Aging and longevity

From Longevity Wiki
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 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.[1] 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.[2][3][4]

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.[5] 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.[4][6]

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.[7][8] Even when narrowly considered in a biological context, an exact consensus definition is difficult among researchers for such a complex phenomenon.[9]

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.[10]

Medically speaking, aging may be thought of as the progressive physiological decline in the body’s resilience and ability to overcome stressors.[11][12] Aging-related decline in physical and mental capacity leads to permanent loss of function, independence, and dignity.[13][14] This occurs due to the accumulation of multiple age-related diseases (ARDs), leading to an extended period of suffering from mid to late life.[15] 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[16] 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[17][18] - though there remains no consensus - and some argue that aging is not a unitary phenomenon.[18][19] 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.[20]

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.[21] 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.[22][23][24][25][26] 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.

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,[27][28] further challenging old assumptions about aging simply being a result of chronological time.

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 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.[29][30] This was achieved by activating only four transcription factors - the Yamanaka factors - OCT4, SOX2, KLF4, and MYC (or OSKM).[29][30]

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.[27] 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.[31][32]

Using epigenetic reprogramming in naturally aged mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.[33][34][28] 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.[35][36] In animals, DR leads to significant improvement to healthy lifespan; however, the proportional lifespan benefit generally declines with increasing species size/complexity.[37][38] Like many therapies that target aging, the effect of DR is not consistent across different studies for various reasons.[39][40] 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.[39][40] 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.[16] Relevant metabolic pathways such as IGF-1, mTOR and AMPK, are influenced by DR in extending healthy lifespan in animals.[41]

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.[38] 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.[37] 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.[42]

Metformin

Metformin extends healthy lifespan in worms, mice and rats.[43][44] 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).[45]

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.[46] As metformin has also shown healthspan and lifespan extension effects in naturally aging worms and mice, some researchers believe that it may slow aging.[45]

The Targeting Aging with Metformin (TAME) trial is a US, nation-wide, six-year clinical trial of over 3000 individuals aged 65 to 79.[45] 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.[47] The aging field continues to debate whether a geroprotector necessarily needs to increase healthspan, or both healthspan and lifespan.[48] 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 biology and 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.[2][3][4]

Rapamycin

Rapamycin has been shown to extend healthy lifespan in worms, yeast, flies, and mice.[49] Some physicians and scientists have thus suggested that rapamycin may slow down aging.[50][51] 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.[52]

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”.[50][53]

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.[54] 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.[55][56] 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.[57]

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[58]
  • Studying aging in animals has led to an understanding that aging is biological and not a mere consequence of time[2]
  • Research in a range of different animals show that there exists extreme variance in rates of aging, within and across species[2]
  • Humans have been observed to exhibit substantial variance in rates of aging, both in terms of accelerated and decelerated aging[59]
  • Centenarians (those living to age 100 or more) live longer due to a delayed onset of all age-related diseases, influenced primarily by genetics[60]
  • 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[61]

Aging and age-related disease

Aging as a risk factor for common diseases
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.

Age is the #1 risk factor for COVID-19 mortality - based on US CDC statistics
* Fold risk of COVID-19 mortality versus reference group aged 5-17 (US CDC statistics)




Age-related diseases can be identified by a characteristic exponential increase in incidence with age, following the 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 "COVID‐19 is an emergent disease of aging",[62] COVID-19 meets several criteria for definition as an age-related disease:[63][64][65][66][67]

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 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.[68]

CDC stat table.jpg

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.[69] 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.[70] 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.[71] Therefore, testing of geroprotectors that target multiple aged and vulnerable organ systems in clinical trials is hypothesized to be desirable.[65][66] 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.[65] 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

Aging dwarfs all other risk factors for heart disease
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.[72]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.[73] Aging is widely accepted among physicians and biomedical scientists as the greatest risk factor for almost all the major diseases in developed countries.[74] 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.[75]

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.[76][77]

The aging population is a major contributor to increasing global healthcare costs, which have risen steadily since the 1900s and are projected only to grow further.[78] 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. 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.[62] 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.[79][80][81][82][83][84][85][86][87][88][89]

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.[90] 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.[21]

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.[78][21] However, many human populations now spend a greater proportion of life in ill health.[78][21][91] 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.[92][93] More importantly, this is permissive for increased periods of suffering from typically non-fatal conditions such as osteoarthritis or cognitive decline.[21]

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.[94]

The infectious disease model of medicine, which originates from 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.[95][96] 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.[94] 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.[94]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.[92][93] Eliminating Alzheimer's disease as a cause of death would add only 2 months to life expectancy.[97][98]

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.[99] Childhood cancer survivors develop heart disease, Alzheimer’s, frailty and other age-related diseases years or even decades earlier.[88]

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 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.[14] 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.[14][16]

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 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"[11]                                                                                                                           

Luigi Ferrucci, MD/PhD, Scientific Director of the National Institute on Aging (NIA, of the US National Institutes of Health)

One of the key aspects that distinguishes a geroprotective therapy from medicine developed in the past is that the former would address what appears to be the primary cause of age-related diseases. The term 'cause' is not typically used rigorously in the biomedical sciences. After all, it implies that a given cause is the (major) reason for producing a disease. Given that the acceleration and deceleration of biological aging influences the development of various diseases that share age as the major risk factor but are otherwise unrelated, there is a case to be made that aging is a primary cause of age-related disease.

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.[100] If she had instead been homozygous for APOE4 with only 1 copy of the disease-predisposing gene, this risk would only be 4x;[100] 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.[101][102] 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, [103]

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.[9] 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.[104] Criteria for disease definitions are often highly inconsistent or debated, and influenced significantly by evolving sociocultural factors.[104][105] 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.[106][107] 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.[108] Despite prevalence approaching 100% with age, blood pressure and cholesterol medications are widely prescribed to prevent atherosclerosis.[108] 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.[109]

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.[109]

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.[110][111][112] Others contend that aging cannot be considered a disease, because aging affects everyone, and that aging is a natural part of life.[113][114] 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.[115][116]



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