. N., Zambataro, C. A., Academia, E. C., Presley, M. P., Garrett, B. J., ... & Melov, S. (2013). Late‐life rapamycin treatment reverses age‐related heart dysfunction. ''Aging cell'', ''12''(5), 851-862.

</ref> This included benefits to ejection fraction, cardiac hormones, and reduced inflammation, although no effect was observed for heart fibrosis.<ref name=":16" /> Additionally, improvements in behaviour and physical function were demonstrated.<ref name=":16" /> Another study in naturally aged mice showed improvements in cardiac muscle stiffness, diastolic function with rapamycin.<ref name=":7">Quarles, E., Basisty, N., Chiao, Y. A., Merrihew, G., Gu, H., Sweetwyne, M. T., ... & Rabinovitch, P. S. (2020). Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. ''Aging Cell'', ''19''(2), e13086.</ref> Improvements in heart function were shown with only a brief treatment course of 8 weeks.<ref name=":7" /> Benefits persisted even after rapamycin was stopped, which appears consistent with the hypothesis that rapamycin slows aging.<ref name=":7" />

===== Alzheimer's =====
Alzheimer's Disease (AD) is a progressive neurodegenerative disease for which age is the greatest risk factor.<ref>https://www.science.org/doi/10.1126/scitranslmed.aar4289</ref> In an Alzheimer's model of transgenic PDAPP mice, rapamycin was shown to reduce Amyloid-β, one of the hallmarks of AD.<ref name=":8" /> This led to alleviation of AD-like symptoms, such as restored cognition and memory.<ref name=":8">Spilman, P., Podlutskaya, N., Hart, M. J., Debnath, J., Gorostiza, O., Bredesen, D., ... & Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease. ''PloS one'', ''5''(4), e9979.</ref> Similarly, another major AD hallmark known as tau was mitigated by rapamycin in a tauopathy mouse model.<ref name=":14">Ozcelik, S., Fraser, G., Castets, P., Schaeffer, V., Skachokova, Z., Breu, K., ... & Winkler, D. T. (2013). Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. ''PloS one'', ''8''(5), e62459.</ref> The mechanism of clearance of these proteins was linked to autophagy, with benefits seen regardless of whether it was dosed early for prevention, or in late life as treatment.<ref name=":14" />

=== Dose response ===
Rapamycin has shown a dose-response in which higher doses produce larger lifespan extension effects. UMHET3 mice of diverse genetic background were treated with varying doses of dietary rapamycin at 4.7, 14, or 42 ppm, revealing that those fed with the highest rapamycin dose had the greatest lifespan extension.<ref>Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":0">[[Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much?. Journal of genetics and genomics= Yi chuan xue bao, 41(9), 459.|Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics,'' ''41''(9), 459.]]</ref> Sex differences in response to rapamycin have been hypothesized to also be related to the effective dose, due to male/female differences in drug metabolism. The optimal dose for longevity in mice remains to be seen, but determining this dose will require consideration of the side effect profile of rapamycin.<ref name=":0" />

== Mechanism ==

=== Manipulating metabolic pathways - differences to calorie restriction ===
Rapamycin has often been described as a 'calorie restriction (CR) mimetic'.<ref name=":15">Miller, R. A., Harrison, D. E., Astle, C. M., Fernandez, E., Flurkey, K., Han, M., ... & Strong, R. (2014). Rapamycin‐mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. ''Aging cell'', ''13''(3), 468-477.</ref><ref name=":4" /> This is in part because CR also inhibits the nutrient-sensing mammalian target of rapamycin (mTOR) pathway.<ref name=":3">Cornu, M., Albert, V., & Hall, M. N. (2013). mTOR in aging, metabolism, and cancer. ''Current opinion in genetics & development'', ''23''(1), 53-62.</ref> mTOR plays key roles in cellular growth in response to amino acids, including effects that inhibit cancer and aging mechanisms.<ref name=":3" /><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> However, later studies have disentangled the effects of rapamycin from that of caloric restriction, showing that they differ significantly.<ref name=":15" /><ref name=":4">Unnikrishnan, A., Kurup, K., Salmon, A. B., & Richardson, A. (2020). Is rapamycin a dietary restriction mimetic?. ''The Journals of Gerontology: Series A'', ''75''(1), 4-13.</ref> For example, unlike 5 months of CR, rapamycin does not decrease leptin, insulin, IGF-1, or FGF-21 in genetically diverse UM-HET3 mice.<ref name=":15" /> This has important implications for understanding biological aging, including the possibility of using CR and rapalogs in combination therapy to slow aging.<ref name=":4" />

Though distinct from CR, fasting inhibits muscle-specific mTOR signaling with reduced effect in old vs young mice, indicating a poorer autophagy and proteosomal degradation response with age.<ref>White, Z., White, R. B., McMahon, C., Grounds, M. D., & Shavlakadze, T. (2016). High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state. ''The international journal of biochemistry & cell biology'', ''78'', 10-21.</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/21179166/ Sengupta, S., Peterson, T. R., Laplante, M., Oh, S., & Sabatini, D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. ''Nature'', ''468''(7327), 1100-1104.]</ref> However, the ability for rapamycin to inhibit mTOR appears to remain robust throughout life, and significant extension of median and maximal lifespan can be achieved even when treatment is initiated in mid-to-late life.<ref name=":5" /><ref>Blagosklonny, M. V. (2019). Rapamycin for longevity: opinion article. ''Aging (Albany NY)'', ''11''(19), 8048.
</ref> Rapamycin contrasts significantly with CR and fasting, in that the latter could be detrimental when used in late life.<ref>Kemnitz, J. W. (2011). Calorie restriction and aging in nonhuman primates. ''Ilar Journal'', ''52''(1), 66-77.</ref><ref>Goto, S., Takahashi, R., Radak, Z., & Sharma, R. (2007). Beneficial biochemical outcomes of late‐onset dietary restriction in rodents. ''Annals of the New York Academy of Sciences'', ''1100''(1), 431-441.</ref><ref>Kristan, D. M. (2008). Calorie restriction and susceptibility to intact pathogens. ''Age'', ''30''(2), 147-156.</ref> Rapamycin also targets multiple diseases of aging, but seemingly in a segmented, tissue-specific manner.<ref>Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., ... & Ehninger, D. (2013). Rapamycin extends murine lifespan but has limited effects on aging. ''The Journal of clinical investigation'', ''123''(8), 3272-3291.</ref>

=== mTORC1 and mTORC2 ===
In non-mammals the mTOR equivalent is known as the target of rapamycin (TOR), first discovered by a team led by Michael Hall in the yeast ''Saccharomyces cerevisiae''.<ref>Thomas, G., & Hall, M. N. (1997). TOR signalling and control of cell growth. ''Current opinion in cell biology'', ''9''(6), 782-787.</ref><ref>Kunz, J., Henriquez, R., Schneider, U., Deuter-Reinhard, M., Movva, N. R., & Hall, M. N. (1993). Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. ''Cell'', ''73''(3), 585-596.</ref> mTOR signalling appears to be evolutionarily conserved, and this extends further to include various mammals, such as mice, rats, and dogs.

Rapamycin acts on mTOR, with multiple signaling functions subdivided across two major protein complexes known as mTORC1 and mTORC2.<ref name=":3" /> There is some evidence suggesting that the health and lifespan benefit of rapamycin is more related to inhibition of mTORC1 than mTORC2.<ref name=":19">Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.</ref><ref name=":11">Lamming, D. W., Mihaylova, M. M., Katajisto, P., Baar, E. L., Yilmaz, O. H., Hutchins, A., ... & Sabatini, D. M. (2014). Depletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan. ''Aging cell'', ''13''(5), 911-917.</ref> In mice, males exhibit weaker lifespan extension effects from rapamycin than in females. One study suggests that inhibiting mTORC2 explains why the sex difference in the response to mTOR inhibition by rapamycin.<ref name=":11" />

=== Effects on glucoregulatory control ===
A noted issue regarding rapamycin is the disruption of glucose metabolism with chronic dosing, which has been observed in both humans and mice. In mice, this side effect has been shown to be due in part to disruption of mTORC2 in the liver, leading to hepatic insulin resistance.<ref name=":19" /> This effect has previously been shown to be reversible upon stopping the drug in both lean and obese mice.<ref name=":18">Liu, Y., Diaz, V., Fernandez, E., Strong, R., Ye, L., Baur, J. A., ... & Salmon, A. B. (2014). Rapamycin-induced metabolic defects are reversible in both lean and obese mice. ''Aging (Albany NY)'', ''6''(9), 742.</ref> Whether disrupted glucose metabolism is dispensable for the lifespan extending effects of rapamycin remains controversial.<ref>Blagosklonny, M. V. (2012). Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. ''Aging (Albany NY)'', ''4''(5), 350.</ref><ref>[https://www.nature.com/articles/s41419-019-1822-8 Blagosklonny, M. V. (2019). Fasting and rapamycin: diabetes versus benevolent glucose intolerance. ''Cell death & disease'', ''10''(8), 1-10.]</ref><ref>[https://www.science.org/doi/full/10.1126/science.1215135 Lamming, D. W., Ye, L., Katajisto, P., Goncalves, M. D., Saitoh, M., Stevens, D. M., ... & Baur, J. A. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. ''science'', ''335''(6076), 1638-1643.]</ref><ref>Strong, R., Miller, R. A., Antebi, A., Astle, C. M., Bogue, M., Denzel, M. S., ... & Harrison, D. E. (2016). Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer. ''Aging cell'', ''15''(5), 872-884.</ref> Rapamycin has previously been shown to increase insulin sensitivity with acute dosing, while decreasing insulin sensitivity with chronic dosing.<ref>Ye, L., Varamini, B., Lamming, D. W., Sabatini, D. M., & Baur, J. A. (2012). Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. ''Frontiers in genetics'', ''3'', 177.</ref>

=== Reducing the effects of cellular senescence ===
The accumulation of senescent cells is thought to be an important mechanism underlying aging. Rapamycin is regarded as a senomorphic that may inhibit the pro-inflammatory secretory phenotype produced by senescent cells in humans, mice, and rats.<ref>[[Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. Aging cell, 16(3), 564-574.|Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., ... & Perez, V. I. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. ''Aging cell'', ''16''(3), 564-574.]]</ref><ref>Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.
</ref> A preliminary study in humans aged 40 years or older showed that topical rapamycin reduced markers of cellular senescence in the skin and improved its physical appearance.<ref>[https://doi.org/10.1007%2Fs11357-019-00113-y Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Nadhan, K., Potnis, M., ... & Sell, C. (2019). Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. ''Geroscience'', ''41''(6), 861-869.]
</ref>

== Human clinical trials ==
[[File:Rapamycin.jpg|thumb|235x235px|Part of the rationale of the PEARL study is to determine the optimal dose of rapamycin to potentially slow aging.<ref name=":2" />]]

=== PEARL study ===
Rapamycin is currently being tested for safety and efficacy in a clinical trial called the Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity (PEARL) study. The clinical trial aims to systematically investigate the use of rapamycin to promote healthy longevity, and is expected to conclude in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>

The study will begin with 200 adults aged 50 years or older who will receive rapamycin for up to one year. The study is being conducted by AgelessRx, a new company dedicated to developing scientifically supported interventions to prevent and treat age-related diseases, in collaboration with the University of California.<ref>[https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/ ''AgelessRx and funding an IRB-approved rapamycin trial - Longevity.Technology''. Longevity.Technology. (2021). Retrieved 27 May 2021, from https://www.longevity.technology/agelessrx-and-funding-an-irb-approved-rapamycin-trial/.]</ref>

The trial aims to obtain clinical data at 6 and 12 months of treatment, such as via testing of blood, body composition DXA, fecal microbiome, immune function, inflammation, skeletal muscle, and epigenetic aging clocks.

== Dog clinical trials ==
The Dog Aging Project is a US Government NIH-funded initiative investigating dog aging.<ref>https://dogagingproject.org/</ref> The project is led by Professor Matt Kaeberlein at the University of Washington.<ref name=":10">Kaeberlein, M., Creevy, K. E., & Promislow, D. E. (2016). The dog aging project: translational geroscience in companion animals. ''Mammalian genome'', ''27''(7), 279-288.</ref>

The Test of Rapamycin In Aging Dogs (TRIAD) study is investigating rapamycin as a treatment to slow aging in dogs. The investigators hope to increase healthy canine lifespan with rapamycin by delaying the onset of age-related diseases like cancer and heart disease.<ref name=":9" /><ref name=":10" />

Aging biology scientists believe that studying dog aging might not only help improve canine healthspan, but also have implications for humans.<ref name=":10" /> Dogs may be a useful animal model because they share the same environment that humans live in, and suffer from similar chronic diseases with aging.<ref>Hoffman, J. M., Creevy, K. E., Franks, A., O'Neill, D. G., & Promislow, D. E. (2018). The companion dog as a model for human aging and mortality. ''Aging Cell'', ''17''(3), e12737.</ref>

===== Heart disease =====
One randomized-controlled trial in 24 middle-aged dogs treated with low-dose rapamycin showed suggestion of partial reversal of age-related heart dysfunction, as measured via echocardiography. The intervention was well-tolerated, with no clinically meaningful adverse events noted with a non-immunosuppressive dose of rapamycin during the 10 week period. This was a small study over a relatively short duration; further testing in larger clinical studies will be necessary to determine whether rapamycin can be used to treat age-related heart disease in dogs.

== Regulatory approval ==
Rapamycin was approved by the US Food and Drug Administration (FDA) in 1999 to prevent organ rejection in liver transplant patients, and has been marketed under the brand name Rapamune.<ref>[https://link.springer.com/article/10.1007/s11357-020-00274-1 Selvarani, R., Mohammed, S., & Richardson, A. (2020). Effect of rapamycin on aging and age-related diseases—past and future. ''GeroScience'', 1-24.]</ref> The patent on rapamycin has expired, and chemically similar compounds called 'rapalogs' are being researched by biotechnology companies.<ref>[https://pubs.acs.org/doi/full/10.1021/acsmedchemlett.9b00215 Abdel-Magid, A. F. (2019). Rapalogs potential as practical alternatives to rapamycin.]
</ref> It is not currently approved for use as an anti-aging medication, due to lack of human clinical data for this purpose.

== Safety ==
Rapamycin has been used to treat millions of patients over several decades since obtaining FDA approval in 1999. It is generally considered safe in humans, but only when used under clinical supervision for specific indications. Rapamycin and its analogs are immunosuppressants, and used as such in the clinic; some rapalogs have received “black-box” FDA warnings due to the risks of infection, as well as the potential risk of cancer due to suppression of tumor immune surveillance.<ref>https://www.pfizermedicalinformation.com/en-us/rapamune/boxed-warning</ref><ref>https://www.pdr.net/drug-summary/Afinitor-everolimus-416.6101</ref>

Various side effects have been reported with the dose of rapamycin used to prevent rejection in organ transplant patients, who are often concurrently treated with multiple other medications.<ref>Webster, A. C., Lee, V. W., Chapman, J. R., & Craig, J. C. (2006). Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. ''Transplantation'', ''81''(9), 1234-1248.</ref> These include pain, headache, fever, high blood pressure, glucose intolerance, new-onset diabetes, nausea, abdominal pain, constipation, diarrhea, thrombocytopenia, leukopenia, among others. However, side effects are mostly reversible (at least if therapy is rapidly discontinued) and represent worst-case scenarios, particularly because the patients sampled in clinical studies are already severely ill and taking the drug along with other medications.<ref>Bischof, E., Siow, R.C., Zhavoronkov, A. and Kaeberlein, M., 2021. The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), pp.e105-e111.
</ref> In subjects taking high doses of rapamycin and analogs for severe, chronic conditions including tuberous sclerosis complex, an inherited genetic disorder of increased mTOR signaling, or for cancer, the side effects have occasionally led life-threatening adverse events or death.<ref>Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W. Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anti-cancer drugs. 2015;26(4):437-42. PMID: [https://pubmed.ncbi.nlm.nih.gov/25719621/ 25719621] DOI: [https://doi.org/10.1097/cad.0000000000000207 10.1097/CAD.0000000000000207]</ref><ref>Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010; 116(18):4256-65. PMID: [https://pubmed.ncbi.nlm.nih.gov/20549832/ 20549832] DOI: [https://doi.org/10.1002/cncr.25219 10.1002/cncr.25219] </ref>

Case studies of the safety profile of rapamycin in the context of overdosing have suggested that it may have a large margin of safety or a high median lethal dose, but only in the acute setting.<ref>Ceschi, A., Heistermann, E., Gros, S., Reichert, C., Kupferschmidt, H., Banner, N. R., ... & Taegtmeyer, A. B. (2015). Acute sirolimus overdose: a multicenter case series. ''PLoS One'', ''10''(5), e0128033.</ref> The distinction with chronic high dose mTOR inhibition must be made because resultant immunosuppression can lead to susceptibility to infection with fatal consequences. Some preclinical data suggests that the longevity benefits of rapamycin may be retained via intermittent dosing.<ref name=":2" /> In considering the known clinical data about rapamycin's controversial safety at continuous, high doses, some researchers have proposed that rapamycin should dosed intermittently to minimize side effects while sufficiently inhibiting mTOR for an effect on aging.<ref name=":2" />

From a longevity perspective, there is a lack of published clinical data demonstrating the safety of rapamycin in healthy adults. One small randomized pilot study of rapamycin in 25 older adults aged 70-95 taking 1 mg/day of rapamycin reported finding no clinically significant effects, including a lack of effect on immune function.<ref name=":13">Kraig, E., Linehan, L. A., Liang, H., Romo, T. Q., Liu, Q., Wu, Y., ... & Kellogg Jr, D. L. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. ''Experimental gerontology'', ''105'', 53-69.</ref> However, laboratory results from this trial suggested that the subjects experienced negative metabolic effects, including a small increase in glycated hemoglobin (within-group p=0.03) and a 40% rise in triglyceride levels (within-group p=0.05).<ref>Lamming, D. Rapamycin and Rapalogs. Preprints 2021, 2021020491 (doi: [https://www.preprints.org/manuscript/202102.0491/v1 10.20944/preprints202102.0491.v1]).</ref> This was a small study with a low dose of rapamycin, dosed over a short duration of 8 weeks. Considering the fact that, based on preclinical animal data, any potential benefit of rapamycin for aging will require long-term dosing, further testing in clinical trials is necessary to better characterize safety.<ref name=":13" />

Clinical trials such as the PEARL study are needed to provide evidence for the safety profile of rapamycin in otherwise healthy older adults.

== Rapalogs ==
Despite mTOR being the prime target against many age-related and chronic pathologies, relatively few mTOR inhibitors have been developed to slow the aging process.<ref>Mao, B., Zhang, Q., Ma, L., Zhao, D. S., Zhao, P., & Yan, P. (2022). Overview of research into mTOR inhibitors. Molecules, 27(16), 5295. PMID: 36014530 PMC9413691 https://doi.org/10.3390/molecules27165295</ref> Rapalogs are molecules with similar mechanism to rapamycin, primarily via mTORC1 inhibition. These drugs are generally predicted to function similarly to rapamycin in enhancing lifespan and reducing age-related decline in physiological function. For example, small molecule, '''TKA001''', selected based on in silico predictions, extends the lifespan of ''Caenorhabditis elegans'', suggesting that TKA001 is able to slow aging in vivo.<ref>Vidovic, T., Dakhovnik, A., Hrabovskyi, O., MacArthur, M. R., & Ewald, C. Y. (2023). AI-Predicted mTOR Inhibitor Reduces Cancer Cell Proliferation and Extends the Lifespan of C. elegans. International journal of molecular sciences, 24(9), 7850. PMID: 37175557 PMC10177929 https://doi.org/10.3390/ijms24097850</ref>
However, only one rapalog, everolimus, has published clinical data in this context.<ref>[https://www.thelancet.com/servlet/linkout?suffix=e_1_5_1_2_55_2&dbid=8&doi=10.1016/S2666-7568(20)30068-4&key=24379984&cf= Kaeberlein, M. (2013). mTOR inhibition: from aging to autism and beyond. ''Scientifica'', ''2013''.]</ref> RTB101 has also been described as a selective mTOR inhibitor, but some controversy exists.<ref>Kaeberlein, M. (2020). RTB101 and immune function in the elderly: interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.</ref><ref>Bischof, E., Siow, R. C., Zhavoronkov, A., & Kaeberlein, M. (2021). The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19. ''The Lancet Healthy longevity'', ''2''(2), e105-e111.</ref>
Newer rapalogs have been discovered that are more selective for mTORC1 than rapamycin. One company that screened a library of modified rapalogs identified a compound, '''DL001''', with significantly greater (40 times more selective than rapamycin) selectivity for mTORC1 than rapamycin.<ref>Schreiber, K. H., Arriola Apelo, S. I., Yu, D., Brinkman, J. A., Velarde, M. C., Syed, F. A., ... & Lamming, D. W. (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nature communications, 10(1), 3194. PMID: 31324799 PMC: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642166/ 6642166] DOI: 10.1038/s41467-019-11174-0</ref> Mice treated with DL001 had reduced glucose intolerance, dyslipidemia and immune disruption as compared to mice treated in parallel with rapamycin. The ''in silico'' molecular docking analysis revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. These molecules can serve as macrocyclic scaffolds for developing new rapalog compounds targeting the mTOR.<ref>Parate, S., Kumar, V., Hong, J. C., & Lee, K. W. (2023). Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches. Computational Biology and Chemistry, 107875. https://doi.org/10.1016/j.compbiolchem.2023.107875</ref>

Antiemetic; piperazine-derivative antihistamine '''meclizine''', which is often available over the counter, is also found to be an mTOR inhibitor that male-specificly extends median lifespan in male mice by '''8%'''.<ref>Harrison, D. E., Strong, R., Reifsnyder, P., Rosenthal, N., Korstanje, R., Fernandez, E., ... & Miller, R. A. (2023). Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used. GeroScience, 1-22. PMID: 38041783 [https://doi.org/10.1007/s11357-023-01011-0 DOI: 10.1007/s11357-023-01011-0]</ref> Meclizine also is Toll-like receptor 4 (TLR4) inhibitor. Toll like receptors role is to detect pathogen molecules and initiate an immunologic response to them especially through production of pro-inflammatory cytokines and increased levels of type I interferon production.<ref>Zali, H., Golchin, A., Farahani, M., Yazdani, M., Ranjbar, M. M., & Dabbagh, A. (2019). FDA approved drugs repurposing of Toll-like receptor4 (TLR4) candidate for neuropathy. Iranian Journal of Pharmaceutical Research: IJPR, 18(3), 1639. PMID: 32641971 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934974/ PMC6934974] DOI: 10.22037/ijpr.2019.2394</ref>

=== mTOR inhibition improves immune function in the elderly ===

In a phase 2 randomized clinical trial published in ''Science Translational Medicine'' in 2014, low-dose TORC1 inhibition with the rapalog everolimus showed improvement in immune function in the elderly. The clinical trial enrolled 218 adults aged ≥65 years, observing decreased incidence of all infections, as well as improved influenza vaccination responses and upregulation of antiviral immunity.<ref name=":17">Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref>

Everolimus enhanced the influenza vaccine response by approximately 20% at relatively well tolerated doses.<ref name=":17" /> One mechanism was related to a reduction in the percentage of CD4 and CD8 T cells expressing the programmed death-1 receptor, which has increased expression with age and a major role in inhibiting T cell signaling.<ref name=":17" /> These findings suggest that, at an appopriate dose, mTOR inhibition may improve the age-related decline in immune function in the elderly.

=== TORC1 inhibition enhances immune function and reduces infections in the elderly ===

A phase 2a trial clinical trial randomized 264 older adults to treatment with everolimus and placebo, and was published in ''Science Translational Medicine'' in 2018. The trial showed potential for reducing the effects of immune aging, with improvement in influenza vaccination response in the elderly.<ref name=":1">Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref>[[File:Rtb101 Ph2 Ph3.jpg|thumb|461x461px|A) Number of patients with laboratory-confirmed RTIs of ''any severity'' caused by specific viruses, comparing RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 RCTs B) Number of patients with laboratory-confirmed RTIs with ''severe symptoms'' caused by specific viruses in the RTB101 group (blue) versus placebo (grey) in the phase 2b, phase 3, and combined phase 2b/3 trials. RTI = respiratory tract infection]]

=== Improving immune function in older adults for respiratory tract infections, including coronaviruses ===
Low-dose mTOR inhibition with dactolisib in a Phase 2b and phase 3 trial in the elderly showed reduced coronavirus (non [[COVID-19]]) incidence, as well as reductions in severe symptoms.<ref name=":12">Mannick, J. B., Teo, G., Bernardo, P., Quinn, D., Russell, K., Klickstein, L., ... & Shergill, S. (2021). Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials. ''The Lancet Healthy Longevity'', ''2''(5), e250-e262.</ref> However, the data remains inconclusive as the study was powered statistically for a reduction in clinically symptomatic respiratory tract infections (RTIs), and not laboratory-confirmed RTIs.<ref name=":12" />

Following the success of two phase 2 clinical trials investigating mTOR inhibition for targeting the aging immune system, dactolisib is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial (ClinicalTrials.gov Identifier: NCT04584710, NCT04409327), exploring the potential for preventing severe disease in elderly adults with no symptoms, who have been exposed to [[COVID-19]].<ref name=":12" />

Unpublished data from the phase 2 trial of RTB101 for COVID-19 among nursing home patients treated within 3 days from testing positive saw promising results. None of those treated with RTB101 developed symptoms (n=18), while the placebo treated control group had 4 severe cases of disease and 2 deaths. While this was a statistically significant finding, larger trials are warranted for further evidence of potential benefit.

This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the National Institute on Aging (NIA/NIH). The studies with dactolisib for COVID-19 is one of several clinical trials in the aging biology field aiming to target aging to improve the aging immune system.<ref name=":12" />

== See also ==
* [https://en.longevitywiki.org/wiki/Isomyosamine Isomyosamine] ('''MYMD-1®''') <ref>Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. 78(2), 227-235 PMID 35914953 doi:10.1093/gerona/glac142</ref>

== References ==
<references />
[[Category:Drugs]]
[[Category:Main list]]
[[Category:Fundamentals]]

Senolytics

2023-09-25T11:39:09Z

Geroscientist: /* Senescent cells as a factor of aging and age-associated diseases */

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]], remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref>[[Cellular senescence|Cellular Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.

==== Markers of cellular senescence ====
The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21<sup>CIP1/WAF1</sup>,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16<sup>INK4a</sup>, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the de-repression of the '''p16<sup>INK4a</sup>''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been shown that the removal of senescent p16<sup>INK4a</sup>-positive cells can slow the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> However, whether cells that express '''p16<sup>INK4a</sup>''' are actually 'senescent cells', and if removal of such cells could cause harm in specific contexts has been questioned by more recent work.<ref name=":1" /> Moreover, a limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations of the genome. It can instead be easier to use small molecule senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics are thought to start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells, such as by differentiation of resident stem cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Notably, this is dependent on the availability of stem cell pools which are known to decline with aging, and this has been identified as a theoretical limitation of senolytics, if the lack of such stem cells means new tissue is not formed. It has also been speculated that '''if''' '''the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref>

=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== ARV825 ====
Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, ARV-825, that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

==== Senolytic CAR T cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/>
Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

<ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref>
<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref>
<ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref name=":0">Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
<references />
{{Draft-article}}
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Senolytics

2023-09-25T11:21:54Z

Geroscientist: /* Prehistory */

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]], remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref>[[Cellular senescence|Cellular Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.

==== Markers of cellular senescence ====
The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21<sup>CIP1/WAF1</sup>,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16<sup>INK4a</sup>, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the de-repression of the '''p16<sup>INK4a</sup>''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been shown that the removal of senescent p16<sup>INK4a</sup>-positive cells can slow the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> A limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations of the genome. It can instead be easier to use small molecule senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Thus, the tissue is rejuvenated. '''If the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref>

=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== ARV825 ====
Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, ARV-825, that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

==== Senolytic CAR T cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/>
Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

<ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref>
<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref>
<ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref name=":0">Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
<references />
{{Draft-article}}
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Senolytics

2023-09-25T11:18:54Z

Geroscientist: /* Senescent cells as a factor of aging and age-associated diseases */

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]], remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref>[[Cellular senescence|Cellular Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.

The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21<sup>CIP1/WAF1</sup>,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16<sup>INK4a</sup>, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the derepression of the '''p16<sup>INK4a</sup>''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been proven that the removal of senescent p16<sup>INK4a</sup>-positive cells can successfully slow down the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> A limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations with the genome. It is much easier to use for this purpose small molecules of senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Thus, the tissue is rejuvenated. '''If the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref>

=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== ARV825 ====
Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, ARV-825, that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

==== Senolytic CAR T cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/>
Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

<ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref>
<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref>
<ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref name=":0">Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
<references />
{{Draft-article}}
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Senolytics

2023-09-25T11:17:36Z

Geroscientist: /* Senescent cells as a factor of aging and age-associated diseases */

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]], remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main causes or predisposing factors to developing [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
One key factor causing the decline of tissue homeostasis, systemic inflammation, DNA damage etc. that contribute to disease are the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref>[[Cellular senescence|Cellular Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells are sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>

Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" />.
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.

The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21<sup>CIP1/WAF1</sup>,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16<sup>INK4a</sup>, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the derepression of the '''p16<sup>INK4a</sup>''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been proven that the removal of senescent p16<sup>INK4a</sup>-positive cells can successfully slow down the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> A limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations with the genome. It is much easier to use for this purpose small molecules of senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Thus, the tissue is rejuvenated. '''If the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref>

=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== ARV825 ====
Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, ARV-825, that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

==== Senolytic CAR T cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/>
Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

<ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref>
<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref>
<ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref name=":0">Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
<references />
{{Draft-article}}
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Senolytics

2023-09-25T11:00:48Z

Geroscientist:

'''Senolytics''' (from ''senile'' - decrepit and ''lytic'' - lysing, destroying) - a class of drugs thought to target aging, a distinctive feature of which is the ability to selectively initiate the death of 'aged' cells<ref name="discovery">Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518-536. PMID: 32686219 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395 link] DOI: 10.1111/joim.13141 </ref><ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref>

== Prehistory ==
The appearance of senolytics was foreseen in the 19th century in studies of the effect of highly dilute solutions of hydrogen cyanide, called prussic acid, on cell survival. It was found that unlike young cells, old and cancerous cells quickly die from such exposure.<ref>Ageing: The Biology of Senescence. By Alex Comfort. Pp. xvi + 365 London: Routledge and Kegan Paul, 1964. Second Edition.</ref> These data were used to scientifically explain a paradox known since ancient times as '''mithridatism''' and later called '''[[hormesis]]''': '''taking very small doses of a non-cumulative poison sometimes leads to better health'''.<ref>Calabrese, E. J. (2014). Hormesis: a fundamental concept in biology. Microbial cell, 1(5), 145. PMID: 28357236 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598 link] DOI: 10.15698/mic2014.05.145</ref>
Obviously, toxins such as hydrogen cyanide, by means of [[Mitochondrial dysfunction#Mitohormesis|mitohormesis]], remove old cells with defective mitochondria unable to withstand temporary hypoxia.<ref>Lin, C. L. (2022). Mitophagy and mitohormetics: Promising antiaging strategy. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging (pp. 279-289). Academic Press. https://doi.org/10.1016/B978-0-323-90235-9.00001-X</ref>

In 1837, the German scientists von Liebig and Woehier found that hydrogen cyanide can be obtained from the constituent of apricot seeds and bitter almonds '''the cyanogenic glycoside amygdalin'''. Its simpler derivative obtained by amygdalin hydrolysis referred to as '''laetrile '''(patented 1961) or '''vitamin B17''', although it is not classified as a vitamin, are still sold as dietary supplements. It was discovered that low doses of amygdalin may exhibit protective effects, yet higher amygdalin concentrations may be toxic to the biological system.<ref>Iyanu Oduwole, A. A. (2020). Amygdalin-therapeutic effects and toxicity. Journal of Biotechnology and Biomedicine, 3(2), 39-49. </ref><ref>Saberi-Hasanabadi, P., & Shaki, F. (2022). The Pharmacological Activities and Toxicological Effects of Amygdalin: A Review. Pharmaceutical and Biomedical Research, 8(1), 1-12. http://pbr.mazums.ac.ir/article-1-387-en.html</ref> Rumors about the healthy aging effect of amygdalin were added to by stories about centenarians among the Hunza people who use apricot seeds as food.<ref>Percy, C. (1974). You Live to Be 100 in Hunza. Parade, 11. </ref>

A principle of synergistic synthetic lethality was developed to search for drugs that have a detrimental effect on the cell only when they are combined.<ref>Simons, A., Dafni, N., Dotan, I., Oron, Y., & Canaani, D. (2001). Establishment of a chemical synthetic lethality screen in cultured human cells. Genome research, 11(2), 266-273. PMID: 11157789 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC311022 link] DOI: 10.1101/gr.154201</ref> “Synthetic lethality” is defined as a type of interaction in which the combination of harmful to the cell influence results in cell death. Synthetic lethality is thought to kill cancer or senescent cells specifically without affecting normal cells by acting on specific genes or common molecular pathways regulated in the aging or carcinogenesis process. <ref name="Synthetic">Tozaki, Y., Aoki, H., Kato, R., Toriuchi, K., Arame, S., Inoue, Y., ... & Aoyama, M. (2023). The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells. Cancers, 15(3), 735. PMID: 36765693 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9913148 link] DOI: 10.3390/cancers15030735</ref>

== [[Cellular senescence|Senescent cells]] as a factor of aging and age-associated diseases ==
The progressive and gradual decline of an aging body is one of the main etiological causes of the onset and development of [[Age-related diseases|aging-related diseases]], such as [[CVD (cardiovascular disease)]], [[Neoplasms|cancer]], [[Diabetes mellitus type 2|diabetes]], and [[Chronic kidney disease|kidney disease]], ultimately [[Causes of death by rate|leading to death]].
[[File:Role of cell competition in ageing.jpg|thumb|Role of cell competition in ageing according to Marques-Reis & Moreno 2021.<ref name="compet">Marques-Reis, M., & Moreno, E. (2021). Role of cell competition in ageing. Developmental Biology, 476, 79-87. PMID: 33753080 DOI:[https://doi.org/10.1016/j.ydbio.2021.03.009 link]</ref>]]
The primary causal factor in the decline of tissue homeostasis and at the same time a consequence of other aging processes such as inflammation and DNA damage are obviously the so-called senescent cells that are known to accumulate with aging.<ref>Reed, R., & Miwa, S. (2023). Cellular Senescence and Ageing. In Biochemistry and Cell Biology of Ageing: Part III Biomedical Science (pp. 139-173). Cham: Springer International Publishing. PMID: 36600133 DOI:[https://doi.org/10.1007/978-3-031-21410-3_7 link]</ref><ref>Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020). A senescence-centric view of aging: implications for longevity and disease. Trends in Cell Biology, 30(10), 777-791. PMID: 32800659 DOI:[https://doi.org/10.1016/j.tcb.2020.07.002 link]</ref><ref>Van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. PMID: 24848057; PMCID: PMC4214092 link] doi: 10.1038/nature13193</ref> [[Cellular senescence|Senescence]] is a form of durable cell cycle arrest elicited in response to a wide range of stimuli. Senescent cells sometimes referred to as "old" or "zombie" cells are cells that have stopped dividing and growing but remain metabolically active.<ref name="zombies">Scudellari, M. (2017). To stay young, kill zombies. Nature, 550(7677), 448-450. PMID: 29072283 DOI:[https://doi.org/10.1038/550448a link]</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref>
[[File:Senescent.jpg|thumb| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),
e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.
Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.

The negative impact of SASP components on the body can be weakened by removing aged cells. There is no single biomarker present in all senescent cells, and conversely the presence of a single biomarker is not a hard indication that a cell is senescent. Therefore identification of senescent cells generally involves multiple biomarkers, of which '''senescence-associated pH6 β-galactosidase,<ref name="Dimri">Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., ... & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences, 92(20), 9363-9367. PMID: 7568133 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985 link] DOI: 10.1073/pnas.92.20.9363</ref> p21<sup>CIP1/WAF1</sup>,<ref>Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., ... & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, 101652. PMID: 36509362 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800630 link] DOI: 10.1016/j.molmet.2022.101652</ref> p16<sup>INK4a</sup>, and intracellular [[lipofuscin]] accumulation<ref>Evangelou, K., Lougiakis, N., Rizou, S. V., Kotsinas, A., Kletsas, D., Muñoz‐Espín, D., ... & Gorgoulis, V. G. (2017). Robust, universal biomarker assay to detect senescent cells in biological specimens. Aging cell, 16(1), 192-197. PMID: 28165661 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242262 link] DOI: 10.1111/acel.12545</ref> are prominent'''.<ref>Berardi, D., Farrell, G., Al Sultan, A., McCulloch, A., Rattray, Z., & Rattray, N. J. (2022). Integration of mass-spectrometry-based metabolomics and proteomics to characterise different senescence induced molecular sub-phenotypes. bioRxiv, 2022-11. https://doi.org/10.1101/2022.11.30.518588</ref>
One of the signs of a cell switching to the path of irreversible aging is the derepression of the '''p16<sup>INK4a</sup>''' gene, which maintains the viability of senescent cells by preventing their apoptosis.<ref>Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., ... & Van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236. PMID: 22048312 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323 link] DOI: 10.1038/nature10600</ref> It has been proven that the removal of senescent p16<sup>INK4a</sup>-positive cells can successfully slow down the progression of age-related disorders even at later stages of life.<ref>Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., ... & Van Deursen, J. M. (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature, 530(7589), 184-189. PMID: 26840489 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845101 link] DOI: 10.1038/nature16932</ref><ref>Guzman, S. D., Judge, J., Shigdar, S. M., Paul, T. A., Davis, C. S., Macpherson, P. C., ... & Brooks, S. V. (2022). Removal of p16INK4 expressing cells in late life has moderate beneficial effects on skeletal muscle function in male mice. Frontiers in Aging, 2, 85. PMID: 35821997 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261355 link] DOI: 10.3389/fragi.2021.821904</ref> A limitation of this approach and similar methods that use genetic engineering<ref>Merino, M. M., Rhiner, C., Lopez-Gay, J. M., Buechel, D., Hauert, B., & Moreno, E. (2015). Elimination of unfit cells maintains tissue health and prolongs lifespan. Cell, 160(3), 461-476. PMID: 25601460 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313366 link] DOI: 10.1016/j.cell.2014.12.017</ref> is the need for manipulations with the genome. It is much easier to use for this purpose small molecules of senolytics capable of activating the process of selective destruction of aged cells.

By removing aged cells, senolytics start the “on demand” regeneration process, the purpose of which is to fill the formed space with new cells.<ref>Dungan, C. M., Murach, K. A., Zdunek, C. J., Tang, Z. J., VonLehmden, G. L., Brightwell, C. R., ... & Peterson, C. A. (2022). Deletion of SA β‐Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell, 21(1), e13528. PMID: 34904366 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761017 link] DOI: 10.1111/acel.13528</ref> Thus, the tissue is rejuvenated. '''If the senolytic is an antineoplastic drug, the risk of carcinogenesis is reduced due to the simultaneous removal of oncogenic cells that would otherwise provoke the formation of a tumor'''.<ref>López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023). Meta-hallmarks of aging and cancer. Cell Metabolism, 35(1), 12-35. PMID: 36599298 DOI:[https://doi.org/10.1016/j.cmet.2022.11.001 link]</ref>

== Small molecules of senolytics ==
[[File:Classification of senolytics.jpg|thumb|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref>

=== [[Dasatinib]] + [[Quercetin]] ===
[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.
D and Q have side effects, including hematologic dysfunction, fluid retention, skin rash, and QT prolongation.<ref>Breccia, M., Molica, M., & Alimena, G. (2014). How tyrosine kinase inhibitors impair metabolism and endocrine system function: a systematic updated review. Leukemia research, 38(12), 1392-1398. PMID: 25449685 DOI:[https://doi.org/10.1016/j.leukres.2014.09.016 link]</ref>

Removal of SCs can improve healthspan and lifespan in animal models of premature aging and normal aging. However, some studies suggest that SCs play a fundamental role in physiology and their removal via senolytics or other methods might have deleterious effects ''in vivo''.<ref>Born, E. ''et al.'' (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” ''Circulation''[Preprint]. Available at: <nowiki>https://doi.org/10.1161/circulationaha.122.058794</nowiki>.</ref>

The use of one of the senolytics, dasatinib, caused endothelial dysfunction and pulmonary hypertension, which could be corrected using ROCK inhibitors.<ref>Fazakas, C., Nagaraj, C., Zabini, D., et al., & Bálint, Z. (2018). Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. Frontiers in physiology, 9. 9: 537 doi: 10.3389/fphys.2018.00537 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962749 link]</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 34776414 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448 link] DOI: 10.5045/br.2021.2021117</ref>

Treatment with dasatinib has been linked to some uncommon adverse events, such as pleural effusion (PE) and pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is a life-threatening condition associated with long-term dasatinib therapy, especially in patients with pleural effusion. In the absence of timely treatment, PAH may lead to right ventricular failure. The majority of patients who experienced PAH were female with history or present PE receiving long-term treatment with dasatinib. Animal studies confirmed that dasatinib increased the biological activities of endothelial dysfunction markers (e.g., soluble vascular cell adhesion molecule 1 [VCAM-1], soluble intercellular adhesion molecule 1 [ICAM-1], and soluble E-selectin), leading to minimization of hypoxic vasoconstriction and impairment of endoplasmic reticulum function.<ref>Guignabert, C., Phan, C., Seferian, A., Huertas, A., Tu, L. Y., Thuillet, R., ... & Humbert, M. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126(9), 3207-3218. PMID: 27482885 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004960 link] DOI: 10.1172/JCI86249</ref><ref>Nekoukar, Z., Moghimi, M., & Salehifar, E. (2021). A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities. Blood research, 56(4), 229-242. PMID: 32527740 DOI:[https://doi.org/10.1183/13993003.00279-2020 link]</ref><ref>Cheng, F., Xu, Q., Li, Q., Cui, Z., Li, W., & Zeng, F. (2023). Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies. Frontiers in Oncology, 13, 349. </ref>

Studies in mice that also demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.<ref>Khosla, S. (2023). Senescent cells, senolytics and tissue repair: the devil may be in the dosing. Nature Aging, 1-3. https://doi.org/10.1038/s43587-023-00365-6</ref>

Use of dasatinib and quercetin has not always been efficacious in every mouse model of metabolic disease, its efficacy seems to be controversial. Although this senolytic cocktail was shown to decrease the burden of senescent cells and reduce hepatic steatosis in one study,<ref>Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., ... & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8: 15691. </ref> it failed to promote clearance of senescent cells and prevent progression of non-alcoholic fatty liver disease in lean mice and in mice with obesity induced by a high-fat diet.

In the pilot study [https://clinicaltrials.gov/study/NCT02874989 NCT02874989] of the senolytic combination of dasatinib and quercetin (D + Q) for only three weeks in patients with an age-related, chronic idiopathic pulmonary fibrosis (IPF) results suggest that (D + Q) is safe and does not lead to an increase of severe adverse events (AE). However, authors did report on an increase in non-serious AEs, including feeling unwell, cough, nausea, fatigue, weakness, and headache. While these side effects do not pose life-threatening consequences, these complaints could ultimately limit compliance with (D + Q) therapy. For instance, cough is already a problem for many IPF patients and gastrointestinal side effects remain a major factor limiting the tolerability of existing IPF anti-fibrotic treatments.<ref>Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., ... & Kirkland, J. (2023). Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 90. PMID: 36857968 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006434 PMC10006434] [https://doi.org/10.1016/j.ebiom.2023.104481 DOI: 10.1016/j.ebiom.2023.104481]</ref>

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid polyphenol plant dye that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, persimmons, cucumbers, and onions.<ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant for health promotion. Antioxidants & redox signaling, 19(2), 151-162. PMID: 23121441 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181 link] DOI: 10.1089/ars.2012.4901</ref><ref>Kubina, R., Krzykawski, K., Kabała-Dzik, A., Wojtyczka, R. D., Chodurek, E., & Dziedzic, A. (2022). Fisetin, a potent anticancer flavonol exhibiting cytotoxic activity against neoplastic malignant cells and cancerous conditions: A scoping, comprehensive review. Nutrients, 14(13), 2604. PMID: 35807785 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268460 link] DOI: 10.3390/nu14132604</ref> <ref name="Fisetin" >Yousefzadeh, M. J., Zhu, Y. I., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., ... & Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 36, 18-28. PMID: 30279143 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652 link] DOI: 10.1016/j.ebiom.2018.09.015</ref>

Fisetin has manifested several health benefits in preclinical models of neurodegenerative diseases such as Alzheimer's disease, Vascular dementia, and Schizophrenia. Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Stroke, Traumatic Brain Injury (TBI), and age-associated changes.<ref>Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022). Fisetin as a senotherapeutic agent: biopharmaceutical properties and crosstalk between cell senescence and neuroprotection. Molecules, 27(3), 738. PMID: 35164003 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8839434 link] DOI: 10.3390/molecules27030738</ref><ref>Ravula, A. R., Teegala, S. B., Kalakotla, S., Pasangulapati, J. P., Perumal, V., & Boyina, H. K. (2021). Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. European Journal of Pharmacology, 910, 174492. PMID: 34516952 DOI:[https://doi.org/10.1016/j.ejphar.2021.174492 link]</ref>

Fisetin also demonstrates an anti-diabetic effect through its α-glucosidase inhibitor activity and anti-oxidant activity.<ref>Shen, B., Shangguan, X., Yin, Z., Wu, S., Zhang, Q., Peng, W., ... & Chen, J. (2021). Inhibitory effect of fisetin on α-glucosidase activity: Kinetic and molecular docking studies. Molecules, 26(17), 5306. PMID: 34500738 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434554 link] DOI: 10.3390/molecules26175306</ref><ref>Qian, X., Lin, S., Li, J., Jia, C., Luo, Y., Fan, R., ... & Chen, Y. (2023). Fisetin Ameliorates Diabetic Nephropathy-Induced Podocyte Injury by Modulating Nrf2/HO-1/GPX4 Signaling Pathway. Evidence-Based Complementary and Alternative Medicine, 2023. Article ID 9331546 https://doi.org/10.1155/2023/9331546</ref> Fiestin could inhibit the development of diabetic cardiomyopathy by ameliorating hyperglycemia/hyperlipidemia-mediated oxidative stress in STZ rat cardiomyocytes, preventing inflammation and apoptosis, and enhancing the antioxidant capacity.<ref>Althunibat, O. Y., Al Hroob, A. M., Abukhalil, M. H., Germoush, M. O., Bin-Jumah, M., & Mahmoud, A. M. (2019). Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Life sciences, 221, 83-92. PMID: 30742869 DOI:[https://doi.org/10.1016/j.lfs.2019.02.017 link]</ref> Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evidence-Based Complementary and Alternative Medicine, 2012. PMID: 23320034 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539716 link] DOI: 10.1155/2012/639469</ref> Fisetin has been shown to attenuate obesity and regulate glucose metabolism in a small single-blind, controlled study in Iraq that investigate the effects of 8 weeks of fisetin (100 mg/day) with obese diabetic patients (21 males and 30 females), and could aid as a complementary anti-obesity agent in the treatment of obese diabetic patients.<ref>Hasoon, D. A. A. W., Kadhim, K. A., Rahmah, A. M., & Alabbassi, M. G. (2023). Potential Effect of Fisetin in A sample of Obese Diabetic Patients in Iraq. HIV Nursing, 23(2), 277-283. https://www.hivnursing.net/index.php/hiv/article/view/1356</ref>

In aged tissues, fisetin can induce apoptosis specifically in senescent cells and reduce the level of cellular oxidative damage. <ref name="inhibitors" >Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., ... & Kirkland, J. L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY), 9(3), 955. PMID: 28273655 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391241 link] DOI: 10.18632/aging.101202</ref>

'''Dietary supplementation with fisetin significantly increase both the mean and maximum lifespan in old mice''', reducing markers of tissue aging and age-related pathologies even when treatment was initiated in older animals.<ref name="Fisetin" />

In ''Caenorhabditis elegans'' fisetin increased the resistance to oxidative stress, but failed to reduce the accumulation of such an aging marker as lipofuscin.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 DOI:[https://doi.org/10.1007/s00204-007-0215-4 link]</ref> However, both the mean and maximum lifespans were significantly extended by fisetin in ''Caenorhabditis elegans''.<ref name="elegans">Park, S., Kim, B. K., & Park, S. K. (2022). Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans. Pharmaceuticals, 15(12), 1528. PMID: 36558979 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786162 link] DOI: 10.3390/ph15121528</ref> '''Lifespan extension by fisetin was accompanied by reduced fertility''' as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin.<ref name="elegans"/> Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy.<ref name="elegans"/>

Fisetin showed more enhanced senotherapeutic activity than quercetin in animal and human tissues,<ref name="inhibitors"/> and is currently undergoing several clinical trials for multiple age-related diseases, including osteoarthritis (NCT04815902, NCT04210986, NCT04770064), coronavirus infection (NCT04771611, NCT04476953, NCT04537299), frail elderly syndrome (NCT03675724, NCT04733534, NCT03430037), chronic kidney diseases (NCT03325322), and femoroacetabular impingement (NCT05025956). Therefore, the clinical merits of fisetin in terms of feasibility, safety, tolerability, and efficacy could soon be established and employed in geriatric medicine.<ref>Mbara, K. C., Devnarain, N., & Owira, P. M. (2022). Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection. Pharmaceutical Medicine, 36(6), 331-352. PMID: 36100824 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9470070 link] DOI: 10.1007/s40290-022-00444-w</ref>

=== Curcumin ===
Although many consider curcumin and its derivatives to be senolytic,<ref>Cherif, H., Bisson, D. G., Jarzem, P., Weber, M., Ouellet, J. A., & Haglund, L. (2019). Curcumin and o-vanillin exhibit evidence of senolytic activity in human IVD cells in vitro. Journal of Clinical Medicine, 8(4), 433. PMID: 30934902 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518239 link] DOI: 10.3390/jcm8040433</ref>, there is clear evidence that curcumin does not have selectivity for senescent cells and kills both old and normal cells equally effectively.<ref>Beltzig, L., Frumkina, A., Schwarzenbach, C., & Kaina, B. (2021). Cytotoxic, genotoxic and senolytic potential of native and micellar curcumin. Nutrients, 13(7), 2385. PMID: 34371895 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308652 link] DOI: 10.3390/nu13072385</ref> However, due to principle of synergistic synthetic lethality,<ref name="Synthetic" /> its analog '''EF24''' can have a senolytic effect in combination with other senolytics.<ref>Li, W., He, Y., Zhang, R., Zheng, G., & Zhou, D. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY), 11(2), 771. PMID: 30694217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366974 link] DOI: 10.18632/aging.101787</ref><ref>Karthika, C. et al. (2023). The Role of Curcumin as an Anti-Aging Compound. In: Rizvi, S.I. (eds) Emerging Anti-Aging Strategies. Springer, Singapore. https://doi.org/10.1007/978-981-19-7443-4_11</ref>

=== Zoledronate ===
Zoledronic acid (ZA) is an effective nitrogen-containing bisphosphonate (NBP), which not only directly induces the apoptosis of tumor cells but also reduces the ''in vivo'' amount of tumor-associated macrophages and facilitates the transformation of tumor-associated macrophages into M1 macrophages.<ref>Wang, L., Liu, Y., Zhou, Y., Wang, J., Tu, L., Sun, Z., ... & Luo, F. (2019). Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways. Journal of Experimental & Clinical Cancer Research, 38(1), 1-18. PMID: 30791957 PMCID: PMC6385443 DOI: 10.1186/s13046-019-1109-z</ref><ref>Lv, J., Chen, F. K., Liu, C., Liu, P. J., Feng, Z. P., Jia, L., ... & Deng, Z. Y. (2020). Zoledronic acid inhibits thyroid cancer stemness and metastasis by repressing M2-like tumor-associated macrophages induced Wnt/β-catenin pathway. Life sciences, 256, 117925.</ref> Large clinical trials found that zoledronate treatment has been associated with ~30% reductions in mortality.<ref>Reid, I. R., Horne, A. M., Mihov, B., Stewart, A., Garratt, E., Bastin, S., & Gamble, G. D. (2020). Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. Journal of Bone and Mineral Research, 35(1), 20-27. PMID: 31603996 DOI: 10.1002/jbmr.3860</ref><ref>Cengiz, Ö., Polat, G., Karademir, G., Tunç, O. D., Erdil, M., Tuncay, İ., & Şen, C. (2016). Effects of zoledronate on mortality and morbidity after surgical treatment of hip fractures. Advances in orthopedics, 2016.2016:3703482 PMID: 27092280 PMCID: PMC4820612 DOI: 10.1155/2016/3703482</ref>
''In vitro'', zoledronate exhibited potent senolytic effects with a high selectivity index on both human and mouse senescent cells; (2) ''in vivo'', in aged mice, treatment with zoledronate was associated with a significant reduction in a panel of circulating SASP factors concomitant with an improvement in grip strength.<ref>Samakkarnthai, P., Saul, D., Zhang, L., Aversa, Z., Doolittle, M. L., Sfeir, J., ... & Khosla, S. (2023). In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers. bioRxiv, 2023-02. PMID: 36865244 PMCID: PMC9980119 DOI: 10.1101/2023.02.23.529777</ref>

=== Anthocyanin ===
Anthocyanins are natural water-soluble pigments of fruits, and flowers that, due to their antioxidant, anti-inflammatory, antitumoral, and antimicrobial properties are responsible for a plethora of health beneficial functions as dietary antioxidants, that can fight free radicals which raise the risk of chronic diseases onset such as: neuronal disorders, inflammatory conditions, diabetes, obesity, cardiovascular diseases and cancer.<ref>Nistor, M., Pop, R., Daescu, A., Pintea, A., Socaciu, C., & Rugina, D. (2022). Anthocyanins as Key Phytochemicals Acting for the Prevention of Metabolic Diseases: An Overview. Molecules, 27(13), 4254. PMID: 35807504 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268666 link] DOI: 10.3390/molecules27134254</ref>
The main mechanism by which anthocyanins are believed to have the ability to prevent the development of aging diseases is related to their antioxidant capacity by which they diminish prooxidative damage.<ref>Tena, N., Martín, J., & Asuero, A. G. (2020). State of the art of anthocyanins: Antioxidant activity, sources, bioavailability, and therapeutic effect in human health. Antioxidants, 9(5), 451. PMID: 32456252 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278599 link] DOI: 10.3390/antiox9050451</ref><ref>Dong, Y., Wu, X., Han, L., Bian, J., He, C., El-Omar, E., ... & Wang, M. (2022). The potential roles of dietary anthocyanins in inhibiting vascular endothelial cell senescence and preventing cardiovascular diseases. Nutrients, 14(14), 2836. PMID: 35889793 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316990 link] DOI: 10.3390/nu14142836</ref>

Anthocyanin has been shown to inhibit the PI3K/Akt/mTOR signaling pathway of senescent cells, leading to an increase in the ratios of pro-apoptotic to anti-apoptotic proteins Bax/Bcl-2 and Bak/Mcl-1 in anthocyanin-treated cells, suggesting that anthocyanin induces apoptosis in aging cells. These results suggested that anthocyanin might promote the clearance of senescent cells by increasing apoptosis and the proportion of healthy cells. Anthocyanin also enhanced autophagic and mitophagic flux in the senescent cells.<ref>Hu, X., Yang, Y., Tang, S., Chen, Q., Zhang, M., Ma, J., ... & Yu, H. (2023). Anti-Aging Effects of Anthocyanin Extracts of Sambucus canadensis Caused by Targeting Mitochondrial-Induced Oxidative Stress. International Journal of Molecular Sciences, 24(2), 1528.</ref>

=== Cycloastragenol ===
Cycloastragenol, a secondary metabolite isolated from ''Astragalus membrananceus'' has a wide spectrum of pharmacological functions, including [[Telomeres|telomere]] elongation, [[telomerase]] activation, anti-inflammatory effects, antioxidative properties<ref>Yu, Y., Zhou, L., Yang, Y., & Liu, Y. (2018). Cycloastragenol: An exciting novel candidate for age‑associated diseases. Experimental and therapeutic medicine, 16(3), 2175-2182. PMID: 30186456 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122403 link] DOI: 10.3892/etm.2018.6501</ref> and potent senolytic, which selectively induces cell death in senescent cells via induction of apoptosis by inhibiting the [[Bcl-2 antiapoptotic family proteins]] and PI3K/AKT/mTOR pathway. <ref name="astragenol">Zhang, Y., Gao, D., Yuan, Y., Zheng, R., Sun, M., Jia, S., & Liu, J. (2023). Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice. International Journal of Molecular Sciences, 24(7), 6554. https://doi.org/10.3390/ijms24076554</ref> Cycloastragenol also suppresses [[SASP]] expression, meaning it can act as a [[senomorphic]] to reduce the impact of senescent cells on the age-related phenotype.<ref name="astragenol" />

=== Fibrates ===
Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

=== p53-regulated apoptosis inducers ===
==== FOXO4-DRI ====
The Forkhead box protein O4 D-retro inverso (FOXO4-DRI), a synthetic peptide of D-amino acids in a reversed sequence, leads to senescent cell apoptosis by interrupting the interaction between [[FOXO4]] and [[p53]], leading to release of p53 available to trigger p53 mediated apoptosis. <ref name="PMC5556182">Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147. PMID: 28340339 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182 link] DOI: 10.1016/j.cell.2017.02.031</ref> Experiments show that FOXO4-DRI can reduce senescence and features of frailty in a fast aged mice model (XpdTTD/TTD) and also can restore loss of renal function in both naturally and fast aged mice.<ref name="PMC5556182"/>

In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.<ref>Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., ... & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY), 12(2), 1272.PMID: 31959736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614 link] DOI: 10.18632/aging.102682</ref> FOXO4-DRI have also been shown to selectively kill senescent chondrocytes.<ref>Huang, Y., He, Y., Makarcyzk, M. J., & Lin, H. (2021). Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Frontiers in Bioengineering and Biotechnology, 9, 677576. PMID: 33996787 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695 link] DOI: 10.3389/fbioe.2021.677576</ref>

==== UBX0101 ====
UBX-0101 is an experimental senolytic that can selectively remove senescent chondrocytes by inhibiting MDM2/p53 interactions. Despite initial promising results that were seen preclinically,<ref>Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., ... & Elisseeff, J. H. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.</ref> and in the phase 1 trial,<ref>Hsu, B., Visich, J., Lane, N. E., Li, L., Mittal, J., An, M., ... & Dananberg, J. (2020). Safety, tolerability, pharmacokinetics, and clinical outcomes following treatment of painful knee osteoarthritis with senolytic molecule UBX0101. Osteoarthritis and Cartilage, 28, S479-S480.</ref> no significant difference was observed between the placebo or UBX-0101-treated group of patients with knee osteoarthritis in a phase 2 trial.<ref>Lane, N., Hsu, B., Visich, J., Xie, B., Khan, A., & Dananberg, J. (2021). A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis. Osteoarthritis and Cartilage, 29, S52-S53. DOI:[https://doi.org/10.1016/j.joca.2021.02.077 10.1016/j.joca.2021.02.077]</ref> -

==== CUDC-907 ====
CUDC-907, a drug already in clinical trials for its antineoplastic effects, that is able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.<ref name="CUDC">Al-Mansour, F., Alraddadi, A., He, B., Saleh, A., Poblocka, M., Alzahrani, W., ... & Macip, S. (2023). Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic. Aging, 15. PMID: 36988504 DOI: 10.18632/aging.204616</ref> Senolytic functions of CUDC-907 depend on the inhibitory effects of both histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K), which leads to an increase in p53 and a reduction in BH3 (the Bcl-2 homology (BH) domain necessary for dimerization with other proteins of Bcl-2 family) pro-survival proteins.<ref name="CUDC"/>

=== UBX1325 ===
UBX1325, a small molecule inhibitor of specific subtypes within the B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins and assessed its efficacy in senescence-associated models of retinopathy. Inhibition of retinal Bcl-xL by UBX1325 promotes apoptosis in the senescence-associated oxygen induced retinopathy model.<ref>Tsuruda, P., Chaney, S., Dejda, A., Dasgupta, S., Crespo-Garcia, S., Rao, S., ... & Beltran, P. (2021). [https://iovs.arvojournals.org/article.aspx?articleid=2774856 UBX1325, a small molecule inhibitor of Bcl-xL, attenuates vascular dysfunction in two animal models of retinopathy]. Investigative Ophthalmology & Visual Science, 62(8), 1163-1163.</ref>

A single intravitreal injection of UBX1325 up to 10 μg was safe and well tolerated in patients with advanced Diabetic macular edema or wet age-related macular degeneration, through 24 weeks.<ref>Bhisitkul, R., Klier, S., Tsuruda, P., Xie, B., Masaki, L., Bautista, J., ... & Dananberg, J. (2022). [https://iovs.arvojournals.org/article.aspx?articleid=2783266 UBX1325, A Novel Senolytic Treatment for Patients with Advanced DME or wet AMD: 24-Week Results of a Phase 1 Study]. Investigative Ophthalmology & Visual Science, 63(7), 4287-4287. </ref>

=== Macrolide antibiotics ===
Two macrolide antibiotics, '''azithromycin''' and '''roxithromycin''', belonging to the erythromycin family, have shown themselves to be senolytics. Unlike erythromycin itself, these acid-resistant analogues, '''in ''in vitro'' tests with aged fibroblasts, removed approximately 97% of aged cells''' and thus reduced the number of aged cells by a factor of 25.<ref>Ozsvari, B., Nuttall, J. R., Sotgia, F., & Lisanti, M. P. (2018). Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging (Albany NY), 10(11), 3294. PMID: 30428454 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845 link] DOI: 10.18632/aging.101633</ref><ref>Zhang, X., Dong, Y., Li, W. C., Tang, B. X., Li, J., & Zang, Y. (2021). Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacologica Sinica, 42(12), 2058-2068. PMID: 33654217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633281 link] DOI: 10.1038/s41401-021-00618-3</ref> They seem to be able to act in a similar way in the body, as roxithromycin (and to a lesser extent azithromycin) is known to have powerful anti-inflammatory abilities, reducing the level of cytokines in the body,<ref>Robbins, R. (2018). [https://www.swjpcc.com/pulmonary/2018/9/21/antibiotics-as-anti-inflammatories-in-pulmonary-diseases.html Antibiotics as anti-inflammatories in pulmonary diseases]. Southwest J Pulm Crit Care. 17(3), 97-107. doi: https://doi.org/10.13175/swjpcc104-18 </ref><ref>Babu, K. S., Kastelik, J., & Morjaria, J. B. (2013). Role of long term antibiotics in chronic respiratory diseases. Respiratory medicine, 107(6), 800-815. </ref><ref>Mann, T. S., Larcombe, A. N., Wang, K. C., Shamsuddin, D., Landwehr, K. R., Noble, P. B., & Henry, P. J. (2022). Azithromycin inhibits mucin secretion, mucous metaplasia, airway inflammation and airways hyperresponsiveness in mice exposed to house dust mite extract. American Journal of Physiology-Lung Cellular and Molecular Physiology. 322(5), L683-L698. PMID: 35348023 DOI:[https://doi.org/10.1152/ajplung.00487.2021 link]</ref> and promoting of tissue repair.<ref>Garey, K. W., Alwani, A., Danziger, L. H., & Rubinstein, I. (2003). Tissue reparative effects of macrolide antibiotics in chronic inflammatory sinopulmonary diseases. Chest, 123(1), 261-265. PMID: 12527628 DOI:[https://doi.org/10.1378/chest.123.1.261 link]</ref> However, systemic administration of azithromycin or roxithromycin has been associated with many adverse effects including cardiotoxicity.<ref>Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert review of anti-infective therapy, 19(2), 147-163. PMID: 32853038 DOI:[https://doi.org/10.1080/14787210.2020.1813024 link]</ref> In addition, there is a risk of the emergence of macrolide resistance with the prolonged administration for other chronic lung conditions.<ref>Serisier, D. J. (2013). Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. The Lancet Respiratory Medicine, 1(3), 262-274. PMID: 24429132 DOI:[https://doi.org/10.1016/S2213-2600(13)70038-9 link]</ref>
In the light of this, novel therapeutic strategies, including the encapsulation of azithromycin or roxithromycin using nanocapsules that preferentially introduce the senolytic toxin specifically to target senescent cells of lungs must be employed, such as nanoformulations suitable for inhalation.<ref name="Lung">Alrashedi, M. G., Ali, A. S., Ahmed, O. A., & Ibrahim, I. M. (2022). Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice. Molecules, 27(23), 8293. PMID: 36500388 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739299 link] DOI: 10.3390/molecules27238293</ref> In particular, the inhalation of Azithromycin Nanoformulation at a low dose of 11 mg/kg, markedly alleviated the pro-inflammatory markers (IL-6, IL-1β, TNF-α, and NF-kB), the ones that were high in the pulmonary tissues of the model of acute lung injury.<ref name="Lung" />

It would be interesting to check also the aptness to the destruction of senescent cells by a non-antibiotic macrolide, EM900, which, like azithromycin, has an anti-inflammatory ability.<ref>Sadamatsu, H., Takahashi, K., Tashiro, H., Kurihara, Y., Kato, G., Uchida, M., ... & Sueoka-Aragane, N. (2020). The nonantibiotic macrolide EM900 attenuates house dust mite-induced airway inflammation in a mouse model of obesity-associated asthma. International Archives of Allergy and Immunology, 181(9), 665-674. PMID: 32599580 DOI:[https://doi.org/10.1159/000508709 link]</ref>

=== Navitoclax (ABT-263) ===
Navitoclax (ABT-263), is an anticancer agent, that induces apoptosis in senescent cells by inhibiting the activities of Bcl-2, Bcl-xL, and BcL-w<ref name="persistent">Cooley, J. C., Javkhlan, N., Wilson, J. A., Foster, D. G., Edelman, B. L., Ortiz, L. A., ... & Redente, E. F. (2023). Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis. JCI insight, 8(3). PMID: 36752201 DOI:[https://doi.org/10.1172/jci.insight.163762 link]</ref><ref>Mohamad Anuar, N. N., Nor Hisam, N. S., Liew, S. L., & Ugusman, A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Frontiers in Pharmacology, 1817. PMID: 33381025 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768911 link] DOI: 10.3389/fphar.2020.564108</ref>

ABT-263 can be used to exclusively eliminate senescent cells, since transcriptome analysis showed that the inhibition of apoptosis through the upregulation of the Bcl family proteins was specific to senescent cells and not found in young cells.<ref name="Achilles"/>
ABT-263 has been shown to attenuate the development of pulmonary fibrosis.<ref>Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., ... & Tager, A. M. (2017). Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. Science Translational Medicine, 9(420), eaal3765. PMID: 29237758 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520471 link] DOI: 10.1126/scitranslmed.aal3765</ref><ref name="persistent"/>

ABT-263 treatment of aged skin from men clearly resulted in rejuvenation through the clearance of senescent cells and inhibition of the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP), compared with that in the original skin or control groups.<ref>Takaya, K., Ishii, T., Asou, T., & Kishi, K. (2023). Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Research. 26(1), 9-20 PMID: 36324221 DOI:[https://doi.org/10.1089/rej.2022.0048 link]</ref>

ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on mouse cranial osteolysis.<ref> PMID: 36638657 DOI:[https://doi.org/10.1016/j.intimp.2023.109694 org/10.1016/j.intimp.2023.109694]</ref>

=== PROTAC technology ===
[[File:Protac.jpg|thumb|Proteolysis targeting chimeras (PROTACs) that trigger degradation of the target proteins<ref>Zhao, C., & Dekker, F. J. (2022). Novel Design Strategies to Enhance the Efficiency of Proteolysis Targeting Chimeras. ACS Pharmacology & Translational Science, 5(9), 710-723. PMID: 36110375 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469497 link] DOI: 10.1021/acsptsci.2c00089</ref> ]]
Proteolysis-targeting chimeras (PROTACs) are an innovative technology to induce degradation of a protein of interest (POI).<ref>Burslem, G. M., & Crews, C. M. (2020). Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell, 181(1), 102-114. PMID: 31955850 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319047 link] DOI: 10.1016/j.cell.2019.11.031</ref> PROTACs are composed of three elements: a ligand that binds to a target POI, an E3 ligase recruiting ligand, and a flexible linker between the two ligands. Thus, a PROTAC can form a stable ternary complex with a POI and E3 ligase, resulting in subsequent ubiquitination and proteasomal degradation of the POI. The PROTAC is then recycled to attack another copy of the POI. This catalytic mode of action eliminates the need to maintain high drug levels, both characteristics that distinguish PROTACs from classical occupancy-driven pharmacology of small-molecule inhibitors.<ref>Graham, H. (2022). The mechanism of action and clinical value of PROTACs: A graphical review. Cellular Signalling, 110446. PMID: 35995302 DOI:[https://doi.org/10.1016/j.cellsig.2022.110446 link]</ref>
PROTACs have several advantages, such as increased potency, higher selectivity, prolonged activity, and reduced toxicity, which make them an attractive strategy for developing senotherapeutics.<ref>Burslem, G. M. (2023). The Future of Heterobifunctional Compounds: PROTACs and Beyond. Inducing Targeted Protein Degradation: From Chemical Biology to Drug Discovery and Clinical Applications, 273-287. </ref>

Aptamers are short oligonucleotides (DNA/RNA) or peptide molecules that can selectively bind to their specific targets with high specificity and affinity.<ref>Lee, S. J., Cho, J., Lee, B. H., Hwang, D., & Park, J. W. (2023). Design and Prediction of Aptamers Assisted by In Silico Methods. Biomedicines, 11(2), 356. https://doi.org/10.3390/biomedicines11020356</ref>
Aptamers, as therapeutic agents, can effectively recognize various proteins on the cell membrane or in the blood circulation to modulate their interaction with receptors and affect the corresponding biological pathways for the treatment of aging and various diseases. Owing to remarkable specificity and binding affinity, aptamers can be utilized as target molecules for the construction of PROTAC that is able to degrade target disease or aging-causing proteins.<ref>Weng, G., Cai, X., Cao, D., Du, H., Shen, C., Deng, Y., ... & Hou, T. (2023). PROTAC-DB 2.0: an updated database of PROTACs. Nucleic Acids Research, 51(D1), D1367-D1372. PMID: 36300631 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9825472 link] DOI: 10.1093/nar/gkac946</ref><ref>Li, M., Zhi, Y., Liu, B., & Yao, Q. (2023). Advancing Strategies for Proteolysis-Targeting Chimera Design. Journal of Medicinal Chemistry. PMID: 36788245 DOI:[https://doi.org/10.1021/acs.jmedchem.2c01555 link]</ref><ref>Kumar, D., & Hassan, M. I. (2022). Targeted protein degraders march towards the clinic for neurodegenerative diseases. Ageing Research Reviews, 101616. PMID: 35378298 DOI:[https://doi.org/10.1016/j.arr.2022.101616 link]</ref><ref>George, N., Akhtar, M. J., Balushi, K. A., Safi, S. Z., Azmi, S. N. H., & Khan, S. A. (2023). The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer’s disease. Medicinal Chemistry Research, 1-16. </ref>

In particular, an aptamer-senolytic molecular prodrug was developed for reliable regulation of vascular senescence through hierarchical recognition of three types of senescence-related hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. According to preliminary data, it can actively target and trigger cell-specific apoptosis in senescent endothelial cells caused by various stimuli, while keeping silent in non-senescent cells, contributing to effective inhibition effects on the senescence burden-induced progress of atherosclerosis. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state.<ref>Xia, Y., Li, J., Wang, L., Xie, Y., Zhang, L., Han, X., ... & Liu, Y. (2023). Engineering Hierarchical Recognition‐Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti‐Atherosclerosis Therapy. Angewandte Chemie International Edition, 62(4), e202214169. PMID: 36445796 DOI:[https://doi.org/10.1002/anie.202214169 link]</ref>

==== ARV825 ====
Expression of bet-1, the ''C. elegans'' ortholog of human BRD2 and BRD4, directly impacts actin organization and function, which has direct significance in longevity. Specifically, loss of function of bet-1 results in premature breakdown of actin structure during aging, while its overexpression protects actin filaments at late age and promotes both healthspan and life span. Importantly, that these effects are conserved in human cells, as inhibition of BRD4 in non-dividing, human senescent cells result in decreased actin filaments, decreased adhesion, and decreased cell survival.<ref>Garcia, G., Bar‐Ziv, R., Averbukh, M., Dasgupta, N., Dutta, N., Zhang, H., ... & Higuchi‐Sanabria, R. (2023). Large‐scale genetic screens identify BET‐1 as a cytoskeleton regulator promoting actin function and life span. Aging Cell, 22(1), e13742. PMID: 36404134 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9835578 link] DOI: 10.1111/acel.13742</ref>
Senescent cells require a stabilized actin network to maintain adherence, which is critical for cell survival.<ref>Shin, E. Y., Park, J. H., You, S. T., Lee, C. S., Won, S. Y., Park, J. J., ... & Kim, E. G. (2020). Integrin-mediated adhesions in regulation of cellular senescence. Science Advances, 6(19), eaay3909. PMID: 32494696 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202880 link] DOI: 10.1126/sciadv.aay3909</ref>

Hetero bifunctional molecule, ARV-825, that cause cleavage and degradation of BET proteins, was designed by connecting a small molecule BRD4 binding moiety (OTX015) to an E3 ligase cereblon binding moiety (pomalidomide) using PROTAC technology.<ref>Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., ... & Crews, C. M. (2015). Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chemistry & biology, 22(6), 755-763. PMID: 26051217 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475452 link] DOI: 10.1016/j.chembiol.2015.05.009</ref>

Unlike previously reported senolytic drugs, ARV825 exhibits robust senolysis activity even at nanomolar concentrations (5–10 nM). The optimum concentration (10 nM) of ARV825 for senolysis does not provoke cell death in quiescent cells. However, a treatment with a high concentration (more than 50 nM) of ARV825 reduce the proliferation of cells. So, it is crucial to determine the optimal concentration of ARV825 in vivo.<ref>Guo, Z., Peng, H., & Xie, Y. (2020). BET family protein degraders poised to join the senolytic arsenal. Signal Transduction and Targeted Therapy, 5(1), 88. PMID: 32528000 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289795 link] DOI: 10.1038/s41392-020-0202-2</ref>

==== PZ15227 ====
PZ15227 was generated by tethering of the senolytic drug '''navitoclax (ABT-263)''' to a cereblon (CRBN) E3 ligand that is expressed minimally in normal platelets.<ref>He, Y., Zhang, X., Chang, J., Kim, H. N., Zhang, P., Wang, Y., ... & Zhou, D. (2020). Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity. Nature communications, 11(1), 1996. PMID: 32332723 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181703 link] DOI: 10.1038/s41467-020-15838-0</ref> PZ15227 binds to BCL-XL, causing it to be degraded by the cereblon (CRBN) E3 ligase. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo.<ref>Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., ... & de Keizer, P. L. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.</ref>

==== DT2216 ====
DT2216 an effective BCL-XL degrader based on VHL E3 ligase. DT2216 exerted almost no effect on the viability of platelets up to a concentration of 3 μM which showed better effect than PZ15227. DT2216 was found to have enhanced efficacy against a variety of BCL-XL-dependent leukemia cell lines and exhibited much less toxic to platelets than ABT263.<ref>Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., ... & Zhou, D. (2019). A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nature medicine, 25(12), 1938-1947. PMID: 31792461 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898785 link] DOI: 10.1038/s41591-019-0668-z</ref> Therefore, DT2216 was approved by FDA to enter phase I clinical trials for the treatment of advanced liquid and solid tumors.

=== Inhibitors of CRYAB ===
Crystallin Alpha B (CRYAB or HspB5) is a stress-induced small (20-kd) heat-shock protein highly expressed in the lens and to a lesser extent in several other tissues, among which heart, skeletal muscle and brain.<ref>Acunzo, J., Katsogiannou, M., & Rocchi, P. (2012). Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. The international journal of biochemistry & cell biology, 44(10), 1622-1631. PMID: 22521623 DOI:[https://doi.org/10.1016/j.biocel.2012.04.002 link]</ref> CRYAB acts as a molecular chaperone involved in protein folding and is associated with apoptosis in cardiovascular disease.<ref>Zhang, Y., Li, C., Meng, H., Guo, D., Zhang, Q., Lu, W., ... & Tu, P. (2018). BYD ameliorates oxidative stress-induced myocardial apoptosis in heart failure post-acute myocardial infarction via the P38 MAPK-CRYAB signaling pathway. Frontiers in Physiology, 9, 505. PMID: 29867551 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951999 link] DOI: 10.3389/fphys.2018.00505</ref>
As a member of the HSPB family and an important molecular chaperone, HSPB5 is involved in cytoskeleton stability, growth and differentiation, proliferation and cell migration and is closely related to the occurrence and development of a variety of diseases.<ref>Delbecq, S. P., & Klevit, R. E. (2019). HSPB5 engages multiple states of a destabilized client to enhance chaperone activity in a stress-dependent manner. Journal of Biological Chemistry, 294(9), 3261-3270. PMID: 30567736 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398148 link] DOI: 10.1074/jbc.RA118.003156</ref><ref>Chebotareva, N. A., Roman, S. G., Borzova, V. A., Eronina, T. B., Mikhaylova, V. V., & Kurganov, B. I. (2020). Chaperone-like activity of HSPB5: The effects of quaternary structure dynamics and crowding. International Journal of Molecular Sciences, 21(14), 4940. PMID: 32668633 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404038 link] DOI: 10.3390/ijms21144940</ref><ref>Dimauro, I., & Caporossi, D. (2022). Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity. Molecules, 27(3), 1147. PMID: 35164412 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840510 link] DOI: 10.3390/molecules27031147</ref> In particular, its overexpression can promote tumorigenesis and metastasis.<ref>Rashidieh, B., Bain, A. L., Tria, S. M., Sharma, S., Stewart, C. A., Simmons, J. L., ... & Khanna, K. K. (2023). Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice. Experimental Hematology & Oncology, 12(1), 4. PMID: 36624493 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830749 link] DOI: 10.1186/s40164-022-00365-z</ref><ref>Hayashi, J., & Carver, J. A. (2020). The multifaceted nature of αB-crystallin. Cell Stress and Chaperones, 25, 639-654. PMID: 32383140 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332646 link] DOI: 10.1007/s12192-020-01098-w</ref>

It was found that '''in living organisms a powerful senolytic is produced that can cause lysis of aged cells by acting on CRYAB''', and this senolytic turned out to be '''25-hydroxycholesterol (25HC)''', which is an endogenous metabolite of cholesterol biosynthesis.<ref>Limbad, C., Doi, R., McGirr, J., Ciotlos, S., Perez, K., Clayton, Z. S., ... & Melov, S. (2022). Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types. Iscience, 25(2), 103848. PMID: 35198901 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851282 link] DOI: 10.1016/j.isci.2022.103848</ref> 25HC targets CRYAB in many cell types, including the lung, and is localized in alveolar macrophages and pneumocytes of COPD patients.
25HC is the only oxysterol induced by bacterial endotoxin lipopolysaccharides (LPS) in the lung and its induction requires enzymatic activity of cholesterol 25-hydroxylase (CH25H) in macrophages.<ref>Sugiura, H., Koarai, A., Ichikawa, T., Minakata, Y., Matsunaga, K., Hirano, T., ... & Ichinose, M. (2012). Increased 25‐hydroxycholesterol concentrations in the lungs of patients with chronic obstructive pulmonary disease. Respirology, 17(3), 533-540. PMID: 22295989 DOI:[https://doi.org/10.1111/j.1440-1843.2012.02136.x link]</ref> So, inhibitors of CRYAB can lead to potent senolysis, and 25-hydroxycholesterol (25HC) represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver. However, it should be borne in mind that the elevated 25HC may contribute to fibroblasts-mediated lung tissue remodeling by promoting myofibroblasts differentiation and the excessive release of matrix metalloproteinases through the NF-kB-TGF-β-dependent pathway.<ref>Ichikawa, T., Sugiura, H., Koarai, A., Kikuchi, T., Hiramatsu, M., Kawabata, H., ... & Ichinose, M. (2013). 25-hydroxycholesterol promotes fibroblast-mediated tissue remodeling through NF-κB dependent pathway. Experimental cell research, 319(8), 1176-1186. PMID: 23485764 DOI:[https://doi.org/10.1016/j.yexcr.2013.02.014 link]</ref>

=== Ginkgetin, oleandrin and periplocin ===
Predicting of senolytic compounds by computational screening using machine learning made it possible to find new potential senolytics, including ginkgetin, oleandrin and periplocin.<ref>Smer-Barreto, V., Quintanilla, A., Elliot, R. J., Dawson, J. C., Sun, J., Carragher, N., ... & Oyarzun, D. A. (2022). Discovery of new senolytics using machine learning. Nat Commun 14, 3445 (2023). https://doi.org/10.1038/s41467-023-39120-1, bioRxiv, 2022-04. https://doi.org/10.1101/2022.04.26.489505</ref> Of the three, '''oleandrin''' was found to be the most effective.

=== Activatable senolytics ===

==== Selective senolytic platform SenTech™ of Rubedo Life Sciences ====
Many known senolytic agents were initially developed as cytotoxic anti-cancer agents and subsequently repurposed for ‘selective’ removal of senescent cell populations. Because proliferating cells are frequently more sensitive to the cytotoxic or cytostatic effect of anti-tumor agents, dose-limiting toxicity, especially in rapidly replicating hematopoietic, skin or gut cells, is a frequently observed side-effect, which strongly limits the clinical utility of these anti-senescence therapies. To minimize the side effects of senolytics, it is necessary to identify senolytics that can be targeted to senescent cells safely, selectively and systemically. The most frequently used assays (e.g. immune-histochemistry or flow cytometry-based) for identifying senescent cells measure the levels of senescence-associated β-galactosidase (SA-β-gal), which is present at a low level in all cells but is substantially increased in senescent cells.<ref name="Dimri"/> Biopharmaceutical company Rubedo Life Sciences has presented its small molecule therapy allowing systemic removal of senescent cells in geriatric mice without noticeable side effects. Based on galactose-derivative prodrug '''5-fluorouridine-5′-O-β-Dgalactopyranoside (5FURGal)''' it can, upon selective activation in senescent cells by the hydrolase activity of SA-βGal, release clinically approved anti-cancer medication 5-Fluorouracil.<ref name="Fluorouracil">Doan, L., Paine, P., Tran, C., Parsons, B., Hiller, A., Joshua, I., ... & Quarta, M. (2020). Targeted senolytic prodrug is well tolerated and results in amelioration of frailty, muscle regeneration and cognitive functions in geriatric mice. https://doi.org/10.21203/rs.3.rs-92962/v1</ref> Geriatric (30 month old) mice that received the prodrug treatment for four weeks altogether improved significantly: 1) frailty profile; 2) skeletal muscle function; 3) muscle stem cell function; 4) cognitive function; and 5) survival.<ref name="Fluorouracil"/> Similar results have been obtained with other such drugs.<ref>Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., ... & Deng, H. (2020). Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell research, 30(7), 574-589. PMID: 32341413 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184167 link] DOI: 10.1038/s41422-020-0314-9</ref><ref>Morsli, S., Doherty, G. J., & Muñoz-Espín, D. (2022). Activatable senoprobes and senolytics: Novel strategies to detect and target senescent cells. Mechanisms of Ageing and Development, 202, 111618. PMID: 34990647 DOI:[https://doi.org/10.1016/j.mad.2021.111618 link]</ref>

==== Photoablation of senescent cells ====
Light as an external medical stimulus is an easy and convenient tool useful for noninvasive therapy. Therefore, a photosensitive senolytic prodrug '''KSL0608-Se''' was created '''for photoablation of senescent cells''', which uses "a combination of the enzyme substrate of senescence-associated β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of senescent cells, construction of a bioorthogonal receptor triggered by SA-β-gal to target and anchor senescent cells with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy". So, KSL0608-Se, is a photosensitive senolytic prodrug, which is selectively activated by SA-β-gal.<ref name="PDT" >Shi, D., Liu, W., Gao, Y., Li, X., Huang, Y., Li, X., ... & Li, J. (2023). Photoactivatable senolysis with single-cell resolution delays aging. Nature Aging, 1-16. DOI:[https://doi.org/10.1038/s43587-023-00360-x 10.1038/s43587-023-00360-x]</ref> In naturally-aged mice, KSL0608-Se-mediated photodynamic therapy prevented upregulation of age-related senescent markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice.<ref name="PDT"/>

=== Future target senolytics ===
The atypical chemokine receptor 3 ('''ACKR3'''), is a cell surface protein, the membrane surface receptor of CXCL12 (CXC motif chemokine 12) that is specifically present in senescent cells but not on proliferating cells.<ref name="ACKR3">Takaya K, Asou T, Kishi K (2022). Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3. International journal of molecular sciences. 23(12): 6531. PMID 35742971 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223754 link] doi:10.3390/ijms23126531</ref> CXCL12 is known to be central to the development of many organs and later on involved in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders.<ref>Liberale, L., Ministrini, S., Carbone, F., Camici, G. G., & Montecucco, F. (2021). Cytokines as therapeutic targets for cardio-and cerebrovascular diseases. Basic Research in Cardiology, 116, 1-26.PMID: 33770265 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997823 link] DOI: 10.1007/s00395-021-00863-x</ref> The selective expression of ACKR3 on the surface of senescent cells allows the preferential elimination of senescent cells and might contribute to the future development of novel senolysis approaches..<ref name="ACKR3" />

<ref>Takaya, K., Asou, T., & Kishi, K. (2022). Identification of Apolipoprotein D as a dermal fibroblast marker of human aging for development of skin rejuvenation therapy. Rejuvenation Research, (ja).</ref>

==== Developments ====
The '''SENSOlytic platform''' is Oisín's patented technology that selectively removes senescent cells based on p16 gene expression in senescent cells rather than surface markers or other characteristics that may be shared with normal, intact cells.
Oisín has developed a therapeutic delivery device that it calls a proteo-lipid vehicle that carries inside of it DNA and can be injected into patients. The vehicle fuses with a patient’s cells and releases its DNA payload into them. When it connects with a target cell — perhaps a senescent or cancerous cell — the DNA triggers its death. The startup has been testing the technology in mice. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.<ref>[https://longevity.technology/news/promising-restorative-therapy-could-potentially-be-available-within-5-years/ A single injection resulted in 90% reduction in solid tumours after 48 hours].</ref> So, the cell is killed by an exogenous gene that causes apoptosis (presumably caspase 9), which is activated only in cells where the p16 gene is active. Delivery of this gene into the cell is carried out by a lipid nanoparticle (artificial liposome) containing DNA with a gene that causes apoptosis.

==== Senolytic CAR T cells ====
Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/>
Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>

<ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref>
<ref>Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 link] DOI: 10.1038/s41392-020-00268-7</ref>
<ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>

==== Senolytic vaccination ====
Analysis of transcriptome data from senescent vascular endothelial cells revealed that glycoprotein nonmetastatic melanoma protein B (GPNMB) was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). Near-end-of-lifespan (27 months) wild-type mice have 35-fold increased hepatic levels of Gpnmb in comparison to young (4 months) mice. GPNMB expression was also upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.<ref name="lysosomal">Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., ... & Minamino, T. (2022). Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Scientific reports, 12(1), 1-14. PMID: 35444208 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021310 link] DOI: 10.1038/s41598-022-10522-3</ref><ref name="vaccination">Suda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., ... & Minamino, T. (2021). Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging, 1(12), 1117-1126. https://doi.org/10.1038/s43587-021-00151-2</ref> Immunization of mice against GNMPB reduced the burden of senescent cells, improved the healthspan of naturally aged mice, and prolonged the lifespan of Zmpste24 knockout progeroid mice.<ref name="vaccination"/> The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis.<ref name="vaccination"/> For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation.<ref name="lysosomal"/> A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.<ref>Mendelsohn, A. R., & Larrick, J. W. (2022). Antiaging vaccines targeting senescent cells. Rejuvenation Research, 25(1), 39-45. https://doi.org/10.1089/rej.2022.0008</ref>

== The proteins and pathways involved in senescent cells apoptotic resistance ==
Elimination of senescent cells has the potential to delay aging, treat age-related diseases and extend healthspan.<ref>Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. The FEBS Journal. PMID: 35015337 DOI:[https://doi.org/10.1111/febs.16350 link]</ref> However, once cells becoming senescent, they are more resistant to apoptotic stimuli.<ref>Wang, E. (1995). Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl 2 is involved. Cancer research, 55(11), 2284-2292. PMID: 7757977</ref><ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI:[https://doi.org/10.1007/s00018-010-0597-y link]</ref> At least 125 different genes are involved in the aging process,<ref>Jochems, F., Thijssen, B., De Conti, G., Jansen, R., Pogacar, Z., Groot, K., ... & Bernards, R. (2021). The Cancer SENESCopedia: A delineation of cancer cell senescence. Cell reports, 36(4), 109441.</ref><ref>Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., ... & Demaria, M. (2019). Cellular senescence: defining a path forward. Cell, 179(4), 813-827. PMID: 31675495 DOI:[https://doi.org/10.1016/j.cell.2019.10.005 link]</ref><ref>Gonzalez-Gualda, E., Baker, A. G., Fruk, L., & Munoz-Espin, D. (2020). A guide to assessing cellular senescencein in vitro and in vivo. FEBS JOURNAL. 288(1), 56-80 PMID: 32961620 DOI:[https://doi.org/10.1111/febs.15570 link]</ref> a set of which, called '''“SenMayo”''', makes it possible to identify old cells.<ref>Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., ... & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), 4827. PMID: 35974106 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381717 link] DOI: 10.1038/s41467-022-32552-1</ref><ref>Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023). The heterogeneity of cellular senescence: Insights at the single-cell level. Trends in cell biology, 33(1), 9-17. PMID: 35599179 PMCID: PMC9812642 link] DOI: 10.1016/j.tcb.2022.04.011</ref> Due to the high heterogeneity in gene expression and their diverse origins, senescent cells may use different anti-apoptotic pathways to maintain their survival, making it difficult to use a single senolytic to kill all types of senescent cells.<ref>Hu, L., Li, H., Zi, M., Li, W., Liu, J., Yang, Y., ... & He, Y. (2022). Why senescent cells are resistant to apoptosis: An insight for senolytic development. Frontiers in Cell and Developmental Biology, 10. PMID: 35252191 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890612 link] DOI: 10.3389/fcell.2022.822816</ref><ref>L'Hôte, V., Mann, C., & Thuret, J. Y. (2022). From the divergence of senescent cell fates to mechanisms and selectivity of senolytic drugs. Open Biology, 12(9), 220171. PMID: 36128715 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490338 link] DOI: 10.1098/rsob.220171</ref>

=== Apoptosis ===
Aging has been associated with decreased apoptosis in most cell types, which acts as an important contributor to aging, and age-related diseases, since high resistance to apoptosis allows functionally deficient, post-mitotic senescent cells to accumulate during aging.<ref>Salminen, A., Ojala, J., & Kaarniranta, K. (2011). Apoptosis and aging: increased resistance to apoptosis enhances the aging process. Cellular and molecular life sciences, 68, 1021-1031. PMID: 21116678 DOI: 10.1007/s00018-010-0597-y</ref> Prolonged persistence of senescent cells is associated with tissue dysfunction and pathology.<ref name="networks">Soto-Gamez, A., Quax, W. J., & Demaria, M. (2019). Regulation of survival networks in senescent cells: from mechanisms to interventions. Journal of molecular biology, 431(15), 2629-2643. PMID:31153901 DOI: 10.1016/j.jmb.2019.05.036</ref>
The key executioners of apoptosis are proteases called caspases; when caspases are activated, apoptosis becomes irreversible.<ref>Kesavardhana, S., Malireddi, R. S., & Kanneganti, T. D. (2020). Caspases in cell death, inflammation, and pyroptosis. Annual review of immunology, 38, 567-595. PMID: 32017655 PMCID: PMC7190443 DOI: 10.1146/annurev-immunol-073119-095439</ref> Caspase activation is tightly controlled by regulatory molecules, including such highly conserved regulators as protein families Bcl-2 and the inhibitor of apoptosis (IAP) proteins.<ref>Deveraux, Q. L., Schendel, S. L., & Reed, J. C. (2001). Antiapoptotic proteins: the bcl-2 and inhibitor of apoptosis protein families. Cardiology Clinics, 19(1), 57-74. PMID: 11787814 DOI: 10.1016/s0733-8651(05)70195-8</ref><ref>Ola, M. S., Nawaz, M., & Ahsan, H. (2011). Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Molecular and cellular biochemistry, 351, 41-58. PMID: 21210296 DOI: 10.1007/s11010-010-0709-x</ref> IAPs are characterized by the presence of '''baculoviral repeat domain (BIR)''' repeats and are recruited into signaling complexes which function as ubiquitin E3 ligases, via their RING (really interesting new gene) domains.<ref>Silke, J., & Vucic, D. (2014). IAP family of cell death and signaling regulators. Methods in enzymology, 545, 35-65. PMID: 25065885 DOI: 10.1016/B978-0-12-801430-1.00002-0</ref> In addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division.<ref>Hrdinka, M., & Yabal, M. (2019). Inhibitor of apoptosis proteins in human health and disease. Genes & Immunity, 20(8), 641-650. PMID: 31110240 DOI: 10.1038/s41435-019-0078-8</ref>

IAPs are regulated by '''mitochondria-derived pro-apoptotic factors''' such as '''Smac''' (second mitochondria-derived activator of caspases)<ref>Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c–dependent caspase activation by eliminating IAP inhibition. Cell, 102(1), 33-42. PMID: 10929711 DOI: 10.1016/s0092-8674(00)00008-8</ref> and heat shock protein '''HtrA2''' (high-temperature requirement A2) peptidase.<ref>Chakraborty, A., Bose, R., & Bose, K. (2022). Unraveling the Dichotomy of Enigmatic Serine Protease HtrA2. Frontiers in Molecular Biosciences, 66. PMID: 35187085 PMCID: PMC8850690 DOI: 10.3389/fmolb.2022.824846</ref> Each of them can bind IAPs, thus freeing caspases to activate apoptosis.<ref>Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. PMID: 23378585 PMCID: PMC3552501 DOI: 10.1101/cshperspect.a008730</ref> The BIR domain found in all IAPs interacts with the conserved '''IAP binding motif (IBM) of caspases'''. Similar IBMs are found on Smac and HtrA2.<ref>Eckelman, B. P., Drag, M., Snipas, S. J., & Salvesen, G. S. (2008). The mechanism of peptide-binding specificity of IAP BIR domains. Cell Death & Differentiation, 15(5), 920-928. PMID: 18239672 DOI: 10.1038/cdd.2008.6</ref>

In particular, the ubiquitin ligase BIRC6 (baculoviral IAP repeat–containing protein 6) inhibit apoptosis by binding to apoptotic proteases, keeping them inactive and targeting these proteins for degradation, preventing cell death.<ref>Hunkeler, M., Jin, C. Y., & Fischer, E. S. (2023). Structures of BIRC6-client complexes provide a mechanism of Smac-mediated release of caspases. Science, 379(6637), 1105-1111 DOI: 10.1126/science.ade57</ref> BIRC6 adopts a dimeric, horseshoe-shaped architecture with a central cavity that allows for binding to target proteases. The pro-apoptotic protein Smac binds very tightly to the same interior site as the proteases through multiple interactions, essentially irreversibly blocking the ability of BIRC6 to bind substrates.<ref>Ehrmann, J. F., Grabarczyk, D. B., Heinke, M., Deszcz, L., Kurzbauer, R., Hudecz, O., ... & Clausen, T. (2023). Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex. Science, 379(6637), 1117-1123 DOI: 10.1126/science.ade88 </ref><ref name="networks"/>

== References ==
<references />
{{Draft-article}}
[[Category:Main list]]
[[Category:Drugs]]
[[Category:Lifespan interventions]]
[[Category:Drafts]]

Longevity Wiki

2023-06-23T00:55:22Z

Geroscientist: ' '

{{DISPLAYTITLE:Longevity Wiki}}
What is aging? Can we cure age-related diseases? Is it possible to eliminate the suffering we all experience as we grow older? Can we live longer, without declining health? On this Wiki you’ll find the '''latest scientific findings on longevity'''. Our aim is to be an accessible, objective and unbiased source of information for this exciting new field.

<div class="container my-5">
<div class="row"><div class="col-sm center">
[[File:Icon of Science.png|frameless|125px|link=]]
<div>'''Science based'''</div>
</div>
<div class="col-sm center">
[[File:Icon of Padlock.png|frameless|125px|link=]]
<div>'''Open access'''</div>
</div>
<div class="col-sm center">
[[File:Icon of Idea.png|frameless|125px|link=]]
<div>'''Understandable'''</div>
</div>
</div>
</div>

=== Get a taste of our content... ===
Have a look at our article about [[Rapamycin]]'','' a potential longevity drug. Or, check out our complete [[Articles|list of articles]]. We also have a [[FAQ|Longevity FAQ]] which covers the 20+ most common questions about longevity biotechnology.

<div class="container highlight>

<div class="row">
<div class="col-sm">
=== Fundamentals ===
<dpl>
category=Fundamentals
count=6
</dpl>
[[:Category:Fundamentals|More]]
</div>
<div class="col-sm">
=== Drugs ===
<dpl>
category=Drugs
count=6
</dpl>
[[:Category:Drugs|More]]
</div>
<div class="col-sm">
=== 'Longevity genes' ===
<dpl>
category=Longevity genes
count=6
</dpl>
[[:Category:Longevity_genes|More]]
</div>
</div></div>

=== Partnerships ===

<div class="container highlight>

<div class="row">
<div class="col-sm">
[[File:Vector-Foresight-Logo-dark-blue.svg|frameless|225px|alt=Foresight's Institute Logo|link=https://foresight.org/ext/ForesightTechTree]]<br/>
[https://foresight.org/ext/ForesightTechTree Foresight's Institute Longevity Tech Tree]
</div>
</div></div>

=== Want to help out? ===
If you wish to contribute to the content, or in another way, you're more than welcome to learn how you can [[How_to_contribute|contribute]]. You can also [https://gitcoin.co/grants/3936/longevity-wiki financially support] the Wiki through the open-source platform Gitcoin.

[[About|About us]] | [[Contact|Contact us]]
__NOTOC__

Aging and longevity

2023-01-29T10:01:37Z

Geroscientist: /* What is aging? */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5.<ref name=":32" /> This disparity is projected to only widen further with a rapidly aging population.<ref name=":32">Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing, such as in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== Healthspan versus lifespan ====
'''The concept of healthspan refers to the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== Lack of consensus on what defines aging ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T09:59:36Z

Geroscientist: /* Healthspan versus lifespan */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5.<ref name=":32" /> This disparity is projected to only widen further with a rapidly aging population.<ref name=":32">Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing, such as in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== Healthspan versus lifespan ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T09:59:04Z

Geroscientist:

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5.<ref name=":32" /> This disparity is projected to only widen further with a rapidly aging population.<ref name=":32">Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing, such as in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T09:58:00Z

Geroscientist: /* Metformin */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing, such as in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T09:57:26Z

Geroscientist: /* Metformin */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" /> However, the data in humans is inconclusive without formal testing in a randomized clinical trial (RCT).

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year RCT of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T09:55:19Z

Geroscientist: /* Economic implications of targeting aging */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine. While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

Additionally, it can be inferred from the current approach to medicine of the belief that ideal medical outcomes come from an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T07:40:16Z

Geroscientist: /* Economic implications of targeting aging */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref name=":31">Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This was justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains.<ref name=":31" /> This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substantial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterized by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term.

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorizes into organ or physiologic systems. This is reflected in increasing subspecialization. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specializing in endocrinology, or even further with diabetology. At the level of single diseases, such specialization can lead to better outcomes. But at the level of population health and in the context of aging, this fails to recognize the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T07:33:27Z

Geroscientist: /* Economic implications of targeting aging */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the US economy.<ref>Scott, A. J., Ellison, M., & Sinclair, D. A. (2021). The economic value of targeting aging. ''Nature Aging'', ''1''(7), 616-623.</ref> This is justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains. This analysis highlights the profound difference between the current approach of targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substanial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term...

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorises into organ or physiologic systems. This is reflected in increasing subspecialisation. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specialising in endocrinology, or even further with diabetology. At the level of single diseases, specialisation makes sense...But at the level of population health, in the context of aging, this fails to recognise the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T07:13:07Z

Geroscientist: /* COVID-19 defined as a disease of aging */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);

2) Greater mortality rate in men, consistent with known sex differences in rates of aging;

3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,

4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the economy. This is justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains. This analysis highlights the profound difference between targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substanial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term...

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorises into organ or physiologic systems. This is reflected in increasing subspecialisation. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specialising in endocrinology, or even further with diabetology. At the level of single diseases, specialisation makes sense...But at the level of population health, in the context of aging, this fails to recognise the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T07:12:41Z

Geroscientist: /* Is aging a disease? */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

'''1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);'''

'''2) Greater mortality rate in men, consistent with known sex differences in rates of aging;'''

'''3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,'''

'''4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan'''

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the economy. This is justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains. This analysis highlights the profound difference between targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substanial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term...

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorises into organ or physiologic systems. This is reflected in increasing subspecialisation. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specialising in endocrinology, or even further with diabetology. At the level of single diseases, specialisation makes sense...But at the level of population health, in the context of aging, this fails to recognise the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T07:12:16Z

Geroscientist: /* Is aging a disease? */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

'''1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);'''

'''2) Greater mortality rate in men, consistent with known sex differences in rates of aging;'''

'''3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,'''

'''4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan'''

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the economy. This is justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains. This analysis highlights the profound difference between targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substanial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term...

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorises into organ or physiologic systems. This is reflected in increasing subspecialisation. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specialising in endocrinology, or even further with diabetology. At the level of single diseases, specialisation makes sense...But at the level of population health, in the context of aging, this fails to recognise the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
'''...Work in Progress...'''

Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a binary decision is made to determine whether treatment is necessary. Under this paradigm, age-related changes not regarded as outright disease may be deemed normal, and so further management is not necessary. Such change with age may be related to function, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This can neglect the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old.<ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

====== '''Lack of consensus on what defines aging''' ======
However, some level of collective confusion in meaning is prevalent among the public, physicians, and scientists. This is predominantly due to the imprecision of the word 'aging'. Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

'''Inconsistencies in criteria for defining a disease'''

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref>

Others have argued that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.<ref name=":23" /> Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref name=":23">Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease. Whether it is a disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>
=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T02:40:14Z

Geroscientist: /* The geroscience hypothesis */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

'''1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);'''

'''2) Greater mortality rate in men, consistent with known sex differences in rates of aging;'''

'''3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,'''

'''4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan'''

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the economy. This is justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains. This analysis highlights the profound difference between targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substanial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term...

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorises into organ or physiologic systems. This is reflected in increasing subspecialisation. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specialising in endocrinology, or even further with diabetology. At the level of single diseases, specialisation makes sense...But at the level of population health, in the context of aging, this fails to recognise the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
'''...Work in Progress...'''

Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a somewhat binary decision must be made to determine whether treatment is necessary. Under this paradigm, age-related changes not immediately regarded as disease may be deemed normal, and so further management is not necessary. Such change with age may be functional, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This thinking neglects the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old, <ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

However, some level of collective confusion in meaning is prevalent among the public, physcians, and scientists. This is predominantly due to the imprecision of the word 'aging'.

Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase human healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref> Some may argue that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.

Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref>Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease; it is Disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>

=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T02:23:48Z

Geroscientist: /* The geroscience hypothesis */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

'''1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);'''

'''2) Greater mortality rate in men, consistent with known sex differences in rates of aging;'''

'''3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,'''

'''4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan'''

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the economy. This is justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains. This analysis highlights the profound difference between targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substanial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term...

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorises into organ or physiologic systems. This is reflected in increasing subspecialisation. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specialising in endocrinology, or even further with diabetology. At the level of single diseases, specialisation makes sense...But at the level of population health, in the context of aging, this fails to recognise the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
'''...Work in Progress...'''

‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />
== Is aging a disease? ==
'''...Work in Progress...'''

Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a somewhat binary decision must be made to determine whether treatment is necessary. Under this paradigm, age-related changes not immediately regarded as disease may be deemed normal, and so further management is not necessary. Such change with age may be functional, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This thinking neglects the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old, <ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

However, some level of collective confusion in meaning is prevalent among the public, physcians, and scientists. This is predominantly due to the imprecision of the word 'aging'.

Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase human healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref> Some may argue that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.

Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref>Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease; it is Disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>

=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]

Aging and longevity

2023-01-29T01:40:54Z

Geroscientist: /* The geroscience hypothesis */

[[File:Updated deaths and aging.png|alt=|thumb|618x618px|Incidence of all age-related diseases increases exponentially with increasing age]]
People have yearned for the fountain of youth all throughout history. However, until recently, there has yet to exist a concerted research effort for actualizing this at a societal level. In the modern era, humanity is supportive of research towards the cure of age-related diseases (e.g. Alzheimer’s, heart disease, and [[Aging and Cancer|most cancers]]) – a desire present at every level of human organisation that spans across individuals, communities, and society. This reflects a core human desire to be healthy. Yet, recognizing that humanity should strive towards a cure for aging is a sentiment that does not attract such widespread popularity.

Lack of societal support stems from two fundamental misconceptions – that ‘aging’ merely represents the natural chronological passage of time, and that aging is an entirely separate category from ''age-related disease.''<ref>Sierra, F. (2016). The emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span. ''Cold Spring Harbor perspectives in medicine'', ''6''(4), a025163.</ref> In contrast, the biology of aging research field (biogerontology) understands the mechanisms of aging as the root cause of most of society’s most prevalent, costly, and debilitating diseases.<ref name=":2">[https://www.nature.com/articles/s41586-019-1365-2 Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]</ref><ref name=":14">[[Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. Nature Reviews Drug Discovery, 19(8), 513-532.|Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]]</ref><ref name=":3">[[Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.|Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., ... & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. ''Aging cell'', ''14''(4), 497-510.]]</ref>

In 2018, for the first time in human history, the number of people aged over 64 became greater than those aged under 5. This disparity is projected to only widen further with a rapidly aging population.<ref>Ritchie, H., & Roser, M. (2019). Age structure. ''Our World in Data''.</ref> The clear implications for a substantial increase in age-related disease burden has led to urgent calls from scientists for global society to support aging biology research to increase healthy life expectancy.<ref name=":3" /><ref>[[Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. Science translational medicine, 2(40), 40cm21-40cm21.|Rae, M. J., Butler, R. N., Campisi, J., De Grey, A. D., Finch, C. E., Gough, M., ... & Logan, B. J. (2010). The demographic and biomedical case for late-life interventions in aging. ''Science translational medicine'', ''2''(40), 40cm21-40cm21.]]</ref>

== What is aging? ==
Aging is an imprecise term with multiple definitions that depend on context. It may describe a time-dependent process in a physical, biological or sociological sense, and apply to the level of molecules, organisms, or inanimate objects.<ref>Hayflick, L. (2002). Anarchy in Gerontological Terminology. Handbook of the Biology of Aging, edited by Edward J. Masoro and Steven N. Austad. ''Gerontologist'', ''42''(3), 416-420.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref> Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.<ref name=":20">Cohen, A. A., Kennedy, B. K., Anglas, U., Bronikowski, A. M., Deelen, J., Dufour, F., ... & Fülöp, T. (2020). Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework. ''Mechanisms of ageing and development'', ''191'', 111316.</ref>

There is now a rapidly growing base of biogerontology researchers that study the biology of aging. This discipline of biomedical science is specifically interested in how the molecular mechanisms of aging are fundamental to the development of age-related diseases, and how these mechanisms unite seemingly unrelated diseases of aging.<ref>Franceschi, C., Garagnani, P., Morsiani, C., Conte, M., Santoro, A., Grignolio, A., ... & Salvioli, S. (2018). The continuum of aging and age-related diseases: common mechanisms but different rates. ''Frontiers in medicine'', ''5'', 61.</ref>

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.<ref name=":9">[https://www.nature.com/articles/s43587-020-00009-z Thuault, S. (2021). Reflections on aging research from within the National Institute on Aging. ''Nature Aging'', ''1''(1), 14-18.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1525861015002273?casa_token=0mXyA5DkGbEAAAAA:IQPQkZclcbJtVBP9n_FSw8f73B6h4ptjncaxATMkzTDU4Q_-I0-gUSoBgGhV2XodczzaItKCcA Fabbri E, Zoli M, Gonzalez-Freire M, Salive ME, Studenski SA, Ferrucci L. Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. Journal of the American Medical Directors Association. 2015 Aug 1;16(8):640-7.]</ref> Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.<ref>de Grey, A.D. (2013). The desperate need for a biomedically useful definition of “aging”. ''Rejuvenation Research'',16:89–90.</ref><ref name=":12">[https://linkinghub.elsevier.com/retrieve/pii/S0092-8674(14)01366-X Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., ... & Sierra, F. (2014). Geroscience: linking aging to chronic disease. ''Cell'', ''159''(4), 709-713.]</ref> This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.<ref>[https://linkinghub.elsevier.com/retrieve/pii/S1525-8610(15)00227-3 Fabbri, E., Zoli, M., Gonzalez-Freire, M., Salive, M. E., Studenski, S. A., & Ferrucci, L. (2015). Aging and multimorbidity: new tasks, priorities, and frontiers for integrated gerontological and clinical research. ''Journal of the American Medical Directors Association'', ''16''(8), 640-647.]</ref> Eventually, people die of a specific ARD, but many will suffer from multiple such diseases before death. Indeed, it is a common misconception that the elderly die of 'old age', although this term is useful when a specific cause of death is elusive.

Over the last few decades, biomedical scientists have identified several ''[[Hallmarks of Aging]]''<ref name=":13">[https://doi.org/10.1016/j.cell.2013.05.039 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.]</ref> that represent fundamental biological mechanisms of aging. These hallmarks form a basis for how aging might be targeted to slow, stop, or even reverse multiple age-related diseases. There are various theories for what is or what causes biological aging<ref>[[Jin, K. (2010). Modern biological theories of aging. Aging and disease, 1(2), 72.|Jin, K. (2010). Modern biological theories of aging. ''Aging and disease'', ''1''(2), 72.]]</ref><ref name=":1" /> - though there remains no consensus - and some argue that aging is not a unitary phenomenon.<ref name=":1">[https://www.sciencedirect.com/science/article/pii/S0047637420301408#bib0210 Cohen, A. A., Legault, V., & Fülöp, T. (2020). What if there’s no such thing as “aging”?. ''Mechanisms of Ageing and Development'', ''192'', 111344.]</ref><ref>[https://www.bmj.com/content/315/7115/1030 Peto, R., & Doll, R. (1997). There is no such thing as aging: Old age is associated with disease, but does not cause it.]</ref> However, it is now widely accepted among biogerontology researchers that various aging processes, such as the ''[[Hallmarks of Aging]]'', may be considered for medical intervention. This change in thinking is reflected by the dramatic increase in biotech companies and human clinical trials targeting aging.<ref>[https://www.sciencedirect.com/science/article/pii/S0167779917301713 De Magalhães, J. P., Stevens, M., & Thornton, D. (2017). The business of anti-aging science. ''Trends in biotechnology'', ''35''(11), 1062-1073.]</ref>

The current approach to medicine is generally focused on increasing lifespan by attempting to cure single diseases. In contrast, therapies that target biological aging are hypothesized to uniquely have the ability to significantly increase ''healthy'' lifespan. This is because the latter approach addresses what appears to be the fundamental biological mechanisms that unite ostensibly unrelated age-related diseases.<ref name=":0" /> This distinction is supported by decades of experimental evidence in animals, where the biology of aging is manipulated. It may also be inferred theoretically: If the incidence of all age-related diseases increases in an exponential relationship from progressive systemic decline with age, then eliminating any single age-related disease would achieve little, as it would merely allow one to develop another age-related disease soon after.

==Animal studies reveal that aging is malleable==
Numerous experimental breakthroughs over the last few decades have shown that, contrary to prevailing thought, biological aging is medically treatable in animals. Slowing or even hastening of aging in animals can be achieved via manipulation of diet, environment, genetics, epigenetics, or with drugs, with experiments ranging from roundworms to mice and even non-human primates.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref><ref>Keil, G., Cummings, E., & de Magalhaes, J. P. (2015). Being cool: how body temperature influences ageing and longevity. ''Biogerontology'', ''16''(4), 383-397.</ref><ref>Moskalev, A., Aliper, A., Smit-McBride, Z., Buzdin, A., & Zhavoronkov, A. (2014). Genetics and epigenetics of aging and longevity. ''Cell Cycle'', ''13''(7), 1063-1077.</ref><ref>Brunet, A., & Berger, S. L. (2014). Epigenetics of aging and aging-related disease. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''69''(Suppl_1), S17-S20.</ref><ref>[[Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature, 571(7764), 183-192.|Campisi, J., Kapahi, P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. ''Nature'', ''571''(7764), 183-192.]]</ref> Among the hundreds of aging laboratories across the world, aging is routinely manipulated by biogerontology researchers. This is a global endeavor attempting to understand what aging is, and to determine how this knowledge may be used to develop medicines for all of humanity.

=== Senolytics ===
An example of the striking differences in health that are possible with therapies that target aging biology can be seen in animal experiments of [[senolytics]], first conducted by researchers at the Mayo Clinic.[[File:Unity mice.png|alt=|center|thumb|664x664px|Senolytic drugs clear the senescent cells that accumulate with aging, partly reversing multiple age-related diseases with extension of healthspan and lifespan in old mice ]]Senescent cells are known to accumulate with aging throughout the body, and drive multiple age-related diseases. Experiments done in mice show that removing these cells with drugs that clear these cells - senolytics - restores health. This is because senolytics can slow and even partially reverse aging, which leads to increased healthspan from addressing multiple age-related diseases. As a side effect of the old mice being rejuvenated, studies have observed increases in median lifespan of up to 35%.

=== Epigenetic reprogramming ===
Recent experimental breakthroughs have provided early evidence that aspects of aging can be reversed,<ref name=":15">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref name=":16">Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020 Dec;588(7836):124-9.

https://www.nature.com/articles/s41586-020-2975-4</ref> further challenging old assumptions about aging simply being a result of chronological time.[[File:ONH regeneration epigenetic reprogramming.png|center|frame|In vivo epigenetic reprogramming can lead to regeneration of the optic nerve in injury and glaucoma mouse models, and lead to visual recovery in natural aging]]

[[Epigenetic reprogramming]] is based on work that earnt [https://embryology.med.unsw.edu.au/embryology/index.php/Embryology_History_-_Shinya_Yamanaka Shinya Yamanaka] the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells that are capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":18">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. ''cell'', ''131''(5), 861-872.</ref> This was achieved by activating only four transcription factors - the [[Yamanaka factors|''Yamanaka factors'']] - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":18" />

Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":15" /> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This research was published in 2016, when the Belmonte lab first showed that temporarily expressing the Yamanaka factors in a controlled manner could rejuvenate multiple aged organs and extend healthy lifespan in mice with accelerated aging.<ref name=":152">[[Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.|Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., ... & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. ''Cell'', ''167''(7), 1719-1733.]]</ref><ref>Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. ''Cell'', ''148''(1-2), 46-57.</ref>

Using epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref><ref name=":16" /> It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans. However, evidence for a truly comprehensive reversal of aging via partial reprogramming in mice, let alone in humans, is lacking. Whether reprogramming based strategies will extend healthy lifespan in normally aged mice is not currently well studied.
=== Dietary restriction mimetics and mTOR inhibitors ===
Dietary restriction (DR) has consistently been shown to extend healthy lifespan in animals ranging from worms, to mice, and to primates.<ref>Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.</ref><ref>Speakman, J. R., & Mitchell, S. E. (2011). Caloric restriction. ''Molecular aspects of medicine'', ''32''(3), 159-221.</ref> In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.<ref name=":24">Katewa, S. D., & Kapahi, P. (2010). Dietary restriction and aging, 2009. ''Aging cell'', ''9''(2), 105-112.</ref><ref name=":25">Selman, C. (2014). Dietary restriction and the pursuit of effective mimetics. ''Proceedings of the Nutrition Society'', ''73''(2), 260-270.</ref> Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.<ref name=":26">Unnikrishnan, A., Matyi, S., Garrett, K., Ranjo‐Bishop, M., Allison, D. B., Ejima, K., ... & Richardson, A. (2021). Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice. Aging Cell, e13500.</ref><ref name=":27">Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V., & Nelson, J. F. (2010). Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. ''Aging cell'', ''9''(1), 92-95.</ref> This is often due to genetic factors, such as several studies showing that while certain strains of mice subjected to DR live longer, other strains show no benefit or even lifespan detriment.<ref name=":26" /><ref name=":27" /> Other reasons may be related to environmental differences, or DR extent or diet composition in DR diets used in these experiments.

Dysregulation of nutrient-sensing is regarded as a hallmark of aging, playing a key role in the aging process.<ref name=":13" /> Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.<ref>de Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. ''New England Journal of Medicine'', ''381''(26), 2541-2551.</ref>

Given the difficulty of implementing DR as medicine for humans, due to difficulty with patient adherence, drugs that mimic the effects of dietary restriction are being developed.<ref name=":25" /> Similarly, there is a significant and ongoing research effort that aims to determine whether intermittent fasting or time restricted eating may capture some of the potential health benefits of DR, while being easier for patients to adhere to.<ref name=":24" /> There is generally a lack of evidence in human clinical trials in justifying the use of these lifestyle interventions for slowing aging in healthy adults.<ref>Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. (2021). Antiaging diets: Separating fact from fiction. ''Science'', ''374''(6570), eabe7365.</ref>

==== Metformin ====
Metformin extends healthy lifespan in worms, mice and rats.<ref>Song, J., Jiang, G., Zhang, J., Guo, J., Li, Z., Hao, K., ... & Dai, F. (2019). Metformin prolongs lifespan through remodeling the energy distribution strategy in silkworm, Bombyx mori. ''Aging (Albany NY)'', ''11''(1), 240.</ref><ref>Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016). Metformin: a hopeful promise in aging research. ''Cold Spring Harbor perspectives in medicine'', ''6''(3), a025932.</ref> Metformin is one of the cheapest and most commonly prescribed medications in the world, and has been linked to lower incidence of cancer, heart disease, dementia, and mortality in patients with type 2 diabetes (T2DM).<ref name=":19">Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. ''Cell metabolism'', ''23''(6), 1060-1065.</ref>

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, currently the first-line therapy for the age-related disease T2DM. One study suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic.<ref>Campbell, J. M., Bellman, S. M., Stephenson, M. D., & Lisy, K. (2017). Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. ''Ageing Research Reviews'', ''40'', 31-44.</ref> As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.<ref name=":19" />

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.<ref name=":19" /> The goal is to investigate whether metformin will slow aging in humans, as it has been shown to extend healthspan in some animals. This will be measured by whether metformin can prevent the onset of multiple age-related diseases such as heart disease, cancer, and dementia.

A key defining aspect in qualifying whether a drug targets aging (a gerotherapeutic or geroprotective drug), is the ability to delay or reverse the onset of multiple age-related diseases in tandem, to increase healthy lifespan.<ref>[https://www.nature.com/articles/s41573-020-0067-7 Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020). The quest to slow ageing through drug discovery. ''Nature Reviews Drug Discovery'', ''19''(8), 513-532.]</ref> The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.<ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869575/ Blagosklonny, M. V. (2021). The goal of geroscience is life extension. ''Oncotarget'', ''12''(3), 131.]</ref> Yet, what is clear now is that aging has a biology of critical relevance to the diseases associated with aging. This, along with multiple other lines of evidence across [[wikipedia:Biology|biology]] and [[wikipedia:Epidemiology|epidemiology]], suggest that the accumulation of multiple age-related diseases with time are not simply disparate processes or chance events that bear no relationship with one another. These diseases of older age, may in fact, be driven by an underlying aging process.<ref name=":2" /><ref name=":14" /><ref name=":3" />

==== Rapamycin ====
Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.<ref>[https://science.sciencemag.org/content/328/5976/321.abstract?casa_token=ptqabKjuDxMAAAAA:qBvrJQ01NpHQ8WyJSQf6HeQIhaaexgZXZMvi9i_AP4fE2iHhvMzLV-z3_eF5T3rEauJkg0eQNQFfbA Fontana, L., Partridge, L., & Longo, V. D. (2010). Extending healthy life span—from yeast to humans. ''science'', ''328''(5976), 321-326.]</ref> Some physicians and scientists have thus suggested that rapamycin may slow down aging.<ref name=":210">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/ Blagosklonny, M. (2019). Rapamycin for longevity: opinion article. ''Aging'', ''11''(19), 8048-8067. https://doi.org/10.18632/aging.102355]</ref><ref>Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. ''Nature'', ''493''(7432), 338-345.</ref> It is currently an approved drug used to prevent the rejection of organ transplants by the immune system. Rapamycin is a natural antifungal produced by soil bacteria of Eastern Island, named after its native island, Rapa Nui.<ref>''Sirolimus - Wikipedia''. En.wikipedia.org. (2021). Retrieved 27 May 2021, from <nowiki>https://en.wikipedia.org/wiki/Sirolimus</nowiki>.</ref>

Scientists who study the biology of aging believe that, due to evidence of rapamycin slowing aging in animals, it could be used to prevent the onset of all age-related diseases in humans – to become one of the first identified “anti-aging drugs”.<ref name=":210" /><ref>Blagosklonny, M. (2006). Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition. ''Cell Cycle'', ''5''(18), 2087-2102. <nowiki>https://doi.org/10.4161/cc.5.18.3288</nowiki></ref>

Among the hundreds of interventions studied within geroscience research, rapamycin is unique in its highly consistent and reproducible effect on healthy lifespan extension in mice.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref> It is also the drug that exhibits the largest lifespan effect extension in multiple strains of mice, both when dosed in early life and at old age.<ref>Johnson, S. C., Martin, G. M., Rabinovitch, P. S., & Kaeberlein, M. (2013). Preserving youth: does rapamycin deliver?. ''Science translational medicine'', ''5''(211), 211fs40.</ref><ref>Kaeberlein, M. (2014). Rapamycin and aging: when, for how long, and how much? ''Journal of genetics and genomics'', ''41''(9), 459.</ref> Rapamycin is being repurposed for humans as an anti-aging drug, such as in the PEARL clinical study, which is expected to provide preliminary results in 2023.<ref>[https://clinicaltrials.gov/ct2/show/NCT04488601 ''Participatory Evaluation (of) Aging (With) Rapamycin (for) Longevity Study - Full Text View - ClinicalTrials.gov''. Clinicaltrials.gov. (2021). Retrieved 27 May 2021, from https://clinicaltrials.gov/ct2/show/NCT04488601.]</ref>
=== The link between lifespan and aging ===
*Lifespan can range from mere days in mayflies, to several years in dogs, and up to centuries in bowhead whales<ref>[[Ogden, L. E. (2019). Travels through Time. BioScience, 69(11), 860-866.|Ogden, L. E. (2019). Travels through Time. ''BioScience'', ''69''(11), 860-866.]]</ref>

*Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time<ref name=":2" />

*Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species<ref name=":2" />
*Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging<ref>[[Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. Experimental gerontology, 64, 78-80.|Margolick, J. B., & Ferrucci, L. (2015). Accelerating aging research: how can we measure the rate of biologic aging?. ''Experimental gerontology'', ''64'', 78-80.]]</ref>
*Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics<ref name=":30">Govindaraju, D., Atzmon, G., & Barzilai, N. (2015). Genetics, lifestyle and longevity: lessons from centenarians. ''Applied & translational genomics'', ''4'', 23-32.</ref>
*Not only do centenarians live longer, but the period of suffering in late life from age-related diseases is also far shorter than non-centenarians - known as the compression of morbidity<ref>Andersen, S. L., Sebastiani, P., Dworkis, D. A., Feldman, L., & Perls, T. T. (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''67''(4), 395-405.</ref>

== Aging and age-related disease==
[[File:Aging as a risk factor.png|alt=Aging as a risk factor for common diseases|thumb|406x406px|Aging as a risk factor for common diseases]]
The totality of age-related diseases is prohibitively long to list in text, but includes Alzheimer’s, cardiovascular disease, most cancers, stroke, osteoarthritis, macular degeneration, and [[COVID-19]].[[File:Age is the -1 risk factor for COVID-19 mortality.jpg|alt=Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics|left|thumb|572x572px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]

Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the [[wikipedia:Gompertz–Makeham_law_of_mortality|Gompertz-Makeham law of mortality]]. This law essentially describes how all-cause mortality rate doubles every 8 years, which is a relationship common to age-related diseases alone.

==== COVID-19 defined as a disease of aging ====
As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging",]<ref name=":29">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576244/ Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]</ref> COVID-19 meets several criteria for definition as an age-related disease:<ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref name=":10">[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref name=":11">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref><ref>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288963/</ref>

'''1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality (characteristic exponential increase shared among major age-related chronic diseases);'''

'''2) Greater mortality rate in men, consistent with known sex differences in rates of aging;'''

'''3) Greater mortality rate for those with comorbidities (age-related diseases), consistent with accelerated biological aging; and,'''

'''4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude, exhibiting several thousand fold increase in risk across the lifespan'''

Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>
[[File:CDC stat table.jpg|center|thumb|883x883px]]
As compared to a reference group ''aged'' ''5-14'', the risk of death for COVID-19 is 8700 fold greater in those aged ''over'' ''85'', as per the [[US Center for Disease Control (CDC)]]. Common ''independent'' risk factors identified in scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2-fold risk of COVID-19 mortality, despite the reputation as a respiratory disease.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> The epidemiological data also makes clear that 'healthy' older adults with one or no comorbidities are still at substantially greater risk of severe disease than in the young. More importantly, those with accelerated biological aging with multiple comorbidities of age are at even greater risk.<ref>Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.</ref> This not only highlights how age is the ultimate risk factor for mortality, but also emphasizes the importance of biological age.

COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications.<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.<ref name=":10" /><ref name=":11" /> What is important about SARS-CoV-2 is that not only does the virus have many consequences across the entire body, but it also disproportionately affects those with higher biological age. Therefore, an emphasis on the specific organ system of respiration (or the virus itself), instead of on the aging host, may be regarded by biogerontology researchers as a short-sighted therapeutic strategy in the long-term.<ref name=":10" /> This is especially important for preventing future pandemics, as well as to address multiple other age-related diseases of an aging population that is burdening global healthcare systems.

==== Traditional risk factors and heart disease ====
[[File:CVD 1st Risk Factor .png|alt=Aging dwarfs all other risk factors for heart disease|center|thumb|933x933px|Aging dwarfs all other risk factors for heart disease - suggesting a central role - yet remains an unexplored target for drug development]]
Hypertension, smoking, and cholesterol are examples of well-known heart disease risk factors that have been used by scientists/physicians to guide the research and development of effective therapies. This strategy originated from the Framingham Heart Study – an initiative spanning decades that observed thousands of people to understand what genetic and environmental factors influence heart disease.<ref>Mahmooda, S. S., Levy, D., Vasan, R. S., & Wang, T. J. (2014). The Framingham Heart Study and the epidemiology of cardiovascular diseases: A historical perspective. ''Lancet'', ''383''(9921), 999-1008.</ref>The resulting risk factor paradigm has since been adopted across all domains of disease in biomedical research, and is core to the practice of clinical medicine
Coordinated research efforts have helped identify genetic and environmental factors important to heart disease risk. Identifying whether risk factors are modifiable enables the development of effective therapeutics, such as for the prevention of cardiovascular diseases. For example, identifying high blood pressure and cholesterol as modifiable risk factors has since led to anti-hypertensive and cholesterol medications being among the most commonly prescribed drugs across the world.<ref>Hajar, R. (2016). Framingham contribution to cardiovascular disease. ''Heart views: the official journal of the Gulf Heart Association'', ''17''(2), 78.</ref> Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.<ref>Kaeberlein, M., Rabinovitch, P. S., & Martin, G. M. (2015). Healthy aging: the ultimate preventative medicine. ''Science'', ''350''(6265), 1191-1193.</ref> However, aging is also traditionally viewed as a risk factor that cannot be modified. Unmodifiable risk factors are regarded as unimportant for the development of interventions. The prevailing assumption that aging is an unmodifiable risk factor is now being challenged by biogerontology researchers.<ref>Olshansky, S. J. (2015). Has the rate of human aging already been modified?. ''Cold Spring Harbor perspectives in medicine'', ''5''(12), a025965.

</ref>

The overall exponential relationship between increasing age and mortality is consistent for various age-related diseases, regardless of whether a disease is acute or chronic. This reflects the continually increasing vulnerability and decreasing resilience of the human body with age.

== Why is population aging a problem? ==
Often described as the ‘climate change of healthcare’, an aging population comes with challenges due to declines in productivity, loss of independence, and increasingly unsustainable healthcare costs.
In 2018, human civilisation reached an unprecedented point in history. People aged over 65 now outnumber those aged under 5, and this disparity is projected only to widen across the world as the global population ages and fertility rates continue to decline.<ref>https://ourworldindata.org/age-structure?source=content_type%3Areact%7Cfirst_level_url%3Aarticle%7Csection%3Amain_content%7Cbutton%3Abody_link</ref><ref>[https://doi.org/10.1038/nature06516 Lutz, W., Sanderson, W., & Scherbov, S. (2008). The coming acceleration of global population ageing. ''Nature'', ''451''(7179), 716-719.]</ref>

The aging population is a major contributor to increasing [https://ourworldindata.org/financing-healthcare global healthcare costs, which have risen steadily since the 1900s] and are projected only to grow further.<ref name=":8">[[Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. Aging and disease, 6(1), 1.|Jin, K., Simpkins, J. W., Ji, X., Leis, M., & Stambler, I. (2015). The critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population. ''Aging and disease'', ''6''(1), 1.]]</ref> These costs are increasingly unsustainable, and demographic change is also expected to place a greater burden on society due to increased dependency and reduced productivity.

The COVID-19 pandemic is an example of what a single age-related disease can do to an aging society. [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html US CDC statistics] show that 97.11% of mortality occurs in those aged over 45, and the exponential increase in mortality risk with age is essentially identical to all other leading causes of death and suffering, such as for cardiovascular diseases and cancer.<ref name=":29" /> The pandemic has highlighted the vulnerability of our aging population, and foreshadows an impending healthcare crisis of an aging world - the climate change of healthcare.

Aging is not just a problem for the ‘elderly’, as various aspects of aging begin well before middle-age. Many people suffer from accelerated aging and develop multiple age-related diseases prematurely, such as with depression, stress, poverty, HIV/AIDs, diabetes, smoking, Down Syndrome, accelerated aging syndromes (e.g. progerias) and in childhood cancer survivors.<ref>[https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2776612 Wertz, J., Caspi, A., Ambler, A., Broadbent, J., Hancox, R. J., Harrington, H., ... & Moffitt, T. E. (2021). Association of History of Psychopathology With Accelerated Aging at Midlife. JAMA psychiatry.]</ref><ref>[[Bersani, F. S., Mellon, S. H., Reus, V. I., & Wolkowitz, O. M. (2019). Accelerated aging in serious mental disorders. Current opinion in psychiatry, 32(5), 381.]] </ref><ref>[[Yegorov, Y. E., Poznyak, A. V., Nikiforov, N. G., Sobenin, I. A., & Orekhov, A. N. (2020). The link between chronic stress and accelerated aging. Biomedicines, 8(7), 198.]]</ref><ref>[[Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(2), 286-292.|Crimmins, E. M., Kim, J. K., & Seeman, T. E. (2009). Poverty and biological risk: the earlier “aging” of the poor. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''64''(2), 286-292.]]</ref><ref>[./Https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. Clinical epigenetics, 11(1), 1-9.]</ref><ref>Aung, H. L., Aghvinian, M., Gouse, H., Robbins, R. N., Brew, B. J., Mao, L., & Cysique, L. A. (2020). Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review. AIDS and Behavior, 1-44.</ref><ref>[https://www.sciencedirect.com/science/article/pii/S1550413119302463 Aguayo-Mazzucato, C., Andle, J., Lee Jr, T. B., Midha, A., Talemal, L., Chipashvili, V., ... & Bonner-Weir, S. (2019). Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell metabolism, 30(1), 129-142.] </ref><ref>[[Gensous, N., Bacalini, M. G., Franceschi, C., & Garagnani, P. (2020, July). Down syndrome, accelerated aging and immunosenescence. In Seminars in Immunopathology (pp. 1-11). Springer Berlin Heidelberg.]] </ref><ref>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559172/ Yamaga, M., Takemoto, M., Shoji, M., Sakamoto, K., Yamamoto, M., Ishikawa, T., ... & Yokote, K. (2017). Werner syndrome: a model for sarcopenia due to accelerated aging. Aging (Albany NY), 9(7), 1738.]</ref><ref name=":4">[https://academic.oup.com/jnci/article/113/2/112/5827003?login=true Guida, J. L., Agurs-Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark-Wahnefried, W., ... & Ness, K. K. (2020). Strategies to Prevent or Remediate Cancer and Treatment-Related Aging. ''JNCI: Journal of the National Cancer Institute'']</ref><ref>Kohanski, R. A., Deeks, S. G., Gravekamp, C., Halter, J. B., High, K., Hurria, A., ... & Sierra, F. (2016). Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health? ''Annals of the New York Academy of Sciences, 1386,'' 30-44</ref>

As a result of the potential for rejuvenation of multiple tissues and organs which has been seen in aging biology research, the applications of such research to human health are not merely limited to age-related diseases. In addition to the above-mentioned examples of accelerated aging, there are also significant implications for orphan or rare diseases.

== Economic implications of targeting aging ==
In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025.<ref>https://www.cnbc.com/2019/05/08/techs-next-big-disruption-could-be-delaying-death.html</ref> This is nearly a six-fold increase over 6 years, reflecting the burgeoning interest in aging biology research.

A recent paper published by Professors at Harvard Medical School, Oxford University, and London Business School, estimated that a drug that slows aging by merely one year could add $US 38 trillion to the economy. This is justified by estimating how slowed aging can result in both improved health and longevity. The resultant increases in independence and productivity is subject to a virtuous cycle of further gains. This analysis highlights the profound difference between targeting single diseases, versus targeting aging.

==== '''Healthspan versus lifespan''' ====
'''The concept of healthspan describes the period of life spent free from disease'''

In the 21st Century, population healthspan contrasts significantly with lifespan. Although the latter has steadily increased over the last two centuries, the evidence strongly suggests that healthspan has not kept up with lifespan.<ref name=":0">[https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true Crimmins, E. M. (2015). Lifespan and healthspan: past, present, and promise. ''The Gerontologist'', ''55''(6), 901-911.]</ref>

Advances in various public health measures, substantial reductions in childhood mortality, and effective treatments for several leading causes of death such as cardiovascular diseases have led to increased human life expectancy.<ref name=":8" /><ref name=":0" /> However, many human populations now spend a greater proportion of life in ill health.<ref name=":8" /><ref name=":0" /><ref>[[Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. Journal of Gerontology: Social Sciences, 66B, 1.|Crimmins, E. M. (2011). Beltrán-‐Sánchez, H.(2010). Mortality and morbidity trends: Is there compression of morbidity. ''Journal of Gerontology: Social Sciences, 66B'', ''1''.]]</ref> Reduced mortality from specific diseases may allow humans to survive into older age, but the quantity of life gained is minimal due to diminishing returns from competing risks of mortality.<ref name=":5">Keyfitz, N. (1977). What difference would it make if cancer were eradicated? An examination of the Taeuber paradox. ''Demography'', ''14''(4), 411-418.</ref><ref name=":6">Mitra, S. (1978). A short note on the Taeuber paradox. ''Demography'', ''15''(4), 621-623.</ref> More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.<ref name=":0" />

'''Single disease medicine'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of 'one disease at a time' medicine.<ref name=":7">[https://www.sciencedirect.com/science/article/pii/S2468501117300081 Kaeberlein, M. (2017). Translational geroscience: A new paradigm for 21st century medicine. ''Translational medicine of aging'', ''1'', 1-4.]</ref>

The infectious disease model of medicine, which originates from [[wikipedia:Germ_theory_of_disease|germ theory]], accounts for historic human public health achievements of the 20th Century. These include substanial reductions in mortality from communicable diseases, such as smallpox, measles, and HIV/AIDS.<ref>Armstrong, G. L., Conn, L. A., & Pinner, R. W. (1999). Trends in infectious disease mortality in the United States during the 20th century. ''Jama'', ''281''(1), 61-66.</ref><ref>Fauci, A. S. (2001). Infectious diseases: considerations for the 21st century. ''Clinical Infectious Diseases'', ''32''(5), 675-685.</ref> This paradigm relies on disease classifications characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease. Treating diseases separately as they come, one by one, defines the current strategy to medicine.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach is to wait until people get sick with various chronic diseases, and then attempt to treat them. In healthcare, there is little emphasis on keeping aging people 'healthy', at least as compared to what is commonly regarded as youthful health.<ref name=":7" /> From the perspective of geroscience, the physiological changes with aging that precede disease should be considered within the domain of medicine.

While originally used for acute diseases such as the Flu, this paradigm has since permeated into chronic diseases that persist in the long-term...

We know that the prognosis of age-related disease means that no one escapes from the long journey of decrepitude, even if we contract different age-related diseases at different chronological ages.

Additionally, it can be inferred from the current approach to medicine of the prevailing belief that medical outcomes are attained with an approach that subcategorises into organ or physiologic systems. This is reflected in increasing subspecialisation. For example, for type 2 diabetes, patients typically begin with a general practitioner; further disease progression may then involve physicians specialising in endocrinology, or even further with diabetology. At the level of single diseases, specialisation makes sense...But at the level of population health, in the context of aging, this fails to recognise the complexities of multimorbidity, the age-related development of multiple chronic diseases.

'''The Taeuber Paradox'''

Assuming that the goal of medicine should be to maximize both quality and length of life, the single disease medicine paradigm is theoretically flawed. Even if a cure for a specific age-related disease were possible, the exponential increase in risk of death from other competing diseases continues unabated.'''<ref name=":7" />'''This flaw can be further understood via the Taeuber Paradox:

Completely curing heart disease or cancer, which are among the leading causes of deaths globally, is estimated to each add only ~2.5 years to life expectancy.''<ref name=":5" />''<ref name=":6" /> Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.<ref>Arias, E., Heron, M. P., & Tejada-Vera, B. (2013). United States life tables eliminating certain causes of death, 1999-2001.</ref><ref>Hayflick, L. (2021). The greatest risk factor for the leading cause of death is ignored. ''Biogerontology'', ''22''(1), 133-141.</ref>

Additionally, such cures would have minimal or even detrimental effects on healthspan. For example, it is well known that the stress induced by cancer therapies accelerates aging.<ref>[https://academic.oup.com/jnci/advance-article/doi/10.1093/jnci/djab064/6207975?login=true Prasanna, P. G., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., ... & Coleman, C. N. (2021). Therapy-Induced Senescence: Opportunities to Improve Anti-Cancer Therapy. ''JNCI: Journal of the National Cancer Institute''.]</ref> Childhood cancer survivors develop heart disease, Alzheimer’s, [[frailty]] and other age-related diseases years or even decades earlier.<ref name=":4" />

Aiming to cure diseases one at a time, instead of addressing aging itself, results in diminishing returns due to competing risks of morbidity and mortality. Delaying heart disease with cholesterol medications does not address incipient frailty, preventing fatality from kidney disease may result in eventual Alzheimer’s. Indeed, the modern rise in Alzheimer's prevalence may have come about due to successes in delaying cardiovascular diseases, which are major causes of death.

== The geroscience hypothesis ==
'''...Work in Progress...'''

‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research mainly concerned with animal aging, to one that is now concerned with human aging. The fundamental link between aging and age-related disease has been identified as the ''geroscience hypothesis''.<ref name=":12" /> This hypothesis posits that there are foundational biological mechanisms or 'pillars' of aging shared between apparently unrelated age-related diseases, which may be targeted for intervention to address multiple diseases in tandem.<ref name=":12" /><ref name=":13" />

In other words, if aging is the primary cause of the various diseases that accumulate with age, then targeting this biology will treat or prevent multiple diseases. This affords a far greater potential to extend healthy lifespan than single-disease approaches. The geroscience hypothesis could therefore, within the context of an aging population, bring about a paradigm shift in the approach to medicine.
'''"There has been a shift in how we have considered aging, from something that we needed to account for and eliminate by statistical adjustment to a causal factor in disease...understanding aging provides the strongest chance to prevent chronic diseases and expand healthspan"<ref name=":9" />'''
<small>''Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)''</small>

One of the key aspects that distinguishes a geroprotector from medicine developed in the past is that the former may address aging as the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. Strictly speaking, a factor that causes a disease implies it is the (major) reason for developing a disease; however, the risk of developing a majority of diseases depends on many factors that each play small roles. Acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor (but are otherwise apparently unrelated). Based on experimental evidence in animals, as well as examples of slowed aging such as in centenarians, there is a case to be made that aging is a primary cause of age-related diseases.<ref name=":2" /><ref name=":30" />

It is possible that in humans, aging drives multiple age-related diseases simultaneously, even if such diseases do not arise at the same period of an individual's life, and do not follow a specific order for a given individual. As the salient risk factor, aging can be understood as the principal driver of age-related disease - for which there are further interactions with individual genetic and environmental factors that predispose to a specific age-related pathology. Therefore, aging ARDs can be understood to be 'symptoms' of aging. E.g. A female with 2 copies of the APOE4 gene might have a 12x greater risk of Alzheimer’s and begin developing early AD symptoms at age 65.<ref name=":23">Ungar, L., Altmann, A., & Greicius, M. D. (2014). Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction. ''Brain imaging and behavior'', ''8''(2), 262-273.</ref> If she had instead been homozygous for APOE4 with only 1 copy of the disease-predisposing gene, this risk would only be 4x;<ref name=":23" /> she may instead die of a heart attack at age 73.

== Is aging a disease? ==
'''...Work in Progress...'''

Aging is often regarded as a natural and universal fact of life. In medicine, physicians are tasked with the need to classify whether the patient in front of them has a disease or not. This is a necessary part of the current approach of disease-centric medicine, because a somewhat binary decision must be made to determine whether treatment is necessary. Under this paradigm, age-related changes not immediately regarded as disease may be deemed normal, and so further management is not necessary. Such change with age may be functional, such as declines in grip strength or exercise capacity; or physiological, such as increased low-grade systemic inflammation.<ref>Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., & Woodhouse, K. W. (2009). Inflammation and frailty measures in older people. ''Journal of cellular and molecular medicine'', ''13''(9b), 3103-3109.</ref><ref>Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007). Inflammation and frailty in older women. ''Journal of the American Geriatrics Society'', ''55''(6), 864-871.</ref> What may be regarded as normal or healthy in clinical practice is also typically compared to chronological age, i.e. being healthy for one's age. This thinking neglects the reality that a healthy 60 year old is functionally impaired compared to the average 20 year old, <ref>Kaeberlein, M. (2019). It is time to embrace 21st-century medicine. ''public policy & aging report'', 29(4), 111-115</ref>

However, some level of collective confusion in meaning is prevalent among the public, physcians, and scientists. This is predominantly due to the imprecision of the word 'aging'.

Even among aging biology researchers there is a lack of consensus as to what aging refers to.<ref name=":20" /> This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into mainstream public consciousness. Yet, there is now consensus among geroscience researchers (the subfield of aging biology concerned with medicine) that aging mechanisms can be targeted to increase human healthspan.

Whether aging is a disease or not is regarded by some researchers as a mere semantic problem. This is as it does not directly interfere with the goals of geroscience. Researchers in the field believe that targeting aging biology will be integral to addressing the ongoing and growing public health crisis of an aging population.

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases.<ref name=":28">Chiong, W. (2001). Diagnosing and defining disease. ''JAMA'', ''285''(1), 89-90.</ref> Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.<ref name=":28" /><ref>Brown, W. M. (1985). On defining ‘disease’. ''The Journal of Medicine and Philosophy'', ''10''(4), 311-328.</ref> For example, before effective treatments for tuberculosis were created, it was commonly regarded as natural and to be accepted. Tuberculosis was actively glorified and romanticized.<ref>Larsson, L. (2019). Dealing with Death: The Romanticising of Tuberculosis in Three Victorian Novels.</ref><ref>Latimer, D. (1990). Erotic susceptibility and tuberculosis: literary images of a pathology. ''MLN'', ''105''(5), 1016-1031.</ref> Some may argue that if an ailment affects everyone, it should not be classified as a disease, which is a common talking point against calling aging a disease.

Atherosclerosis, the hardening of arteries, is near ubiquitous with aging, yet has disease status.<ref name=":22">Head, T., Daunert, S., & Goldschmidt-Clermont, P. J. (2017). The aging risk and atherosclerosis: a fresh look at arterial homeostasis. ''Frontiers in genetics'', ''8'', 216.</ref> Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.<ref name=":22" /> In a paper published by the inventor of statins, Akira Endo comments: "Serious research on the role of cholesterol in human atherosclerosis did not really get underway until the 1940s, due to a prevailing view that the disease was a simple consequence of aging and could not be prevented." A more recent example is sarcopenia, a term referring to the age-related, progressive loss of muscle function. In 2016, sarcopenia was added to the World Health Organization's ICD-10 list of diseases.<ref name=":21">Anker, S. D., Morley, J. E., & von Haehling, S. (2016). Welcome to the ICD‐10 code for sarcopenia.</ref>

Disease definitions in medicine are continually changing, and often depending on whether we have treatments for a given disease or not. This has implications for regulation, such as in considering the scope of the Federal Drug Administration (FDA) in the US. Additionally, classification as a disease spurs further research into developing diagnostics, and also for pharmaceutical companies to develop treatments.<ref name=":21" />

There are growing numbers of aging researchers calling on governments to classify aging as a disease at a regulatory level, at least in the biological sense of the word as it relates to age-related disease.<ref>Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., ... & Church, G. (2019). To help aging populations, classify organismal senescence. ''Science'', ''366''(6465), 576-578.</ref><ref>Zhavoronkov, A., & Bhullar, B. (2015). Classifying aging as a disease in the context of ICD-11. ''Frontiers in genetics'', ''6'', 326.</ref><ref>Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. ''Frontiers in genetics'', ''6'', 205.</ref> Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.<ref>Rattan, S. I. (2014). Aging is not a disease: implications for intervention. ''Aging and disease'', ''5''(3), 196.</ref><ref>Kirkwood, T. B. (2003). The most pressing problem of our age. ''Bmj'', ''326''(7402), 1297-1299.</ref> Another line of thought is that aging is neither a disease or not a disease; it is Disease or not, if the biology of aging causatively influences health and vulnerability to disease, then there is moral imperative to develop medicines that alleviate such suffering.<ref>Gladyshev, T. V., & Gladyshev, V. N. (2016). A disease or not a disease? Aging as a pathology. ''Trends in molecular medicine'', ''22''(12), 995-996.</ref><ref>Faragher, R. G. (2015). Should we treat aging as a disease? The consequences and dangers of miscategorisation. ''Frontiers in genetics'', ''6'', 171.</ref>

=== References ===
<references />
[[Category:Main list]]
[[Category:Longevity concepts]]
[[Category:Fundamentals]]