Medical technology is improving quickly. Unless there is a global disaster and human progress is set back significantly, e.g. by an asteroid or a global nuclear war, there will come a day when humans can live indefinitely. This does not mean infinitely- people will still die in vehicle accidents, get murdered, etc. Also, at least at first, access will be prohibitive due to costs and possibly outright selection/rejection of patients.
Based on trends in the progress of biomedical research, what is the consensus in the biomedical research community for approximately what year will the average person vs. a very elite person be able to get treatment to live indefinitely?
Live for ever: Scientists say they’ll soon extend life ‘well beyond 120’
I n Palo Alto in the heart of Silicon Valley, hedge fund manager Joon Yun is doing a back-of-the-envelope calculation. According to US social security data, he says, the probability of a 25-year-old dying before their 26th birthday is 0.1%. If we could keep that risk constant throughout life instead of it rising due to age-related disease, the average person would – statistically speaking – live 1,000 years. Yun finds the prospect tantalising and even believable. Late last year he launched a $1m prize challenging scientists to “hack the code of life” and push human lifespan past its apparent maximum of about 120 years (the longest known/confirmed lifespan was 122 years).
Yun believes it is possible to “solve ageing” and get people to live, healthily, more or less indefinitely. His Palo Alto Longevity Prize, which 15 scientific teams have so far entered, will be awarded in the first instance for restoring vitality and extending lifespan in mice by 50%. But Yun has deep pockets and expects to put up more money for progressively greater feats. He says this is a moral rather than personal quest. Our lives and society are troubled by growing numbers of loved ones lost to age-related disease and suffering extended periods of decrepitude, which is costing economies. Yun has an impressive list of nearly 50 advisers, including scientists from some of America’s top universities.
Yun’s quest – a modern version of the age old dream of tapping the fountain of youth – is emblematic of the current enthusiasm to disrupt death sweeping Silicon Valley. Billionaires and companies are bullish about what they can achieve. In September 2013 Google announced the creation of Calico, short for the California Life Company. Its mission is to reverse engineer the biology that controls lifespan and “devise interventions that enable people to lead longer and healthier lives”. Though much mystery surrounds the new biotech company, it seems to be looking in part to develop age-defying drugs. In April 2014 it recruited Cynthia Kenyon, a scientist acclaimed for work that included genetically engineering roundworms to live up to six times longer than normal, and who has spoken of dreaming of applying her discoveries to people. “Calico has the money to do almost anything it wants,” says Tom Johnson, an earlier pioneer of the field now at the University of Colorado who was the first to find a genetic effect on longevity in a worm.
In March 2014, pioneering American biologist and technologist Craig Venter – along with the tech entrepreneur founder of the X Prize Foundation, Peter Diamandis – announced a new company called Human Longevity Inc. It isn’t aimed at developing anti-ageing drugs or competing with Calico, says Venter. But it plans to create a giant database of 1 million human genome sequences by 2020, including from supercentenarians. Venter says that data should shed important new light on what makes for a longer, healthier life, and expects others working on life extension to use his database. “Our approach can help Calico immensely and if their approach is successful it can help me live longer,” explains Venter. “We hope to be the reference centre at the middle of everything.”
In an office not far from Google’s headquarters in Mountain View, with a beard reaching almost to his navel, Aubrey de Grey is enjoying the new buzz about defeating ageing. For more than a decade, he has been on a crusade to inspire the world to embark on a scientific quest to eliminate ageing and extend healthy lifespan indefinitely (he is on the Palo Alto Longevity Prize board). It is a difficult job because he considers the world to be in a “pro-ageing trance”, happy to accept that ageing is unavoidable, when the reality is that it’s simply a “medical problem” that science can solve. Just as a vintage car can be kept in good condition indefinitely with periodic preventative maintenance, so there is no reason why, in principle, the same can’t be true of the human body, thinks de Grey. We are, after all, biological machines, he says.
His claims about the possibilities (he has said the first person who will live to 1,000 years is probably already alive), and some unconventional and unproven ideas about the science behind ageing, have long made de Grey unpopular with mainstream academics studying ageing. But the appearance of Calico and others suggests the world might be coming around to his side, he says. “There is an increasing number of people realising that the concept of anti-ageing medicine that actually works is going to be the biggest industry that ever existed by some huge margin and that it just might be foreseeable.”
Since 2009, de Grey has been chief scientific officer at his own charity, the Strategies for Engineered Negligible Senescence (Sens) Research Foundation. Including an annual contribution (about $600,000 a year) from Peter Thiel, a billionaire Silicon Valley venture capitalist, and money from his own inheritance, he funds about $5m of research annually. Some is done in-house, the rest sponsored at outside institutions. (Even his critics say he funds some good science.)
Aubrey de Grey is chief scientific officer of his own charity, the Strategies for Engineered Negligible Senescence (Sens) Research Foundation. He funds about $5m of research annually. Photograph: Tim E White/Rex
De Grey isn’t the only one who sees a new flowering of anti-ageing research. “Radical life extension isn’t consigned to the realm of cranks and science fiction writers any more,” says David Masci, a researcher at the Pew Research Centre, who recently wrote a report on the topic looking at the scientific and ethical dimensions of radical life extension. “Serious people are doing research in this area and serious thinkers are thinking about this .”
Although funding pledges have been low compared to early hopes, billionaires – not just from the technology industry – have long supported research into the biology of ageing. Yet it has mostly been aimed at extending “healthspan”, the years in which you are free of frailty or disease, rather than lifespan, although an obvious effect is that it would also be extended (healthy people after all live longer).
“If a consequence of increasing health is that life is extended, that’s a good thing, but the most important part is keeping people healthy as long as possible,” says Kevin Lee, a director of the Ellison Medical Foundation, founded in 1997 by tech billionaire Larry Ellison, and which has been the field’s largest private funder, spending $45m annually. (The Paul F Glenn Foundation for Medical Research is another.) Whereas much biomedical research concentrates on trying to cure individual diseases, say cancer, scientists in this small field hunt something larger. They investigate the details of the ageing process with a view to finding ways to prevent it at its root, thereby fending off the whole slew of diseases that come along with ageing. Life expectancy has risen in developed countries from about 47 in 1900 to about 80 today, largely due to advances in curing childhood diseases. But those longer lives come with their share of misery. Age-related chronic diseases such as heart disease, cancer, stroke and Alzheimer’s are more prevalent than ever.
The standard medical approach – curing one disease at a time – only makes that worse, says Jay Olshansky, a sociologist at the University of Chicago School of Public Health who runs a project called the Longevity Dividend Initiative, which makes the case for funding ageing research to increase healthspan on health and economic grounds. “I would like to see a cure for heart disease or cancer,” he says. “But it would lead to a dramatic escalation in the prevalence of Alzheimer’s disease.”
American biologist and technologist Craig Venter whose company Human Longevity Inc plans to create a database of a million human genome sequences by 2020. Photograph: Mike Blake/Reuters
By tackling ageing at the root they could be dealt with as one, reducing frailty and disability by lowering all age-related disease risks simultaneously, says Olshansky. Evidence is now building that this bolder, age-delaying approach could work. Scientists have already successfully intervened in ageing in a variety of animal species and researchers say there is reason to believe it could be achieved in people. “We have really turned a corner,” says Brian Kennedy, director of the Buck Institute for Research on Ageing, adding that five years ago the scientific consensus was that ageing research was interesting but unlikely to lead to anything practical. “We’re now at the point where it’s easy to extend the lifespan of a mouse. That’s not the question any more, it’s can we do this in humans? And I don’t see any reason why we can’t,” says David Sinclair, a researcher based at Harvard.
Reason for optimism comes after several different approaches have yielded promising results. Some existing drugs, such as the diabetes drug metformin, have serendipitously turned out to display age-defying effects, for example. Several drugs are in development that mimic the mechanisms that cause lab animals fed carefully calorie-restricted diets to live longer. Others copy the effects of genes that occur in long-lived people. One drug already in clinical trials is rapamycin, which is normally used to aid organ transplants and treat rare cancers. It has been shown to extend the life of mice by 25%, the greatest achieved so far with a drug, and protect them against diseases of ageing including cancer and neurodegeneration.
A recent clinical trial by Novartis, in healthy elderly volunteers in Australia and New Zealand, found a variant of the drug enhanced their response to flu vaccine by 20% – our immunity to flu being something that declines with old age.
“[This was] the first [trial] to take a drug suspected to slow ageing, and examine whether it slows or reverses a property of ageing in older, healthy individuals,” says Kennedy. Other drugs set to be tested in humans are compounds inspired by resveratrol, a compound found in red wine. Some scientists believe it is behind the “French paradox” that French people have a low incidence of heart disease despite eating comparatively rich diets.
In 2003, Sinclair published evidence that high doses of resveratrol extend the healthy lives of yeast cells. After Sirtris, a company co-founded by Sinclair, showed that resveratrol-inspired compounds had favourable effects in mice, it was bought by drug giant GlaxoSmithKline for $720m in 2008. Although development has proved more complicated than first thought, GSK is planning a large clinical trial this year, says Sinclair. He is now working on another drug that has a different way of activating the same pathway.
One of the more unusual approaches being tested is using blood from the young to reinvigorate the old. The idea was borne out in experiments which showed blood plasma from young mice restored mental capabilities of old mice. A human trial under way is testing whether Alzhemier’s patients who receive blood transfusions from young people experience a similar effect. Tony Wyss-Coray, a researcher at Stanford leading the work, says that if it works he hopes to isolate factors in the blood that drive the effect and then try to make a drug that does a similar thing. (Since publishing his work in mice, many “healthy, very rich people” have contacted Wyss-Coray wondering if it might help them live longer.)
James Kirkland, a researcher who studies ageing at the Mayo Clinic, says he knows of about 20 drugs now – more than six of which had been written up in scientific journals – that extended the lifespan or healthspan of mice. The aim is to begin tests in humans, but clinical studies of ageing are difficult because of the length of our lives, though there are ways around this such as testing the drugs against single conditions in elderly patients and looking for signs of improvements in other conditions at the same time. Quite what the first drug will be, and what it will do, is unclear. Ideally, you might take a single pill that would delay ageing in every part of your body. But Kennedy notes that in mice treated with rapamycin, some age-related effects, such as cataracts, don’t slow down. “I don’t know any one drug is going to do everything,” he says. As to when you might begin treatment, Kennedy imagines that in future you could start treatment sometime between the age of 40 and 50 “because it keeps you healthy 10 years longer”.
With treatments at such an early stage, guesses as to when they might arrive or how far they will stretch human longevity can only be that. Many researchers refuse to speculate. But Kirkland says the informal ambition in his field is to increase healthspan by two to three years in the next decade or more. (The EU has an official goal of adding two years to healthspan by 2020). Beyond that, what effects these drugs might have on extending our healthy lives is even harder to predict. A recent report by UK Human Longevity Panel, a body of scientists convened by insurer Legal and General, based on interviews with leading figures in the field, said: “There was disagreement about how far the maximum lifespan could increase, with some experts believing that there was a maximum threshold that could not be stretched much more than the current 120 years or so, and others believing that there was no limit.”
Nir Barzilai, director of the Institute for Ageing Research at the Albert Einstein College of Medicine, is one of the pessimists. “Based on the biology that we know today, somewhere between 100 and 120 there is a roof in play and I challenge if we can get beyond it.” Venter is one of the optimists. “I don’t see any absolute biological limit on human age,” he says, arguing that cellular immortality – in effect running the clock backwards – should be possible. “We can expect biological processes to eventually get rid of years. Whether this will happen this century or not, I can’t tell you”. Such ideas are just speculation for now. But John Troyer, who studies death and technology at the Centre for Death and Society at the University of Bath, says we need to take them seriously. “You want to think about it now before you are in the middle of an enormous mess.”
What happens if we all live to 100, 110, 120 or beyond? Society will start to look very different. “People working and living longer might make it more difficult for a new generation to get into the labour force or find houses,” says Troyer. And, with ageing delayed, how many children are we talking about as being a normal family? “There is a very strong likelihood there would be an impact on things like family structures.” A 2003 American president’s Council on Bioethics report looked at some of these issues suggesting there may be repercussions for individual psychology, too.
One of the “virtues of mortality” it pointed out is that it may instill a desire to make each day count. Would knowing you had longer to live decrease your willingness to make the most of life? De Grey acknowledges potential practical challenges but cheerily says society would adapt, for example by having fewer children, and with people able to decide when to end their lives. There are pressing questions too about who would benefit if and when these interventions become available. Will it just be the super rich or will market incentives – who wouldn’t want it? – push costs down and make treatment affordable?
Will Britain’s NHS or health insurers in other countries pay for drugs that extend peoples lives? The medical cost of caring for people in their twilight years would fall if they remained healthier longer, but delayed ageing will also mean more people draw pensions and state benefits. But advocates say these challenges don’t negate the moral imperative. If the period of healthy life can be extended, then doing so is the humanitarian thing to do, says Nick Bostrom, director of Oxford’s Future of Humanity Institute. “There seems to be no moral argument not to,” he says. Troyer agrees but asks whether living longer does necessarily mean you will be healthier – what does “healthy” or “healthier” mean in this context? he asks.
The far future aside, there are challenges for the new tech entrants. Calico may get too side-tracked by basic research, worries de Grey Venter’s approach may take years to bear fruit because of issues about data gathering, thinks Barzilai while the money on offer from the Palo Alto prize is a paltry sum for the demanded outcome and potential societal impact, says Johnson. Still, history reminds us, even if they don’t succeed, we may still benefit.
Aviator Charles Lindbergh tried to cheat death by devising ways to replace human organs with machines. He didn’t succeed, but one of his contraptions did develop into the heart-lung machine so crucial for open-heart surgery. In the quest to defeat ageing, even the fruits of failure may be bountiful.
Position Statement on Human Aging
In the past century a combination of successful public health campaigns, changes in living environments and advances in medicine have led to a dramatic increase in human life expectancy. Long lives experienced by unprecedented numbers of people in developed countries are a triumph of human ingenuity. This remarkable achievement has produced economic, political and societal changes that are both positive and negative. Although there is every reason to be optimistic that continuing progress in public health and the biomedical sciences will contribute to even longer and healthier lives in the future, a disturbing and potentially dangerous trend has also emerged in recent years. There has been a resurgence and proliferation of health care providers and entrepreneurs who are promoting antiaging products and lifestyle changes that they claim will slow, stop or reverse the processes of aging. Even though in most cases there is little or no scientific basis for these claims , the public is spending vast sums of money on these products and lifestyle changes, some of which may be harmful . Scientists are unwittingly contributing to the proliferation of these pseudoscientific antiaging products by failing to participate in the public dialogue about the genuine science of aging research. The purpose of this document is to warn the public against the use of ineffective and potentially harmful antiaging interventions and to provide a brief but authoritative consensus statement from 51 internationally recognized scientists in the field about what we know and do not know about intervening in human aging. What follows is a list of issues related to aging that are prominent in both the lay and scientific literature, along with the consensus statements about these issues that grew out of debates and discussions among the 51 scientists associated with this paper.
Life span is defined as the observed age at death of an individual maximum lifespan is the highest documented age at death for a species. From time to time we are told of a new highest documented age at death, as in the celebrated case of Madame Jeanne Calment of France who died at the age of 122 . Although such an extreme age at death is exceedingly rare, the maximum life span of humans has continued to increase because world records for longevity can move in only one direction: higher. Despite this trend, however, it is almost certainly true that, at least since recorded history, people could have lived as long as those alive today if similar technologies, lifestyles and population sizes had been present. It is not people that have changed it is the protected environments in which we live and the advances made in biomedical sciences and other human institutions that have permitted more people to attain, or more closely approach, their life-span potential  Longevity records are entertaining, but they have little relevance to our own lives because genetic, environmental and lifestyle diversity  guarantees that an overwhelming majority of the population will die long before attaining the age of the longest-lived individual.
Life expectancy in humans is the average number of years of life remaining for people of a given age, assuming that everyone will experience, for the remainder of their lives, the risk of death based on a current life table. For newborns in the U.S. today, life expectancy is about 77 years.6 Rapid declines in infant, child, maternal and late-life mortality during the 20th century led to an unprecedented 30-year increase in human life expectancy at birth from the 47 years that it was in developed countries in 1900. Repeating this feat during the lifetimes of people alive today is unlikely. Most of the prior advances in life expectancy at birth reflect dramatic declines in mortality risks in childhood and early adult life. Because the young can be saved only once and because these risks are now so close to zero, further improvements, even if they occurred, would have little effect on life expectancy [7-9]. Future gains in life expectancy will, therefore, require adding decades of life to people who have already survived seven decades or more. Even with precipitous declines in mortality at middle and older ages from those present today, life expectancy at birth is unlikely to exceed 90 years (males and females combined) in the 21st century without scientific advances that permit the modification of the fundamental processes of aging . In fact, even eliminating all aging-related causes of death currently written on the death certificates of the elderly will not increase human life expectancy by more than 15 years. To exceed this limit, the underlying processes of aging that increase vulnerability to all the common causes of death will have to be modified.
Eliminating all the aging-related  causes of death presently written on death certificates would still not make humans immortal . Accidents, homicides, suicide and the biological processes of aging would continue to take their toll. The prospect of humans living forever is as unlikely today as it has always been, and discussions of such an impossible scenario have no place in a scientific discourse.
Geriatric Medicine versus Aging
Geriatric medicine is a critically important specialty in a world in which population aging is already a demographic reality in many countries and a future certainty in others. Past and anticipated advances in geriatric medicine will continue to save lives and help to manage the degenerative diseases associated with growing older [13,14], but these interventions only influence the manifestations of aging–not aging itself. The biomedical knowledge required to modify the processes of aging that lead to age-associated pathologies confronted by geriatricians does not currently exist. Until we better understand the aging processes and discover how to manipulate them, these intrinsic and currently immutable forces will continue to lead to increasing losses in physiological capacity and death even if age-associated diseases could be totally eliminated [15-20].
Advocates of what has become known as antiaging medicine claim that it is now possible to slow, stop or reverse aging through existing medical and scientific interventions [21-26]. Claims of this kind have been made for thousands of years , and they are as false today as they were in the past [28-31]. Preventive measures make up an important part of public health and geriatric medicine, and careful adherence to advice on nutrition, exercise and smoking can increase one’s chances of living a long and healthy life, even though lifestyle changes based on these precautions do not affect the processes of aging [32-33]. The more dramatic claims made by those who advocate antiaging medicine in the form of specific drugs, vitamin cocktails or esoteric hormone mixtures are, however, not supported by scientific evidence, and it is difficult to avoid the conclusion that these claims are intentionally false, misleading or exaggerated for commercial reasons . The misleading marketing and the public acceptance of antiaging medicine is not only a waste of health dollars it has also made it far more difficult to inform the public about legitimate scientific research on aging and disease . Medical interventions for age-related diseases do result in an increase in life expectancy, but none have been proved to modify the underlying processes of aging. The use of cosmetics, cosmetic surgery, hair dyes and similar means for covering up manifestations of aging may be effective in masking age changes, but they do not slow, stop or reverse aging. At present there is no such thing as an antiaging intervention.
The scientifically respected free-radical theory of aging  serves as a basis for the prominent role that antioxidants have in the antiaging movement. The claim that ingesting supplements containing antioxidants can influence aging is often used to sell antiaging formulations. The logic used by their proponents reflects a misunderstanding of how cells detect and repair the damage caused by free radicals and the important role that free radicals play in normal physiological processes (such as the immune response and cell communication) [37-39]. Nevertheless, there is little doubt that ingesting fruits and vegetables (which contain antioxidants) can reduce the risk of having various age-associated diseases, such as cancer , heart disease [41,42], macular degeneration and cataracts [43,44]. At present there is relatively little evidence from human studies that supplements containing antioxidants lead to a reduction in either the risk of these conditions or the rate of aging, but there are a number of ongoing randomized trials that address the possible role of supplements in a range of age-related conditions [45-49], the results of which will be reported in the coming years. In the meantime, possible adverse effects of single-dose supplements, such as beta-carotene , caution against their indiscriminate use. As such, antioxidant supplements may have some health benefits for some people, but so far there is no scientific evidence to justify the claim that they have any effect on human aging [51-52].
Telomeres, the repeated sequence found at the ends of chromosomes, shorten in many normal human cells with increased cell divisions. Statistically, older people have shorter telomeres in their skin and blood cells than do younger people [53,54]. In the animal kingdom, though, long-lived species often have shorter telomeres than do short-lived species, indicating that telomere length probably does not determine life span [55-57]. Solid scientific evidence has shown that telomere length plays a role in determining cellular life span in normal human fibroblasts and some other normal cell types . Increasing the number of times a cell can divide, however, may predispose cells to tumor formation [59-60]. Thus, although telomere shortening may play a role in limiting cellular life span, there is no evidence that telomere shortening plays a role in the determination of human longevity.
A number of hormones, including growth hormone, testosterone, estrogen and progesterone, have been shown in clinical trials to improve some of the physiological changes associated with human aging [61,62]. Under the careful supervision of physicians, some hormone supplements can be beneficial to the health of some people. No hormone, however, has been proved to slow, stop or reverse aging. Instances of negative side effects associated with some of these products have already been observed, and recent animal studies suggest that the use of growth hormone could have a life-shortening effect [63-65]. Hormone supplements now being sold under the guise of antiaging medicine should not be used by anyone unless they are prescribed for approved medical uses.
The widespread observation that caloric restriction will increase longevity must be tempered with the recognition that it has progressively less effect the later in life it is begun , as well as with the possibility that the control animals used in these studies feed more than wild animals, predisposing them to an earlier death. Although caloric restriction might extend the longevity of humans, because it does so in many other animal species [67-69], there is no study in humans that has proved that it will work. A few people have subjected themselves to a calorically restricted diet, which, in order to be effective, must approach levels that most people would find intolerable. The fact that so few people have attempted caloric restriction since the phenomenon was discovered more than 60 years ago suggests that for most people, quality of life seems to be preferred over quantity of life. The unknown mechanisms involved in the reduced risk of disease associated with caloric restriction are of great interest  and deserve further study because they could lead to treatments with pharmacological mimetics of caloric restriction that might postpone all age-related diseases simultaneously.
Determining Biological Age
Scientists believe that random damage that occurs within cells and among extracellular molecules are responsible for many of the age-related changes that are observed in organisms [72-74]. In addition, for organisms that reproduce sexually, including humans, each individual is genetically unique. As such, the rate of aging also varies from individual to individual . Despite intensive study, scientists have not been able to discover reliable measures of the processes that contribute to aging . For these reasons, any claim that a person’s biological or “real age”  can currently be measured, let alone modified, by any means must be regarded as entertainment, not science.
Are There Genes That Govern Aging Processes?
No genetic instructions are required to age animals, just as no instructions on how to age inanimate machines are included in their blueprints [79-80]. Molecular disorder occurs and accumulates within cells and their products because the energy required for maintenance and repair processes to maintain functional integrity for an indefinite time is unnecessary after reproductive success. Survival beyond the reproductive years and, in some cases, raising progeny to independence, is not favored by evolution because limited resources are better spent on strategies that enhance reproductive success to sexual maturity rather than longevity . Although genes certainly influence longevity determination, the processes of aging are not genetically programmed. Overengineered systems and redundant physiological capacities are essential for surviving long enough to reproduce in environments that are invariably hostile to life. Because humans have learned how to reduce environmental threats to life, the presence of redundant physiological capacity permits them and the domesticated animals we protect to survive beyond the reproductive ages. Studies in lower animals that have led to the view that genes are involved in aging have demonstrated that significant declines in mortality rates and large increases in average and maximum life span can be achieved experimentally [82-85]. Without exception, however, these genes have never produced a reversal or arrest of the inexorable increase in mortality rate that is one important hallmark of aging. The apparent effects of such genes on aging therefore appear to be inadvertent consequences of changes in other stages of life, such as growth and development, rather than a modification of underlying aging processes. Indeed, the evolutionary arguments presented above suggest that a unitary programmed aging process is unlikely to even exist and that such studies are more accurately interpreted to have an effect on longevity determination, not the various biological processes that contribute to aging. From this perspective, longevity determination is under genetic control only indirectly [86,87]. Thus, aging is a product of evolutionary neglect, not evolutionary intent [88-91].
Can We Grow Younger?
Although it is possible to reduce the risk of aging-related diseases and to mask the signs of aging, it is not possible for individuals to grow younger. This would require reversing the degradation of molecular integrity that is one of the hallmarks of aging in both animate and inanimate objects. Other than performing the impossible feat of replacing all of the cells, tissues or organs in biological material as a means of circumventing aging processes, growing younger is a phenomenon that is currently not possible.
After the publication of the human genome sequences, there have been assertions that this new knowledge will reveal genes whose manipulation may permit us to intervene directly in the processes of aging. Although it is likely that advances in molecular genetics will soon lead to effective treatments for inherited and age-related diseases, it is unlikely that scientists will be able to influence aging directly through genetic engineering [92,93]. because, as stated above, there are no genes directly responsible for the processes of aging. Centuries of selective breeding experience (in agricultural, domesticated and experimental plants and animals) has revealed that genetic manipulations designed to enhance one or only a few biological characteristics of an organism frequently have adverse consequences for health and vigor. As such, there is a very real danger that enhancing biological attributes associated with extended survival late in life might compromise biological properties important to growth and development early in life.
Replacing Body Parts
Suggestions have been made that the complete replacement of all body parts with more youthful components could increase longevity. Though possible in theory, it is highly improbable that this would ever become a practical strategy to extend length of life. Advances in cloning and embryonic stem cell technology may make the replacement of tissues and organs possible [94-99] and will likely have an important positive impact on public health in the future through the treatment of age-related diseases and disorders. But replacing and reprogramming the brain that defines who we are as individuals is, in our view, more the subject of science fiction than science fact.
Lifestyle Modification and Aging
Optimum lifestyles, including exercise and a balanced diet along with other proven methods for maintaining good health, contribute to increases in life expectancy by delaying or preventing the occurrence of age-related diseases. There is no scientific evidence, however, to support the claim that these practices increase longevity by modifying the processes of aging.
Since recorded history individuals have been, and are continuing to be, victimized by promises of extended youth or increased longevity by using unproven methods that allegedly slow, stop or reverse aging. Our language on this matter must be unambiguous: there are no lifestyle changes, surgical procedures, vitamins, antioxidants, hormones or techniques of genetic engineering available today that have been demonstrated to influence the processes of human aging [100,101]. We strongly urge the general public to avoid buying or using products or other interventions from anyone claiming that they will slow, stop or reverse aging. If people, on average, are going to live much longer than is currently possible, then it can only happen by adding decades of life to people who are already likely to live for 70 years or more. This “manufactured survival time”  will require modifications to all of the processes that contribute to aging–a technological feat that, though theoretically possible, has not yet been achieved. What medical science can tell us is that because aging and death are not programmed into our genes, health and fitness can be enhanced at any age, primarily through the avoidance of behaviors (such as smoking, excessive alcohol consumption, excessive exposure to sun, and obesity) that accelerate the expression of age-related diseases and by the adoption of behaviors (such as exercise and a healthy diet) that take advantage of a physiology that is inherently modifiable .
We enthusiastically support research in genetic engineering, stem cells, geriatric medicine and therapeutic pharmaceuticals, technologies that promise to revolutionize medicine as we know it. Most biogerontologists believe that our rapidly expanding scientific knowledge holds the promise that means may eventually be discovered to slow the rate of aging. If successful, these interventions are likely to postpone age-related diseases and disorders and extend the period of healthy life. Although the degree to which such interventions might extend length of life is uncertain, we believe this is the only way another quantum leap in life expectancy is even possible. Our concern is that when proponents of antiaging medicine claim that the fountain of youth has already been discovered, it negatively affects the credibility of serious scientific research efforts on aging. Because aging is the greatest risk factor for the leading causes of death and other age-related pathologies, more attention must be paid to the study of these universal underlying processes. Successful efforts to slow the rate of aging would have dramatic health benefits for the population by far exceeding the anticipated changes in health and length of life that would result from the complete elimination of heart disease, cancer, stroke and other age-associated diseases and disorders.
Authors and Endorsers
Dr. Olshansky is Senior Research Scientist and Professor at the School of Public Health, University of Illinois at Chicago. Dr. Hayflick is Professor of Anatomy at the University of California at San Francisco. Dr. Carnes is Assistant Professor of Geriatric Medicine at the University of Oklahoma. Drs. Olshansky and Carnes are also coauthors of The Quest for Immortality (Norton, 2001), a book-length antidote to anti-aging hype.
The Truth about Human Aging
Antiaging products are big business, but the marketing of these products often misrepresents the science. Rather than let their silence imply their support, 51 leading scientists in the field of aging research collaborated on a position paper that sets out the current state of the science and separates fact from fiction. The entire report appears here
Antiaging products are big business--a multibillion-dollar industry. But the marketing of these products often misrepresents the science. Rather than let their silence imply compliance, 51 of the top researchers in the field of aging research collaborated to create a position paper that sets out the current state of the science. A shorter, more pointed essay, called "No Truth to the Fountain of Youth," by three of the position paper's signers, S. Jay Olshansky, Leonard Hayflick and Bruce A. Carnes, is in Scientific American 's June 2002 issue the position paper itself is here. -- The Editors
Position Statement on Human Aging
Authors and Endorsers
In the past century a combination of successful public health campaigns, changes in living environments and advances in medicine have led to a dramatic increase in human life expectancy. Long lives experienced by unprecedented numbers of people in developed countries are a triumph of human ingenuity. This remarkable achievement has produced economic, political and societal changes that are both positive and negative. Although there is every reason to be optimistic that continuing progress in public health and the biomedical sciences will contribute to even longer and healthier lives in the future, a disturbing and potentially dangerous trend has also emerged in recent years. There has been a resurgence and proliferation of health care providers and entrepreneurs who are promoting antiaging products and lifestyle changes that they claim will slow, stop or reverse the processes of aging. Even though in most cases there is little or no scientific basis for these claims, 1 the public is spending vast sums of money on these products and lifestyle changes, some of which may be harmful. 2 Scientists are unwittingly contributing to the proliferation of these pseudoscientific antiaging products by failing to participate in the public dialogue about the genuine science of aging research. The purpose of this document is to warn the public against the use of ineffective and potentially harmful antiaging interventions and to provide a brief but authoritative consensus statement from 51 internationally recognized scientists in the field about what we know and do not know about intervening in human aging. What follows is a list of issues related to aging that are prominent in both the lay and scientific literature, along with the consensus statements about these issues that grew out of debates and discussions among the 51 scientists associated with this paper.
A Systems Biology approach (Metabolomics: mainly genomics proteomics and lipidomics for brain) can in future lead to a “Personalized medical treatment” and biomarkers of aging. Neuroimaging-biomarkers of Mild Cognitive Impairment (MCI) allow an early diagnosis in preclinical stages of mild-Alzheimer’s disease (m-AD) and dementia. With an aging population in the developed countries emphasis on neuroimaging and smart ligand Pet-scan biomarkers should take place. A second topic of interest –which is still a hypothesis- is the nearly unexploited research area of cognitive reserve. The ability of an individual to demonstrate no cognitive signs of aging despite an aging brain is called cognitive reserve [78,79]. This hypothesis suggests that two patients might have the same brain pathology, with one person experiencing noticeable clinical symptoms, while the other continues to function relatively normally. Studies of cognitive reserve exploring the specific biological, genetic and environmental differences which make one person susceptible to cognitive decline, and allowing another to age more gracefully and in studying this topic biomarkers of aging are clearly warranted.
3 THE TRANSLATIONAL VALUE OF ASSESSING BIOLOGICAL AGING
Substantial investment is necessary to develop an estimator of biological aging that is robust, precise, reliable, and sensitive to change. Thus, a fair question is whether such a titanic project is worth the effort and cost. The answer is YES, without hesitation. Developing an index of biological aging is perhaps the most critical milestone required to advance the field of aging research and, especially, to bring relieve from the burden of multimorbidity and disability in an expanding aging population. Ideally, these measures would be obtained by running tests using blood samples without performing a biopsy, preferably quickly and at low cost. An index of biological aging could be used to empirically address the geroscience hypothesis: “Is biological aging is the cause of the global susceptibility to disease with aging.” Data collected longitudinally—ideally in a life course epidemiological study—could then be used to test if individuals that accumulate coexisting diseases faster than in the general population also have accelerated biological aging. Similarly, these data could be used to test if individuals who are biologically “older,” independent of chronological age, are at a higher risk of developing different medical or functional conditions that do not share physiological mechanisms. Once validated, the fundamental basis of biological aging can be used to probe deeper into questions related to the mechanisms of aging, such as the following: Are there genetic traits that are associated with faster or slower biological aging? Are there “hallmarks” that are better at capturing biological aging at different stages of life?
These questions have immense relevance for geriatric medicine. Despite the rising emphasis on prevention, most current medical care is dedicated to diagnosing and managing diseases that are already symptomatic, which does not address the underlying issues related to geriatric health conditions. By understanding the intrinsic mechanisms of biological aging, including damage and resilience, medical professional will be able to best orient and prescribe therapeutic choices. These mechanisms are summarized in Table 1 according to the current state of knowledge. The first column lists measures of damage for each one of the hallmarks of aging, the second lists the compensatory measures that we would like to have available, and the third lists the compensatory measures that are currently available. Clearly, the current ability to measure biological compensations and resilience is very limited, although most are vital to human health. In fact, it has been proposed that chronic diseases, especially those that emerge in old age, may be cross-classified based on their dependence on the force of the “noxa patogena” and the robustness of resilience.
- Somatic mutations (including in stem cells)
- Inappropriate clonal expansion
- DNA modifications (8-oxoG, gammaH2AX, etc.)
- DNA repair mechanisms
- Cellular checkpoint responses (e.g., cell cycle arrest, senescence, apoptosis)
- Integrity of replication fidelity mechanisms
- Antioxidant mechanisms
- Single-cell/clonal NGS
- Tests of DNA repair mechanisms
- Measures of DNA modifications
- Telomere dysfunction in mitotic cells, stem cells, and germline cells
- Cellular checkpoint responses
- Telomere length
- Markers of DNA damage response
- Telomerase activity
- Arrested cell proliferation
- SASP, chronic inflammation
- Immune clearance of senescent cells
- SASP suppression by mTOR signaling
- Prevention of irreversible senescence
- Senescent markers in blood and tissue
- SASP proteins in blood and tissue
- Inappropriate increase or decrease in DNA methylation at specific sites
- Inappropriate increase or decrease in specific histone modifications
- Maladaptive epigenetic changes
- Epigenetic maintenance system
- Mechanism of epigenomic reprogramming
- Adaptive changes in epigenetic markers
- Suppression of negative and enhancement of positive transcriptional programs
- Histone acetylation
- Impaired respiration/ox/phosph
- Ineffective mitochondrial biogenesis
- Ineffective mitochondrial recycling
- Mitochondrial disorganization
- ROS-mediated oxidative damage
- Mitochondrial biogenesis
- Mitochondrial remodeling (fission/fusion cycles), mitophagy
- Maintained mtDNA replication fidelity
- Antioxidant defenses
- Mitochondrial volume/number/shape
- Mito respiration
- P 31 MRI spectroscopy
- Markers of biogenesis
- mtDNA copy number and haplotypes
- Increased damaged/misfolded proteins
- Decreased protein function
- Permanence of unrecycled proteins/organelles
- Cell death due to increased autophagy
- Activity of macro-, micro-, and chaperone-mediated autophagy-related proteins
- Enhanced signaling pathways (e.g., mTOR signaling) that regulate levels of autophagy
- Autophagy markers and flux (+ TEM)
- Chaperon proteins
- Reduced stem cell number
- Decreased proliferative capacity
- Decreased differentiation capacity
- Quiescence maintenance
- Proliferative capacity in vitro
- Resistance to stress
- The second column lists measures of damage, some of which are already feasible in humans, while others are only theoretically feasible. The third column lists measures of resilience that would be theoretically desirable, while the fourth column lists measures that are currently feasible. Importantly, regarding many of the available measures, understanding if they reflect damage or compensation requires further investigation.
- Abbreviations: NGS, new-generation sequencing SASP, senescence-associated secretory phenotype TEM, transmission electron microscopy.
The approach described above is not too farfetched from our experience. Hopefully, we all take good care of our cars before they break or malfunction we make sure that the water an oil levels are ok, that the brake pads are not consumed, that the pressure in the tires is according to factory recommendations. We carefully follow maintenance schedule because we want to maximize the healthy life of our cars and avoid expensive repairs and replacements. Shouldn't we pay the same attention to our bodies? In the field of geriatrics, the situation is even more extreme and often patients come to the clinic when they are already affected by multiple diseases, have lost their autonomy, and have economic and social constrains. In other words, they come to observation when all the mechanisms of compensation and resilience are exhausted. Despite these odds, geriatricians sometime make miracles, but certainly not often enough. The possibility of measuring biological aging swaps this perspective and allows the assessment of health status at a time when our physiology is still resilient, there are still no symptoms, and interventions are more likely to be effective.
A robust biomarker of biological aging would have benefits beyond the early identification of persons who age “faster” than others. First, the genetic, environmental, and behavioral risk factors associated with accelerated aging could be identified. Then, longitudinal studies could be utilized to identify specific time points at which the trajectories of aging change and relate to those other health-related triggers, such as the exposure to pollution associated with moving to a different city. As biological aging is the primary cause of resilience loss, measuring damage and compensation may help in determining between interventions with potentially serious side effects. Longitudinally, a marker of aging could be used to track if interventions with similar efficacy toward a specific target affect the “speed of aging” differently, which may impact accelerated declines in health. This approach could be used to both refine choices in alternative therapies and develop new medications in order to avoid damage accumulation or curtail compensatory mechanisms. Clinical trials then can be designed to specifically target the speed of aging, the underlying causes of multimorbidity, or both as the primary outcomes of interest. The list of interventions is almost limitless, even without considering the many other applications that are currently unknown and will only become evident as the field progresses.
Telomere extension turns back aging clock in cultured human cells, study finds
Researchers delivered a modified RNA that encodes a telomere-extending protein to cultured human cells. Cell proliferation capacity was dramatically increased, yielding large numbers of cells for study.
A new procedure can quickly and efficiently increase the length of human telomeres, the protective caps on the ends of chromosomes that are linked to aging and disease, according to scientists at the Stanford University School of Medicine.
Treated cells behave as if they are much younger than untreated cells, multiplying with abandon in the laboratory dish rather than stagnating or dying.
The procedure, which involves the use of a modified type of RNA, will improve the ability of researchers to generate large numbers of cells for study or drug development, the scientists say. Skin cells with telomeres lengthened by the procedure were able to divide up to 40 more times than untreated cells. The research may point to new ways to treat diseases caused by shortened telomeres.
Telomeres are the protective caps on the ends of the strands of DNA called chromosomes, which house our genomes. In young humans, telomeres are about 8,000-10,000 nucleotides long. They shorten with each cell division, however, and when they reach a critical length the cell stops dividing or dies. This internal “clock” makes it difficult to keep most cells growing in a laboratory for more than a few cell doublings.
‘Turning back the internal clock’
“Now we have found a way to lengthen human telomeres by as much as 1,000 nucleotides, turning back the internal clock in these cells by the equivalent of many years of human life,” said Helen Blau, PhD, professor of microbiology and immunology at Stanford and director of the university’s Baxter Laboratory for Stem Cell Biology. “This greatly increases the number of cells available for studies such as drug testing or disease modeling.”
A paper describing the research was published today in the FASEB Journal. Blau, who also holds the Donald E. and Delia B. Baxter Professorship, is the senior author. Postdoctoral scholar John Ramunas, PhD, of Stanford shares lead authorship with Eduard Yakubov, PhD, of the Houston Methodist Research Institute.
The researchers used modified messenger RNA to extend the telomeres. RNA carries instructions from genes in the DNA to the cell’s protein-making factories. The RNA used in this experiment contained the coding sequence for TERT, the active component of a naturally occurring enzyme called telomerase. Telomerase is expressed by stem cells, including those that give rise to sperm and egg cells, to ensure that the telomeres of these cells stay in tip-top shape for the next generation. Most other types of cells, however, express very low levels of telomerase.
Transient effect an advantage
The newly developed technique has an important advantage over other potential methods: It’s temporary. The modified RNA is designed to reduce the cell's immune response to the treatment and allow the TERT-encoding message to stick around a bit longer than an unmodified message would. But it dissipates and is gone within about 48 hours. After that time, the newly lengthened telomeres begin to progressively shorten again with each cell division.
The transient effect is somewhat like tapping the gas pedal in one of a fleet of cars coasting slowly to a stop. The car with the extra surge of energy will go farther than its peers, but it will still come to an eventual halt when its forward momentum is spent. On a biological level, this means the treated cells don’t go on to divide indefinitely, which would make them too dangerous to use as a potential therapy in humans because of the risk of cancer.
The researchers found that as few as three applications of the modified RNA over a period of a few days could significantly increase the length of the telomeres in cultured human muscle and skin cells. A 1,000-nucleotide addition represents a more than 10 percent increase in the length of the telomeres. These cells divided many more times in the culture dish than did untreated cells: about 28 more times for the skin cells, and about three more times for the muscle cells.
“We were surprised and pleased that modified TERT mRNA worked, because TERT is highly regulated and must bind to another component of telomerase,” said Ramunas. “Previous attempts to deliver mRNA-encoding TERT caused an immune response against telomerase, which could be deleterious. In contrast, our technique is nonimmunogenic. Existing transient methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging. This suggests that a treatment using our method could be brief and infrequent.”
Potential uses for therapy
“This new approach paves the way toward preventing or treating diseases of aging,” said Blau. “There are also highly debilitating genetic diseases associated with telomere shortening that could benefit from such a potential treatment.”
Blau and her colleagues became interested in telomeres when previous work in her lab showed that the muscle stem cells of boys with Duchenne muscular dystrophy had telomeres that were much shorter than those of boys without the disease. This finding not only has implications for understanding how the cells function — or don’t function — in making new muscle, but it also helps explain the limited ability to grow affected cells in the laboratory for study.
The researchers are now testing their new technique in other types of cells.
“This study is a first step toward the development of telomere extension to improve cell therapies and to possibly treat disorders of accelerated aging in humans,” said John Cooke, MD, PhD. Cooke, a co-author of the study, formerly was a professor of cardiovascular medicine at Stanford. He is now chair of cardiovascular sciences at the Houston Methodist Research Institute.
“We’re working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally useful,” said Blau, who also is a member of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.
“One day it may be possible to target muscle stem cells in a patient with Duchenne muscular dystrophy, for example, to extend their telomeres. There are also implications for treating conditions of aging, such as diabetes and heart disease. This has really opened the doors to consider all types of potential uses of this therapy.”
Other Stanford co-authors of the paper are postdoctoral scholars Jennifer Brady, PhD, and Moritz Brandt, MD senior research scientist Stéphane Corbel, PhD research associate Colin Holbrook and Juan Santiago, PhD, professor of mechanical engineering.
The work was supported by the National Institutes of Health (grants R01AR063963, U01HL100397 U01HL099997 and AG044815), Germany’s Federal Ministry of Education and Research, Stanford Bio-X and the Baxter Foundation.
Ramunas, Yakubov, Cooke and Blau are inventors on patents for the use of modified RNA for telomere extension.
Sex gap in aging and longevity due to asymmetries in genetic inheritance between sexes
The mother’s curse
An aspect of the biology of males and females that could contribute to the sex gap in longevity and aging is the inheritance of some genetic factors that differ between sexes. This is the case with the mitochondrial genome, which is inherited maternally, and of the sex chromosomes that differ between sexes. In most species, mitochondria are transmitted through the female lineage and natural selection can only operate in that lineage. In particular, natural selection will be completely blind to deleterious mutations that (mainly) have a male-specific effect and those mutations can be passed through generations by females as if they were neutral mutations . The accumulation of mainly male deleterious mutations in the mitochondrial genome could, in principle, explain why males age faster and die younger, which is called the “mother’s curse” hypothesis . This hypothesis, however, predicts that longevity should systematically be female-biased (except for species with biparental transmission of mitochondria as for example some bivalves), which is not always what it is observed. Moreover, the mitochondrial genome includes very few genes in animals, and the potential to drive aging through the mother’s curse is probably small. Unfortunately, the mother’s curse has been studied in very few organisms and mainly in Drosophila. In Drosophila, some data support this theory . In humans, some genetic diseases with a mitochondrial origin are known to affect males more than females. In one of them, Leber’s optic neuropathy, the mother’s curse has acted over 290 years and could be observed in a human population . In plants, where mitochondria have a much larger genome size and gene content (e.g., ), and where chloroplasts also have a maternal inheritance, the mother’s curse has a much greater potential for explaining differences in longevity between males and females, which remain to be characterized.
The effects of sex chromosomes
An obvious difference between men and women are the sex chromosomes, which could impact aging and longevity in a number of ways. A first obvious effect of having sex chromosomes is that males have one X and are hemizygous for that chromosome while females have two Xs. In women, however, X-chromosome inactivation (XCI) in the soma means that only one X is expressed in each cell. However, XCI is random in humans and other placentals, which means that, at the level of the tissue, on average, half of the cells will express the paternal X and the other half the maternal one, and functional diploidy is restored at the level of the tissue. This implies that if present in a male, a deleterious mutation on the X will always be expressed . If present in a female, it will depend whether the mutation is recessive or dominant and whether that female is homozygous or heterozygous for this mutation. Indeed, it is known that most of the genetic diseases/conditions carried by the X chromosome have a much higher prevalence in men than in women (e.g., daltonism, hemophilia, Duchenne muscular dystrophy). This mechanism, called the “unguarded X”, could contribute to aging and longevity (Fig. 2b). Of course, the unguarded X effect depends on how well functional diploidy is restored in females in species with XCI. In humans, a skewed XCI is associated with faster aging and a shorter lifespan, and centenarian females tend to have a balanced XCI [15, 96, 97]. Why some individuals exhibit skewed XCI and not others remains to be understood.
A general prediction of the unguarded X is that, in XY systems, males should die faster. In some species (e.g., birds, butterflies), females are heterogametic (i.e., have different sex chromosomes) these systems are called ZW (females: ZW, males: ZZ). The W is equivalent to the Y and the Z to the X (). In these systems, the unguarded Z effect should result in the opposite pattern: ZW females should die faster. Until recently, however, very little data was available and they tended to support the idea that sex chromosomes would not have a major role in sex-specific aging patterns. In particular, fragmented data on patterns of longevity and aging in birds suggested that females might outlive males in this taxon, contrary to what is expected with the unguarded Z. Sex chromosomes were thus disregarded in the literature about the sex gap in aging and longevity (e.g., ).
Some recent data have changed this view. Pipoly et al. (2015) have investigated the connection between sex chromosomes and aging/longevity by compiling data on adult sex ratios (ASRs) as a proxy for the sex gap in longevity and sex chromosome types (XY, ZW) for 344 species of tetrapods (including mammals, birds, lizards, crocodiles, snakes, amphibians), by far the largest dataset analyzed so far. They found a strong statistical association between the sex chromosome type and ASRs . In the XY species, ASRs are female-biased, which suggests that males tend to die younger, whereas it is the opposite pattern in ZW species (Fig. 1a). Sex chromosomes are a widespread sex determination system in animals but also in other groups, such as plants and algae , and they could contribute to the sex gap in mortality in many groups and could be the major contributor in those where sexual dimorphism is not very strong, such as plants and algae . Some other recent data suggests that the unguarded X/Z might be just one mechanism among several. In Drosophila, the Y chromosome, despite its very small gene content, has a major effect on the epigenetics of the other chromosomes . Some recent data suggests that the epigenetics of the Y chromosome (i.e., DNA methylation, histone marks) change throughout life. In old male flies, Y chromatin is more open and transposable elements (TEs) tend to be de-repressed, which could result in those elements jumping around in the male genome, causing deleterious mutations and speeding up aging . In line with this idea, another study in flies has shown that part of the variance in aging could be attributed to the genetic variance of the Y chromosome . To further test the idea that the Y chromosome causes faster aging in males than in female flies, Brown and Bachtrog (2017) looked at aging and longevity in XXY females and monosomic X and XYY males, and confirmed that the Y increases aging in Drosophila . This suggests that sex chromosomes may contribute to aging through a “toxic Y/W” effect because of particularly high transposable element content (Fig. 2b and Box 2).
The contribution of sex chromosomes to sex-specific differences in longevity and possible mechanisms. a The relationship between either female-biased or male-biased adult sex ratios and the sex chromosome type in vertebrates (adapted from ). The mechanisms through which sex chromosomes can impact longevity: (b) the unguarded X effect, (c) the toxic Y effect and (d) the loss of Y chromosomes. See text for details
Another possible mechanism through which sex chromosomes could affect longevity is cellular mosaicism (Fig. 2d). Cellular mosaicism is the presence of cells with different genotypes caused by somatic mutations. They include large-scale intra-chromosomic rearrangements and gain or loss of entire chromosomes. Cellular mosaicism is known to increase with age for all chromosomes in somatic tissues, but this increase is much higher for the sex chromosomes [105,106,107,108,109]. Large-scale somatic mutations, and, in particular, loss of the Y, increase in aging men and are associated with an increase in the risk of cancer . Some external factors such as smoking are associated with increased rates of Y loss, and Y cellular mosaicism may contribute to an increased cancer risk with smoking . Cellular mosaicism involving the X is also more frequent than that of autosomes . The precise mechanism underlying these chromosome-specific differences in cellular mosaicism is not well understood, but in females, the inactive X is mostly affected . In centenarian interphase cells, the loss of X in women (
22%) is higher than the loss of Y in men (
10%), which may suggest that the loss of the inactivated X has less consequence than the loss of the Y .
Investigation of stem cell aging provides new insights into understanding aging
Complex biological systems are designed to be robust against internal and external challenges to maintain the homeostasis of their functions (Kitano 2004). Aging process seriously compromises this fundamental feature and leaves aged organisms highly susceptible to lesser/minimal changes and damages, as manifested by a reduced capacity of resident stem cells to replenish cells lost to age-related pathological changes (Oh et al. 2014). Stem cell exhaustion with age is consistently observed in diverse tissue-specific stem cells including muscle (Cerletti et al. 2008), hematopoietic (Kollman et al. 2001), and neural stem cells (Enwere et al. 2004), necessitating studies for a comprehensive understanding of aged stem cells associated with the progressive regenerative deterioration. A parabiosis study showed that when exposed to the niche of young mice’s muscles, aged mice are able to ameliorate the age-related cognitive impairments, suggesting therapeutic potential for enhancing or replacing aged stem cells and significance of stem cell aging study (Villeda et al. 2014). Many molecular processes implicated in stem cell aging are evolutionarily conserved such as the accumulation of damaged macromolecules, DNA damage, reactive oxygen species (ROS) production, TOR, and WNT signaling (Jones and Rando 2011 Oh et al. 2014). To facilitate the clinical translation of knowledge acquired from the study of aged stem cells to the process of aging, an exploration of the overlapping or conserved processes between aging and stem cells would yield interesting leads. Therefore, a comprehensive understanding of the molecular mechanisms regulating stem cell aging and their surrounding niches will provide a valuable clue for developing therapeutic strategies to delay or reverse age-related diseases. Hereafter, we will focus on the important molecular processes regulating stem cell aging before discussing the integration of OMICS technology with stem cell aging research.