StemCell Therapy

Ageing, also spelled aging, is the process of becoming older. The term refers especially to human beings, many animals, and fungi, whereas for example bacteria, perennial plants and some simple animals are potentially immortal. In the broader sense, ageing can refer to single cells within an organism which have ceased dividing (cellular senescence) 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 damage (such as DNA breaks, oxidised DNA and/or mitochondrial malfunctions)[3] may cause biological systems to fail, or to the programmed ageing concept, whereby internal processes (such as DNA telomere shortening) may cause ageing. Programmed ageing should not be confused with programmed cell death (apoptosis).

The discovery, in 1934, that calorie restriction can extend lifespan by 50% in rats has motivated research into delaying and preventing ageing.

Human beings and members of other species, especially animals, necessarily experience ageing and mortality. Fungi, too, can age.[4] In contrast, many 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.

Early life forms on Earth, starting at least 3.7 billion years ago,[5] were single-celled organisms. Such single-celled organisms (prokaryotes, protozoans, algae) multiply by fissioning into daughter cells, thus do not age and are innately immortal.[6][7]

Ageing and mortality of the individual organism became possible with the evolution of sexual reproduction,[8] which occurred with the emergence of the fungal/animal kingdoms approximately a billion years ago, and with the evolution of flowering plants 160 million years ago. The sexual organism could henceforth pass on some of its genetic material to produce new individuals and itself could become disposable with regards to the survival of its species.[8] This classic biological idea has however been perturbed recently by the discovery that the bacterium E. coli may split into distinguishable daughter cells, which opens the theoretical possibility of "age classes" among bacteria.[9]

Even within humans and other mortal species, there are cells with the potential for immortality: cancer cells which have lost the ability to die when maintained in cell culture such as the HeLa cell line,[10] and specific stem cells such as germ cells (producing ova and spermatozoa).[11] In artificial cloning, adult cells can be rejuvenated back to embryonic status and then used to grow a new tissue or animal without ageing.[12] Normal human cells however die after about 50 cell divisions in laboratory culture (the Hayflick Limit, discovered by Leonard Hayflick in 1961).[10]

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

Dementia becomes more common with age.[35] About 3% of people between the ages of 6574 have dementia, 19% between 75 and 84 and nearly half of those over 85 years of age.[36] The spectrum includes mild cognitive impairment and the neurodegenerative diseases of Alzheimer's disease, cerebrovascular disease, Parkinson's disease and Lou Gehrig's disease. Furthermore, many types of memory may decline with ageing, but not semantic memory or general knowledge such as vocabulary definitions, which typically increases or remains steady until late adulthood[37] (see Ageing brain). 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.[38] There might be changes to the brain: after 20 years of age there may be a 10% reduction each decade in the total length of the brain's myelinated axons.[39][40]

Age can result in visual impairment, whereby non-verbal communication is reduced,[41] which can lead to isolation and possible depression. Macular degeneration causes vision loss and increases with age, affecting nearly 12% of those above the age of 80.[42] This degeneration is caused by systemic changes in the circulation of waste products and by growth of abnormal vessels around the retina.[43]

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).[38]

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 thirds100,000 per daydie from age-related causes. In industrialised nations, the proportion is higher, reaching 90%.[44][45][46]

At present, researchers are only just beginning to understand the biological basis of ageing even in relatively simple and short-lived organisms such as yeast.[47] 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 23 weeks, the ability to easily perform genetic manipulations or suppress gene activity with RNA interference, and other factors.[48] Most known mutations and RNA interference targets that extend lifespan were first discovered in C. elegans.[49]

Factors that are proposed to influence biological ageing[50] 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 defence responses. Damage-related factors include internal and environmental assaults to living organisms that induce cumulative damage at various levels.[51]

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

It is likely that most of these pathways affect ageing separately, because targeting them simultaneously leads to additive increases in lifespan.[53]

The rate of ageing varies substantially across different species, and this, to a large extent, is genetically based. For example, numerous perennial plants ranging from strawberries and potatoes to willow trees typically produce clones of themselves by vegetative reproduction and are thus potentially immortal, while annual plants such as wheat and watermelons die each year and reproduce by sexual reproduction. In 2008 it was discovered that inactivation of only two genes in the annual plant Arabidopsis thaliana leads to its conversion into a potentially immortal perennial plant.[54]

Clonal immortality apart, there are certain species whose individual lifespans stand out among Earth's life-forms, including the bristlecone pine at 5062 years[55] (however Hayflick states that the bristlecone pine has no cells older than 30 years), invertebrates like the hard clam (known as quahog in New England) at 508 years,[56] the Greenland shark at 400 years,[57] fish like the sturgeon and the rockfish, and the sea anemone[58] and lobster.[59][60] Such organisms are sometimes said to exhibit negligible senescence.[61] 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.[62]

Caloric restriction substantially affects lifespan in many animals, including the ability to delay or prevent many age-related diseases.[103] Typically, this involves caloric intake of 6070% of what an ad libitum animal would consume, while still maintaining proper nutrient intake.[103] In rodents, this has been shown to increase lifespan by up to 50%;[104] similar effects occur for yeast and Drosophila.[103] No lifespan data exist for humans on a calorie-restricted diet,[76] but several reports support protection from age-related diseases.[105][106] Two major ongoing studies on rhesus monkeys initially revealed disparate results; while one study, by the University of Wisconsin, showed that caloric restriction does extend lifespan,[107] the second study, by the National Institute on Ageing (NIA), found no effects of caloric restriction on longevity.[108] Both studies nevertheless showed improvement in a number of health parameters. Notwithstanding the similarly low calorie intake, the diet composition differed between the two studies (notably a high sucrose content in the Wisconsin study), and the monkeys have different origins (India, China), initially suggesting that genetics and dietary composition, not merely a decrease in calories, are factors in longevity.[76] However, in a comparative analysis in 2014, the Wisconsin researchers found that the allegedly non-starved NIA control monkeys in fact are moderately underweight when compared with other monkey populations, and argued this was due to the NIA's apportioned feeding protocol in contrast to Wisconsin's truly unrestricted ad libitum feeding protocol.[109] They conclude that moderate calorie restriction rather than extreme calorie restriction is sufficient to produce the observed health and longevity benefits in the studied rhesus monkeys.[110]

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.[need quotation to verify][111] Similarly, it is sometimes claimed that moderate obesity in later life may improve survival, but newer research has identified confounding factors such as weight loss due to terminal disease. Once these factors are accounted for, the optimal body weight above age 65 corresponds to a leaner body mass index of 23 to 27.[112]

Alternatively, the benefits of dietary restriction can also be found by changing the macro nutrient profile to reduce protein intake without any changes to calorie level, resulting in similar increases in longevity.[113][114] Dietary protein restriction not only inhibits mTOR activity but also IGF-1, two mechanisms implicated in ageing.[74] Specifically, reducing leucine intake is sufficient to inhibit mTOR activity, achievable through reducing animal food consumption.[115][116]

The Mediterranean diet is credited with lowering the risk of heart disease and early death.[117][118] The major contributors to mortality risk reduction appear to be a higher consumption of vegetables, fish, fruits, nuts and monounsaturated fatty acids, i.e., olive oil.[119]

The amount of sleep has an impact on mortality. People who live the longest report sleeping for six to seven hours each night.[120][121] Lack of sleep (<5 hours) more than doubles the risk of death from cardiovascular disease, but too much sleep (>9 hours) is associated with a doubling of the risk of death, though not primarily from cardiovascular disease.[122] Sleeping more than 7 to 8 hours per day has been consistently associated with increased mortality, though the cause is probably other factors such as depression and socioeconomic status, which would correlate statistically.[123] Sleep monitoring of hunter-gatherer tribes from Africa and from South America has shown similar sleep patterns across continents: their average sleeping duration is 6.4 hours (with a summer/winter difference of 1 hour), afternoon naps (siestas) are uncommon, and insomnia is very rare (tenfold less than in industrial societies).[124]

Physical exercise may increase life expectancy.[125] People who participate in moderate to high levels of physical exercise have a lower mortality rate compared to individuals who are not physically active.[126] Moderate levels of exercise have been correlated with preventing aging and improving quality of life by reducing inflammatory potential.[127] The majority of the benefits from exercise are achieved with around 3500 metabolic equivalent (MET) minutes per week.[128] For example, climbing stairs 10 minutes, vacuuming 15 minutes, gardening 20 minutes, running 20 minutes, and walking or bicycling for 25 minutes on a daily basis would together achieve about 3000 MET minutes a week.[128]

Avoidance of chronic stress (as opposed to acute stress) is associated with a slower loss of telomeres in most but not all studies,[129][130] and with decreased cortisol levels. A chronically high cortisol level compromises the immune system, causes cardiac damage/arterosclerosis and is associated with facial ageing, and the latter in turn is a marker for increased morbidity and mortality.[131][132] Stress can be countered by social connection, spirituality, and (for men more clearly than for women) married life, all of which are associated with longevity.[133][134][135]

The following drugs and interventions 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.

Evidence in both animals and humans suggests that resveratrol may be a caloric restriction mimetic.[136]

As of 2015 metformin was under study for its potential effect on slowing ageing in the worm C.elegans and the cricket.[137] Its effect on otherwise healthy humans is unknown.[137]

Rapamycin was first shown to extend lifespan in eukaryotes in 2006 by Powers et al. who showed a dose-responsive effect of rapamycin on lifespan extension in yeast cells.[138] In a 2009 study, the lifespans of mice fed rapamycin were increased between 28 and 38% from the beginning of treatment, or 9 to 14% in total increased maximum lifespan. Of particular note, the treatment began in mice aged 20 months, the equivalent of 60 human years.[139] Rapamycin has subsequently been shown to extend mouse lifespan in several separate experiments,[140][141] and is now being tested for this purpose in nonhuman primates (the marmoset monkey).[142]

Cancer geneticist Ronald A. DePinho and his colleagues published research in mice where telomerase activity was first genetically removed. Then, after the mice had prematurely aged, they restored telomerase activity by reactivating the telomerase gene. As a result, the mice 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. "[The finding] offers the possibility that normal human ageing could be slowed by reawakening the enzyme in cells where it has stopped working" says Ronald DePinho. However, activating telomerase in humans could potentially encourage the growth of tumours.[143]

Most known genetic interventions in C. elegans increase lifespan by 1.5 to 2.5-fold. As of 2009[update], the record for lifespan extension in C. elegans is a single-gene mutation which increases adult survival by tenfold.[49] 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.[49]

Some research effort is directed to slow ageing and extend healthy lifespan.[144][145][146]

The US National Institute on Aging currently funds an intervention testing programme, 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.[147] Previous age-related testing in mammals has proved largely irreproducible, because of small numbers of animals and lax mouse husbandry conditions.[citation needed] The intervention testing programme 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,[148]SENS Research Foundation, and Science for Life Extension in Russia,[149] 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.[150][151][152][153][154]

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).[155]

In a UNFPA report about ageing in the 21st century, it highlighted the need to "Develop a new rights-based culture of ageing and a change of mindset and societal attitudes towards ageing and older persons, from welfare recipients to active, contributing members of society."[156] 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 recognise older people as autonomous subjects."[156] Older persons make contributions to society including caregiving and volunteering. For example, "A study of Bolivian migrants who [had] moved to Spain found that 69% left their children at home, usually with grandparents. In rural China, grandparents care for 38% of children aged under five whose parents have gone to work in cities."[156]

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.[157]

In the 21st century, one of the most significant population trends is ageing.[158] 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%.[156] 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."[159]

As life expectancy rises and birth rates decline in developed countries, the median age rises accordingly. According to the United Nations, this process is taking place in nearly every country in the world.[160] 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.[161] 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.[161]

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."[156]

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."[156]

It has been argued that population ageing has undermined economic development.[162] 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."[156]

Due to increasing share of the elderly in the population, health care expenditures will continue to grow relative to the economy in coming decades. This has been considered as a negative phenomenon and effective strategies like labour productivity enhancement should be considered to deal with negative consequences of ageing.[163]

In the field of sociology and mental health, ageing is seen in five different views: ageing as maturity, ageing as decline, ageing as a life-cycle event, ageing as generation, and ageing as survival.[164] Positive correlates with ageing often include economics, employment, marriage, children, education, and sense of control, as well as many others. The social science of ageing 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.[165] As cyborgs currently are on the rise some theorists argue there is a need to develop new definitions of ageing and for instance a bio-techno-social definition of ageing has been suggested.[166]

With age inevitable biological changes occur that increase the risk of illness and disability. UNFPA states that,[159]

"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.[167]

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.[168] 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% since 1970. In addition, certain reforms to the Medicare system in the United States decreased elderly spending on home health care by 12.5% per year between 1996 and 2000.[169]

Positive self-perception of health has been correlated with higher well-being and reduced mortality in the elderly.[170][171] 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.[172] This finding is generally stronger for men than women,[171] though this relationship is not universal across all studies and may only be true in some circumstances.[172]

As people age, subjective health remains relatively stable, even though objective health worsens.[173] In fact, perceived health improves with age when objective health is controlled in the equation.[174] This phenomenon is known as the "paradox of ageing." This may be a result of social comparison;[175] for instance, the older people get, the more they may consider themselves in better health than their same-aged peers.[176] Elderly people often associate their functional and physical decline with the normal ageing process.[177][178]

The concept of successful ageing can be traced back to the 1950s and was popularised in the 1980s. Traditional definitions of successful ageing have emphasised absence of physical and cognitive disabilities.[179] In their 1987 article, Rowe and Kahn characterised successful ageing as involving three components: a) freedom from disease and disability, b) high cognitive and physical functioning, and c) social and productive engagement.[180]

The ancient Greek dramatist Euripides (5th century BC) describes the multiply-headed mythological monster Hydra as having a regenerative capacity which makes it immortal, which is the historical background to the name of the biological genus Hydra. The Book of Job (c. 6th century BC) describes human lifespan as inherently limited and makes a comparison with the innate immortality that a felled tree may have when undergoing vegetative regeneration.[181]

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Ageing - Wikipedia

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