Aging and longevity

2021-06-24T03:19:07Z

Mxschons: Added a link + some formatting

[[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 (biogerontology) research field understands the mechanisms of aging as the root cause 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>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 developing 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 various animal experiments 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 clearly that, contrary to common knowledge, 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 endeavour attempting to understand what aging is, and to determine how this knowledge may be used to develop widely-accessible medicines for 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 to treat multiple age-related diseases, leading to extension of healthspan and lifespan in normally aging 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.
=== 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. In animals, DR leads to substantial benefits to healthy lifespan; however, proportional lifespan benefit generally declines with increasing species size/complexity.

given the difficulty of implement DR as an intervention in humans, drugs that mimic the effects of dietary restriction are being developed.

Nutrient-sensing pathways (e.g. IGF-1, mTOR and AMPK) play key roles in the aging process.

==== Metformin ====
Metformin extends healthy lifespan in worms and mice.

The Targeting Aging with Metformin (TAME) trial is investigating a drug with over 6 decades of human use, which is currently the first-line therapy for the age-related disease type 2 diabetes (T2DM). 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 T2DM. Some studies have suggested that despite the life-shortening effects of diabetes, T2DM patients on metformin, but not other medications, outlive those who are not diabetic. As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may be slowing aging.

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79. The goal is to investigate whether the type 2 diabetes drug 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 age-related diseases such as heart diseases, cancers, and dementias.

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 gerotherapeutic 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" />

==== 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>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>[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 2x greater risk of COVID-19 mortality<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>, despite reputation as a 'respiratory disease'. 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, geroprotectors that provide improvement to multiple aged and vulnerable organ systems would 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 uniquely affects those with higher biological age disproportionately. 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. As scientific research has identified whether these risk factors are modifiable, been critical to developing effective therapeutics. For example, identified risk factors, such as high blood pressure and cholesterol, have led to anti-hypertensive and cholesterol medications now being among the most commonly prescribed drugs across the world for the prevention of cardiovascular diseases.<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.

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 (albeit one that is more acute than chronic) can do to 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. The pandemic has highlighted the vulnerability of our aging population, and foreshadows how global societies are unprepared for the 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, smoking, HIV/AIDs, diabetes, 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?.</ref>

== Economic Implications of Targeting Aging ==
'''...Work in Progress...'''

In 2019, the Bank of America projected the longevity industry to reach $600 billion by 2025. This is almost a six-fold increase over 6 years, reflecting how rapidly aging biology research is gaining traction.

[https://www.calicolabs.com/ Calico Labs], a subsidiary of Google, is a biotech company that aims to target aging to address age-related diseases.

The company launched a partnership with the pharmaceutical giant AbbVie, starting from 2014. This collaboration has since developed into a $2.5 billion venture in the pursuit of improving “health, wellbeing and longevity.” Calico, which stands for “California Life Company”,

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 and the Taeuber Paradox'''

A major problem in the current healthcare strategy for an aging population lies in the traditional medical paradigm of single-disease 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 model may also be referred to as single-disease medicine, where diagnoses are made based on disease classifications. These classifications are characterised by sets of symptoms and signs, which are then treated with intervention(s) targeting the given disease.

The current approach to medicine is often described by proponents of preventive medicine as 'sick care' rather than healthcare. The overall approach being taken for various chronic diseases is to wait until people get sick, and then attempt to treat them. From the perspective of aging, there is much less emphasis on keeping people healthy, as humans generally are in their 20s.

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. Geriatricians... ?

This paradigm may theoretically be flawed. Even if a cure for a specific age-related disease is possible, the exponential increase in risk of death from other ARDs 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, would 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, treating kidney disease to live longer may result in eventual Alzheimer’s...

== The Geroscience Hypothesis ==
'''...Work in Progress...'''

‘Geroscience’ represents the maturation of the research field of aging biology, transitioning from a research field mainly concerned with animal aging, to one that is now concerned with human aging. The inextricable link between aging and age-related disease has been formally identified by the aging research field 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 lead to the amelioration of multiple diseases. This affords far greater potential to extend healthy lifespan than single-disease approaches. The implications of the geroscience hypothesis is therefore - within the context of an aging population - of revolutionary potential for human society.
'''"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 therapy that targets aging from medicine developed in the past is that the former would address what appears to be the primary cause of age-related diseases. - Cause implies that it is the major reason for the disease, for example, the above-mentioned risk factor of

idea that 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. If she had instead been homozygous for APOE4 with only 1 copy of the disease-predisposing gene, this risk would only be 4x; 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 binary decision must be made to determine whether treatment is needed or not.

However, some level of confusion is prevalent among the public, physcians, and scientists. A subsantial reason for this is 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. This remains a significant problem among scientists, and is regarded by some as a barrier to advancing the field into public consciousness. However, there is now consensus among geroscience researchers (the subfield of aging biology directly concerned with human medicine) that aging mechanisms can be targeted to increase healthy human life expectancy.

However, this is more of a semantic problem, because researchers in the geroscience field believe that increasing human healthspan with interventions that target aging biology could be integral to addressing the ongoing public health crisis of an aging population.

level of society or regulation.

There are various historical examples of prevalent diseases that were once accepted as normal, but have since become thought of as diseases. For example, before effective treatments for tuberculosis were created,

There are growing numbers of aging researchers who are calling on government organizations to classify aging as a disease, at least in the biological sense of the word.

==== Citations ====
*

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