Ageing

Ageing
A human face showing signs of ageing
Classification and external resources
OMIM	502000
MeSH	D000375

Ageing (British English) or aging (American English) is the process of becoming older. In the narrow sense, the term refers to biological ageing of human beings, animals and other organisms. In the broader sense, ageing can refer to single cells within an organism (cellular ageing) or to the population of a species (population ageing).

In humans, ageing represents the accumulation of changes in a human being over time,^[1] encompassing physical, psychological, and social change. Reaction time, for example, may slow with age, while knowledge of world events and wisdom may expand. Ageing is among the greatest known risk factors for most human diseases:^[2] of the roughly 150,000 people who die each day across the globe, about two thirds die from age-related causes.

The causes of ageing are unknown; current theories are assigned to the damage concept, whereby the accumulation of externally induced damage (such as DNA point mutations) may cause biological systems to fail, or to the programmed ageing concept, whereby internal processes (such as DNA telomere shortening) may cause ageing.

The discovery, in 1934, that calorie restriction can extend lifespan twofold in rats, and the existence of species having negligible senescence and potentially immortal species such as Hydra, have motivated research into delaying and preventing ageing and thus age-related diseases.

Ageing versus immortality

Human beings and members of many other species necessarily experience ageing and mortality. In contrast, some species can be considered immortal: for example, bacteria fission to produce daughter cells, strawberry plants grow runners to produce clones of themselves, and animals in the genus Hydra have a regenerative ability with which they avoid dying of old age.

Even within humans and other mortal species, there are arguably cells with the potential for immortality: cancer cells which have lost the ability to die such as the HeLa cell line, stem cells, and specifically germ cells (producing ova and spermatozoa).^[3] In artificial cloning, adult cells can be rejuvenated back to embryonic status and then used to grow a new tissue or animal without ageing.^[4] Normal human cells however die after about 50 cell divisions in laboratory culture (the Hayflick Limit, discovered by Leonard Hayflick in 1961).

After a period of near perfect renewal (in humans, between 20 and 35 years of age), ageing is characterised by the declining ability to respond to stress, increasing homeostatic imbalance and the increased risk of disease. This currently irreversible series of changes inevitably ends in death.

Effects of ageing

A number of characteristic ageing symptoms are experienced by a majority or by a significant proportion of humans during their lifetimes.

• Teenagers lose the young child's ability to hear high-frequency sounds above 20 kHz.
• A continuous decline in several cognitive processes occurs after a peak performance in the mid-20s age group.^[5]
• By age 30, wrinkles develop mainly due to photoageing, particularly affecting sun-exposed areas (face, hands) of fair-skinned individuals.
• Around age 35, female fertility declines sharply.
• In the mid-forties, presbyopia generally becomes apparent.
• Around age 50, hair turns grey in Caucasoids.^[6] Many men are affected by balding, and women enter menopause.
• In the 60–64 age cohort, osteoarthritis rises to 53%. Only 20% however report disabling osteoarthritis at this age.^[7]
• In the 70–79 age range, partial hearing loss affecting communication rises to 65%, predominantly among low-income males.^[8]
• Over the age of 85, thirst perception decreases, such that 41% of the elderly drink insufficiently.^[9] Frailty, defined as loss of muscle mass and mobility, affects 25% of those over 85.^[10][11]

Ageing furthermore is among the greatest known risk factors for most human diseases.^[2] Specifically, age is a major risk factor for most common neurodegenerative diseases. Dementia becomes more common with age.^[12] About 3% of people between the ages of 65–74 have dementia, 19% between 75 and 84 and nearly half of those over 85 years of age.^[13] The spectrum includes mild cognitive impairment, Alzheimer's disease, cerebrovascular disease, Parkinson's disease and Lou Gehrig's disease. Research has focused in particular on memory and ageing and has found decline in many types of memory with ageing, but not in semantic memory or general knowledge such as vocabulary definitions, which typically increases or remains steady until the late adulthood.^[14] Early studies on changes in cognition with age generally found declines in intelligence in the elderly, but studies were cross-sectional rather than longitudinal and thus results may be an artefact of cohort rather than a true example of decline. However, longitudinal studies could be confounded due to prior test experience.^[15] Intelligence may decline with age, though the rate may vary depending on the type and may in fact remain steady throughout most of the lifespan, dropping suddenly only as people near the end of their lives. Individual variations in rate of cognitive decline may therefore be explained in terms of people having different lengths of life.^[16] There are changes to the brain: though neuron loss is minor after 20 years of age there is a 10% reduction each decade in the total length of the brain's myelinated axons.^[17]

Age can result in communication barriers, such as due to hearing loss and visual impairment.^[18] Sensory impairments include hearing and vision deficits. Changes in cognition, hearing, and vision are associated with healthy ageing and can cause problems when diagnosing dementia and aphasia due to the similarities.^[19] Common conditions that can increase the risk of hearing loss in elderly people are high blood pressure, diabetes or the use of certain medications harmful to the ear.^[20] Hearing aids are commonly referred to as personal amplifying systems, which can generally improve hearing by about 50%. In visual impairment, non-verbal communication is reduced, which can lead to isolation and possible depression. Macular degeneration is a common cause of vision loss in elderly people. This degeneration is caused by systemic changes in the circulation of waste products and growth of abnormal vessels around the retina causing the photoreceptors not to receive proper images.^[21]

A distinction can be made between "proximal ageing" (age-based effects that come about because of factors in the recent past) and "distal ageing" (age-based differences that can be traced back to a cause early in person's life, such as childhood poliomyelitis).^[16]

Of the roughly 150,000 people who die each day across the globe, about two thirds—100,000 per day—die from age-related causes. In industrialised nations, the proportion is much higher, reaching 90%.^[22][23][24]

Biological basis of ageing

At present, the biological basis of ageing is unknown, even in relatively simple and short-lived organisms. Less still is known about mammalian ageing, in part due to the much longer lives in even small mammals such as the mouse (around 3 years). A primary model organism for studying ageing is the nematode C. elegans, thanks to its short lifespan of 2–3 weeks, the ability to easily perform genetic manipulations or suppress gene activity with RNA interference, and other factors.^[25] Most known mutations and RNA interference targets that extend lifespan were first discovered in C. elegans.^[26]

Factors that are proposed to influence biological ageing fall into two main categories, programmed and damage-related. Programmed factors follow a biological timetable, perhaps a continuation of the one that regulates childhood growth and development. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair and defense responses. Damage-related factors include environmental assaults to living organisms that induce cumulative damage at various levels.^[27]

There are four main metabolic pathways which can influence the rate of ageing:

• caloric restriction, probably acting on the Sirtuin pathway
• the FOXO3/Sirtuin pathway
• the Growth hormone/IGF-1-like signalling pathway
• the activity levels of the electron transport chain in mitochondria and (in plants) in chloroplasts.

It is likely that most of these pathways affect ageing separately, because targeting them simultaneously leads to additive increases in lifespan.^[28]

Programmed factors

The rate of ageing varies substantially across different species, and this, to a large extent, is genetically based. For example, perennial plants can produce clones of themselves by vegetative reproduction and are thus potentially immortal, while annual plants die each year and reproduce by sexual reproduction. Clonal immortality apart, there are certain species whose individual lifespans stand out among Earth's life-forms, including the bristlecone pine (however Hayflick states that the bristlecone pine has no cells older than 30 years), fish like the sturgeon and the rockfish, invertebrates like the hard clam (known as quahog in New England) and the sea anemone^[29] and lobster.^[30][31] The genetic aspect has also been demonstrated in studies of human centenarians.

In laboratory settings, researchers have demonstrated that selected alterations in specific genes can extend lifespan quite substantially in yeast and roundworms, less so in fruit flies and less again in mice. Some of the targeted genes have homologues across species and in some cases have been associated with human longevity.^[32]

• Telomeres: In humans and other animals, cellular senescence has been attributed to the shortening of telomeres at each cell division; when telomeres become too short, the cells senesce or die. The length of telomeres is therefore the "molecular clock", predicted by Hayflick. This agrees with the 'ageing-clock theory', which suggests that an ageing sequence is built into the operation of the nervous or endocrine system of the body. In rapidly dividing cells, shortening of the telomeres would provide such a clock. This idea is in contradiction with the evolutionary theory of ageing.^[33][34] Telomeres have experimentally been shown to shorten with each successive cell division.^[35] Shortened telomeres activate a mechanism that prevents further cell multiplication.^[36][37] This may be particularly limiting to tissues such as bone marrow and the arterial lining where cell division occurs repeatedly throughout life.^[38] The quantity of the hematopoietic stem cells that produce the blood components residing in the bone marrow of human beings have been found to decline with ageing.^[39] Mice lacking the telomerase enzyme do not have a dramatically reduced lifespan,^[40] although laboratory mice may be an exception due to their long hypervariable telomeres.^[41] Telomere length in wild mouse strains is unrelated to lifespan.^[42]
• A variation in the gene FOXO3A is known to have a positive effect on the life expectancy of humans, and is found much more often in people living to 100 and beyond - moreover, this appears to be true worldwide.^[43] FOXO3A acts on the sirtuin family of genes which have also been shown to have a significant effect on lifespan, in yeast and in nematodes.
• DNA methylation: The strong effect of age on DNA methylation levels has been known since the late 1960s.^[44] Horvath hypothesised that DNA methylation age measures the cumulative effect of an epigenetic maintenance system but details are unknown. The fact that DNA methylation age of blood predicts all-cause mortality in later life ^[45][46][47] suggests that it relates to a process that causes aging.
• Over-expression of the Ras2 gene increases lifespan in yeast by 30%.^[48] A yeast mutant lacking the genes sch9 and ras2 has recently been shown to have a tenfold increase in lifespan under conditions of calorie restriction and is the largest increase achieved in any organism.^[49][50]
• Diet (specifically, caloric restriction) substantially increases lifespan in many animals, including the delay or prevention of many age-related diseases.^[51] Typically, this involves caloric intake of 60–70% of what an ad libitum animal would consume, while still maintaining proper nutrient intake.^[51] In rodents, this has been shown to increase lifespan by up to 50%;^[52] this effect occurs for many other species besides mice, including species as diverse as yeast and Drosophila,^[51] and likely includes primates as well.^[51][53][54] There are two major studies of caloric restriction being performed in rhesus monkeys, one at the US National Institutes of Health, and the other at the University of Wisconsin-Madison.^[53] The basis for caloric restriction remains unclear,^[28] though it is likely mediated by nutrient-sensing pathways such as the mTOR pathway.^[54] Evidence in both animals and humans suggests that resveratrol may be a caloric restriction mimetic.^[55] However, in his book How and Why We Age, Hayflick says that caloric restriction may not be effective in humans, citing data from the Baltimore Longitudinal Study of Aging which shows that being thin does not favour longevity.^[56] Alternatively, the benefits of dietary restriction can also be found by changing the macro nutrient profile to reduce protein intake with similar increases in longevity.^[57][58] Dietary protein restriction not only inhibits mTOR activity but also IGF-1, two other mechanisms implicated in ageing.^[59] Specifically, reducing leucine intake is sufficient to inhibit mTOR activity, achievable through reducing animal food consumption.^[60][61]
• mTOR, a protein that inhibits autophagy, has been linked to ageing through the insulin signalling pathway. It has been found, in various model species, that caloric restriction leads to longer lifespans, an effect that is likely mediated by the nutrient-sensing function of the mTOR pathway.^[54] mTOR functions through nutrient and growth cues leading scientists to believe that dietary restriction and mTOR are related in terms of longevity. When organisms restrict their diet, mTOR activity is reduced, which allows an increased level of autophagy. This recycles old or damaged cell parts, which increases longevity and decreases the chances of being obese. This is thought to prevent spikes of glucose concentration in the blood, leading to reduced insulin signalling. This has been linked to less mTOR activation as well. Therefore, longevity has been connected to caloric restriction and insulin sensitivity inhibiting mTOR, which in turns allows autophagy to occur more frequently. It may be that mTOR inhibition and autophagy reduce the effects of reactive oxygen species on the body, which damage DNA and other organic material, so longevity would be increased.^[62]
• A decreased Growth hormone (GH)/Insulin Growth Factor-1 (IGF-1) signaling pathway has been associated with increased life span in various organisms including fruit flies, nematodes and mice.^[63] Even though the mechanism by which decreased GH/IGF-1 signaling increases longevity is unknown; various long-lived mice models with decreased GH and/or IGF-1 induced signaling have similar phenotype. This phenotype includes increased insulin sensitivity, enhanced stress resistance and protection from carcinogenesis. Long lived mice with decreased GH signaling (Ames, Snell, Ghrh and GHR -/- mice) showed between 20% and 68% increased longevity when compared with control mice. On the other hand, mice with decreased IGF-1 induced signaling, such as the IGF1R +/- and the Klotho transgenic mice revealed a 19 to 33% increase in life span when compared to control mice.^[64]
• Evolutionary theories of aging: Many have argued that life-span, like other phenotypes, is selected. Traits that benefit early survival and reproduction will be selected for even if they contribute to an earlier death. Such a genetic effect is called the antagonistic pleiotropy effect when referring to a gene (pleiotropy signifying the gene has a double function - enabling reproduction at a young age but costing the organism life expectancy in old age) and is called the disposable soma effect when referring to an entire genetic programme (the organism diverting limited resources from maintenance to reproduction).^[65] Some evidence is provided by oxygen-deprived bacterial cultures.^[66] This would explain why the autosomal dominant disease, Huntington's disease, can persist even though it is inexorably lethal. Also, some of the genetic variants that increase fertility in the young are now known to increase cancer risk in the old. Such genes include p53^[67] and BRCA1.^[68] The biological mechanisms which regulate lifespan evolved several hundred million years ago.^[26]
• Reproductive-cell cycle theory: The idea that ageing is regulated by reproductive hormones that act in an antagonistic pleiotropic manner via cell cycle signalling, promoting growth and development early in life to achieve reproduction, but becoming dysregulated later in life, driving senescence (dyosis) in a futile attempt to maintain reproductive ability.^[1][69] The endocrine dyscrasia that follows the loss of follicles with menopause, and the loss of Leydig and Sertoli cells during andropause, drive aberrant cell cycle signaling that leads to cell death and dysfunction, tissue dysfunction (disease) and ultimately death. Moreover, the hormones that regulate reproduction also regulate cellular metabolism, explaining the increases in fat deposition during pregnancy through to the deposition of centralized adiposity with the dysregulation of the HPG axis following menopause and during andropause (Atwood and Bowen, 2006). This theory, which introduced a new definition of aging, has facilitated the conceptualization of why and how aging occurs at the evolutionary, physiological and molecular levels.^[1]
• Autoimmunity: The idea that ageing results from an increase in autoantibodies that attack the body's tissues. A number of diseases associated with ageing, such as atrophic gastritis and Hashimoto's thyroiditis, are probably autoimmune in this way. While inflammation is very much evident in old mammals, even SCID mice in SPF colonies still experience senescence.

Damage-related factors

• DNA damage theory of ageing: Genetic damage, including mutations (damages to the DNA sequence) and epimutations (damage to the DNA scaffolding which regulates gene expression), causes abnormal gene expression and can lead to diseases such as cancer. Lifelong studies of mice suggest that most mutations happen during embryonic and childhood development, when cells divide often, as each cell division is a chance for errors in DNA replication.^[70] Known causes of cancer (radiation, chemical and viral) account for about 30% of the total cancer burden and for about 30% of the total DNA damage. DNA damage causes the cells to stop dividing or induces apoptosis, often affecting stem cell pools and hence hindering regeneration. DNA damage is thought to be the common pathway causing both cancer and ageing. Viral infection would appear to be the most likely cause of the other 70% of DNA damage, especially in cells that are not exposed to smoking and sunlight. It has also been argued that intrinsic causes of DNA damage are more important drivers of ageing.^[71][72][73]
• Genetic instability: In heart muscle cells, dogs annually lose approximately 3.3% of the DNA in their heart muscle cells while humans lose approximately 0.6% of their heart muscle DNA each year. These numbers are close to the ratio of the maximum longevities of the two species (120 years vs. 20 years, a 6/1 ratio). The comparative percentage is also similar between the dog and human for yearly DNA loss in the brain and lymphocytes. As stated by lead author, Bernard L. Strehler, "... genetic damage (particularly gene loss) is almost certainly (or probably the) central cause of aging."^[74]
• Accumulation of waste: a buildup of waste products in cells presumably interferes with metabolism. For example, a waste product called lipofuscin is formed by a complex reaction in cells that binds fat to proteins. This waste accumulates in the cells as small granules, which increase in size as a person ages.^[75]
• Wear-and-tear theory: The very general idea that changes associated with ageing are the result of chance damage that accumulates over time.^[76]
• Accumulation of errors: The idea that ageing results from chance events that escape proof reading mechanisms, which gradually damages the genetic code.
• Cross-linkage: The idea that ageing results from accumulation of cross-linked compounds that interfere with normal cell function.^[34][77]
• Free-radical theory: Damage by free radicals, or more generally reactive oxygen species or oxidative stress, create damage that may gives rise to the symptoms we recognise as ageing.^[34][78][79] Michael Ristow's group has provided evidence that the effect of calorie restriction may be due to increased formation of free radicals within the mitochondria, causing a secondary induction of increased antioxidant defence capacity.^[80]

Society and culture

Different cultures express age in different ways. The age of an adult human is commonly measured in whole years since the day of birth. Arbitrary divisions set to mark periods of life may include: juvenile (via infancy, childhood, preadolescence, adolescence), early adulthood, middle adulthood, and late adulthood. More casual terms may include "teenagers," "tweens," "twentysomething", "thirtysomething", etc. as well as "vicenarian", "tricenarian", "quadragenarian", etc.

Most legal systems define a specific age for when an individual is allowed or obliged to do particular activities. These age specifications include voting age, drinking age, age of consent, age of majority, age of criminal responsibility, marriageable age, age of candidacy, and mandatory retirement age. Admission to a movie for instance, may depend on age according to a motion picture rating system. A bus fare might be discounted for the young or old. Each nation, government and non-governmental organisation has different ways of classifying age. In other words, chronological ageing may be distinguished from "social ageing" (cultural age-expectations of how people should act as they grow older) and "biological ageing" (an organism's physical state as it ages).^[81]

In a UNFPA report about aging in the 21st century, it highlighted the need to "Develop a new rights-based culture of aging and a change of mindset and societal attitudes towards ageing and older persons, from welfare recipients to active, contributing members of society." ^[82] UNFPA said that this "requires, among others, working towards the development of international human rights instruments and their translation into national laws and regulations and affirmative measures that challenge age discrimination and recognize older people as autonomous subjects." ^[82] Older persons make vast contributions to society including caregiving and volunteering. For example, "A study of Bolivian migrants who moved to Spain found that 69 percent left their children at home, usually with grandparents. In rural China, grandparents care for 38 percent of children aged under five whose parents have gone to work in cities." ^[82]

Economics

Population ageing is the increase in the number and proportion of older people in society. Population ageing has three possible causes: migration, longer life expectancy (decreased death rate) and decreased birth rate. Ageing has a significant impact on society. Young people tend to have fewer legal privileges (if they are below the age of majority), they are more likely to push for political and social change, to develop and adopt new technologies, and to need education. Older people have different requirements from society and government, and frequently have differing values as well, such as for property and pension rights.^[83]

In the 21st century, one of the most significant population trends is aging.^[84] Currently, over 11% of the world's current population are people aged 60 and older and the United Nations Population Fund (UNFPA) estimates that by 2050 that number will rise to approximately 22%.^[82] Ageing has occurred due to development which has enabled better nutrition, sanitation, health care, education and economic well-being. Consequently, fertility rates have continued to decline and life expectancy have risen. Life expectancy at birth is over 80 now in 33 countries. Ageing is a "global phenomenon," that is occurring fastest in developing countries, including those with large youth populations, and poses social and economic challenges to the work which can be overcome with "the right set of policies to equip individuals, families and societies to address these challenges and to reap its benefits." ^[85]

As life expectancy rises and birth rates decline in developed countries, the median age itself rises accordingly. According to the United Nations, this process is taking place in nearly every country in the world.^[86] A rising median age can have significant social and economic implications, as the workforce gets progressively older and the number of old workers and retirees grows relative to the number of young workers. Older people generally incur more health-related costs than do younger people in the workplace and can also cost more in worker's compensation and pension liabilities.^[87] In most developed countries an older workforce is somewhat inevitable. In the United States for instance, the Bureau of Labor Statistics estimates that one in four American workers will be 55 or older by 2020.^[87]

Among the most urgent concerns of older persons worldwide is income security. This poses challenges for governments with ageing populations to ensure investments in pension systems continues in order to provide economic independence and reduce poverty in old age. These challenges vary for developing and developed countries. UNFPA stated that, "Sustainability of these systems is of particular concern, particularly in developed countries, while social protection and old-age pension coverage remain a challenge for developing countries, where a large proportion of the labour force is found in the informal sector." ^[82]

The global economic crisis has increased financial pressure to ensure economic security and access to health care in old age. In order to elevate this pressure "social protection floors must be implemented in order to guarantee income security and access to essential health and social services for all older persons and provide a safety net that contributes to the postponement of disability and prevention of impoverishment in old age." ^[82]

It has been argued that population ageing has undermined economic development however there is no solid evidence to substantiate this. Evidence suggests that pensions, while making a difference to the well-being of older persons, also benefit entire families especially in times of crisis when there may be a shortage or loss of employment within households. A study by the Australian Government in 2003 estimated that "women between the ages of 65 and 74 years contribute A$16 billion per year in unpaid caregiving and voluntary work. Similarly, men in the same age group contributed A$10 billion per year." ^[82]

Sociology

In the field of sociology and mental health, aging is seen in five different views: aging as maturity, aging as decline, aging as a life-cycle event, aging as generation, and aging as survival.^[88] Positive correlates with aging often include economics, employment, marriage, children, education, and sense of control, as well as many others. The social science of aging includes disengagement theory, activity theory, selectivity theory, and continuity theory. Retirement, a common transition faced by the elderly, may have both positive and negative consequences.^[89]

Health care demand

With age inevitable biological changes occur that increase the risk of illness and disability. UNFPA states that,^[85]

"A life-cycle approach to health care – one that starts early, continues through the reproductive years and lasts into old age – is essential for the physical and emotional well-being of older persons, and, indeed, all people. Public policies and programmes should additionally address the needs of older impoverished people who cannot afford health care."

Many societies in Western Europe and Japan have ageing populations. While the effects on society are complex, there is a concern about the impact on health care demand. The large number of suggestions in the literature for specific interventions to cope with the expected increase in demand for long-term care in ageing societies can be organised under four headings: improve system performance; redesign service delivery; support informal caregivers; and shift demographic parameters.^[90]

However, the annual growth in national health spending is not mainly due to increasing demand from ageing populations, but rather has been driven by rising incomes, costly new medical technology, a shortage of health care workers and informational asymmetries between providers and patients.^[91] A number of health problems become more prevalent as people get older. These include mental health problems as well as physical health problems, especially dementia.

It has been estimated that population ageing only explains 0.2 percentage points of the annual growth rate in medical spending of 4.3 percent since 1970. In addition, certain reforms to the Medicare system in the United States decreased elderly spending on home health care by 12.5 percent per year between 1996 and 2000.^[92]

Self-perception of ageing

Positive self-perception of health has been correlated with higher well-being and reduced mortality in the elderly.^[93][94] Various reasons have been proposed for this association; people who are objectively healthy may naturally rate their health better than that of their ill counterparts, though this link has been observed even in studies which have controlled for socioeconomic status, psychological functioning and health status.^[95] This finding is generally stronger for men than women,^[94] though this relationship is not universal across all studies and may only be true in some circumstances.^[95]

As people age, subjective health remains relatively stable, even though objective health worsens.^[96] In fact, perceived health improves with age when objective health is controlled in the equation.^[97] This phenomenon is known as the "paradox of ageing." This may be a result of social comparison;^[98] for instance, the older people get, the more they may consider themselves in better health than their same-aged peers.^[99] Elderly people often associate their functional and physical decline with the normal ageing process.^[100][101]

Successful ageing

The concept of successful ageing can be traced back to the 1950s and was popularised in the 1980s. Previous research into ageing exaggerated the extent to which health disabilities, such as diabetes or osteoporosis, could be attributed exclusively to age, and research in gerontology exaggerated the homogeneity of samples of elderly people.^[102][103] Other research shows that even late in life, potential exists for physical, mental, and social growth and development.^[104]

Traditional definitions of successful aging have emphasized absence of physical and cognitive disabilities.^[105] In their 1987 article, Rowe and Kahn characterized successful aging as involving three components: a) freedom from disease and disability, b) high cognitive and physical functioning, and c) social and productive engagement.^[103]

Prevention and reversal

Some researchers (specifically biogerontologists) who study the biology of ageing believe that the development of interventions which slow ageing is inevitable.^[62] Several drugs and food supplements have been shown to retard or reverse the biological effects of ageing in animal models, but none has yet been proven to do so in humans.

Ronald A. DePinho, a cancer geneticist at the Dana-Farber Cancer Institute and Harvard Medical School, published a paper in Nature magazine in November 2010 which indicated that the organs of genetically altered mice, designed to activate telomerase after feeding them with a chemical, were rejuvenated. Shrivelled testes grew back to normal and the animals regained their fertility. Other organs, such as the spleen, liver, intestines and brain, recuperated from their degenerated state. In this experiment mice were engineered to not produce telomerase naturally but after a chemical "switch" the system would then restore telomerase. Importantly, this chemical does not have the ability to produce telomerase in animals that are not genetically altered. Moreover, telomerase activation is also associated with the growth of cancerous tumours which could prevent anti-ageing treatments using this discovery.^[106]

mTOR inhibition and the frequent activation of autophagy has been shown to increase longevity in model organisms such as yeast, flies and mice. mTor inhibition and autophagy have also been linked to insulin sensitivity and the reduction of reactive oxygen species (ROS) damage, which is another major proposed cause to ageing. It has become clear that autophagy activation in the body by mTOR inhibition increases longevity. mTOR inhibition reduces ROS damage by activating autophagy, which will recycle the damaged parts of cells and re use them for functioning parts. This process reduces ROS damage to a reasonable amount, therefore increasing longevity. mTOR inhibition has also been linked to other major ageing diseases. mTOR inhibition has helped treat neurodegenerative diseases like Alzheimer's in mice. It has also been used to reduce tumor growth in several cancers including renal, breast and several other rare cancers. Finally mTOR inhibition is also linked to reducing obesity and increasing immune function. The mTOR inhibition reduces the likelihood of diet induced and age induced obesity in mice, but in some cases led to glucose intolerance. Caloric restriction and exercise are two ways to activate autophagy and inhibit mTOR which can help resolve all of these common age related health issues.^[62] Reducing dietary protein intake without any changes to calorie level as an alternative to caloric restriction has also been shown to have similar effects on inhibiting mTOR activity.^[59] Specifically, reducing leucine intake from protein sources was considered most beneficial in inhibiting mTOR activity, primarily achieved through consuming more plant based foods.^[60][61]

The cellular balance between energy generation and consumption (energy homeostasis) requires tight regulation during ageing. In 2011, it was demonstrated that acetylation levels of AMP-activated protein kinase change with age in yeast and that preventing this change slows yeast ageing.^[107]

Caloric restriction substantially affects lifespan in many animals, including the ability to delay or prevent many age-related diseases.^[51] Evidence in both animals and humans suggests that resveratrol may be a caloric restriction mimetic.^[55]

Most known genetic interventions in C. elegans increase lifespan by 1.5 to 2.5-fold. As of 2009, the record for lifespan extension in C. elegans is a single-gene mutation which increases adult survival by tenfold.^[26] The strong conservation of some of the mechanisms of ageing discovered in model organisms imply that they may be useful in the enhancement of human survival. However, the benefits may not be proportional; longevity gains are typically greater in C. elegans than fruit flies, and greater in fruit flies than in mammals. One explanation for this is that mammals, being much longer-lived, already have many traits which promote lifespan.^[26]

Research projects and prizes

Some research effort is directed to slow ageing and extend healthy lifespan.^{[108][109][110]}

The US National Institute on Aging currently funds an intervention testing program, whereby investigators nominate compounds (based on specific molecular ageing theories) to have evaluated with respect to their effects on lifespan and age-related biomarkers in outbred mice.^[111] Previous age-related testing in mammals has proved largely irreproducible, because of small numbers of animals and lax mouse husbandry conditions. The intervention testing program aims to address this by conducting parallel experiments at three internationally recognised mouse ageing-centres, the Barshop Institute at UTHSCSA, the University of Michigan at Ann Arbor and the Jackson Laboratory.

Several companies and organisations, such as Google Calico, Human Longevity, Craig Venter, Gero,^[112] SENS Research Foundation, and Science for Life Extension in Russia,^[113] declared stopping or delaying ageing as their goal.

Prizes for extending lifespan and slowing ageing in mammals exist. The Methuselah Foundation offers the Mprize. Recently, the $1 Million Palo Alto Longevity Prize was launched. It is a research incentive prize to encourage teams from all over the world to compete in an all-out effort to "hack the code" that regulates our health and lifespan. It was founded by Joon Yun.^{[114][115][116][117][118]}

See also

References

External links

Look up vicenarian, tricenarian, quadragenarian, or centenarian in Wiktionary, the free dictionary.

Wikiquote has quotations related to: Ageing

• Global AgeWatch Statistics on population ageing and life expectancy
• HelpAge International and UNFPA (2012). Ageing in the 21st Century – A Celebration and A Challenge.
• The dictionary definition of ageing at Wiktionary
• Media related to Ageing at Wikimedia Commons

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Developmental biology Ageing Compartment Embryogenesis Human Drosophila Fish polarity Embryology Metamerism Metamorphosis Model organisms Ontogeny Puberty Regeneration Human Teratology Evolutionary developmental biology

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Longevity Terminology Ageless Centenarian Super Cognitive epidemiology Maximum life span Life extension Life expectancy Immortality Biological immortality Digital immortality Eternal youth Issues Longevity claims Longevity myths Notable centenarians (over age 100) Living Activists, non-profit leaders, and philanthropists Actors, filmmakers, and entertainers Artists Authors, poets, and journalists Businesspeople Educators, school administrators, social scientists, and linguists Explorers Jurists and practitioners of law Medical professionals Military commanders Musicians, composers, and music patrons Philosophers and theologians Politicians and government servants Religious figures Royalty and nobility Scientists and mathematicians Sportspeople Miscellaneous Supercentenarians (over age 110) Oldest people List of oldest living people 100 verified oldest people (males females) By region (Africa Asia Europe North America Oceania South America) By country (Australia Belgium Canada Denmark Finland France Germany Ireland Italy Japan Netherlands Norway Poland Portugal Spain Sweden United Kingdom United States) Oldest people by country Miscellaneous Last surviving veterans of military insurgencies and wars (European American Canadian) Last surviving World War I veterans by country Surviving veterans of the Spanish Civil War List of surviving veterans of World War II Last survivors of historic events Oldest twins Longest marriages See also Gerontology Ageing Biodemography of human longevity Senescence Life extension-related topics FOXO3 longevity gene Immortality in fiction

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