Supercentenarians Awards: $1 Million for the First 123-Year-Old
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Dmitry Kaminskiy of Deep Knowledge Ventures is one of a small group of technology entrepreneurs turned venture investors with a strong interest in bringing aging under medical control. I think the size of this group will grow in the future: many of the wealthy individuals you see in the press today talking about longevity science, such as Kaminskiy, Peter Thiel, Paul Glenn, and those steering Google Venture's Calico initiative, have been involved less vocally for years behind the scenes. Thiel has funded SENS rejuvenation research for the past decade, while Kaminskiy has been a trustee of the Biogerontology Research Foundation for some years, for example. Glenn was far ahead of both of them, but has never seemed particularly interested in making a big splash of the work of his foundation outside the scientific community: he continues to establish and reinforce funding for aging research labs year after year.

One of the big shifts in longevity science and its perception over the past couple of years has been the move from quiet support to vocal support, with a corresponding rise in accompanying press attention and public statements of intent from influential individuals. This is all to the good. It grants greater legitimacy to the field in the eyes of those who care more about opinion than fact, which sadly includes the controllers of most sources of large-scale funding. Other quiet supporters are more likely to speak out themselves. This all makes it easier for researchers in the field to raise funding. It also makes it easier for grassroots efforts to gather more supporters and raise more money for the cause. This change in the environment is a necessary step towards taking the defeat of aging, and the prospect for real, working rejuvenation treatments, from something that the average fellow in the street laughs at to something that is as widely supported as cancer research is today.

This leads me to note Kaminskiy's latest advocacy and awareness initiative, a $1 million prize to be awarded to the first individual verified to reach 123 years of age, beating the record set by Jeanne Calment almost twenty years ago now:

Supercentenarians Awards

Dmitry Kaminskiy will present a $1 million prize to the first man or woman to reach the age of 123. The current longevity record is held by Jeanne Calment, who lived for 122 years and 164 days. Those with the highest odds of besting Calmant's record can be found among today's elderly population with proof of age recorded by either the Gerontology Research Group, Max Plank Institute for Demographic Research, or Guinness World Records.

The goals of this prize are to raise awareness of issues related to longevity and encourage people to take measures to extend their own lives and youth, encourage progress by drawing the attention of the scientific community to longevity issues, and stimulate business activity and institutions in the fields of health and gerontology.

As advocacy goes, this seems a fairly shrewd approach if kept fresh and well publicized. Nothing of this ilk has been tried before in the longevity science community for all the obvious reasons: people who might reach a new record longevity in the next decade will likely do so in isolation of any relevant modern efforts in the scientific and medical community. Rewarding long-lived individuals is very distant from any focus on research and medical development relevant to rejuvenation, especially if talking about how long someone presently older than 110 might live. Nonetheless, I think you'll agree that this could be a great source of recurring press and public attention if well managed.

Further, the initiative seems unlikely to cost Kaminskiy the $1 million prize at any point in the near future, which is always an important consideration when thinking about whether or not such an education and awareness effort is worthwhile. By a peculiarity of fate, Jeanne Calment's lifespan was a good three years longer than that of Sarah Knauss, the second longest lived individual with verified records to prove it. In turn, Knauss herself lived for a year and a half out beyond the life spans of the next few record individuals. Anywhere past 110 years of age the mortality rate month by month is enormous, never mind year by year. For people this frail and damaged by age, balanced on a knife-edge of chance and fragility, it seems unlikely that any of the initial implementations of prospective treatments for aging, those currently under development or in the laboratory, could be safely applied any time soon. There is a world of difference between trying to apply stem cell treatments or infusions or medical nanotechnology in a 70-year-old versus a 110-year-old: the latter will be much, much harder.

So, all things considered, I'll watch this prize effort with interest. It is one of many signs of the times, that the early days of the change years are upon us, in which treating aging so as to prevent degeneration and greatly extend healthy life span will move from fringe concern in the scientific community to mainstream research goal, widely supported and appreciated, and massively funded. There is a way to go yet, but this is the time for it. The first seeds are growing.

A Little mTOR Triumphalism
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It's always good to listen to viewpoints that you happen to disagree with. This is why I pay attention to research strategies and researchers informed by programmed aging theories such as the hyperfunction hypothesis that builds on antagonistic pleiotropy. In this view aging is the consequence of various developmental processes running off the rails, colliding, and fighting one another along the way, producing dysregulation and damage. This is programmed in the sense that it is an inevitable consequence of the way in which the many biological systems evolved to perform in early life. Thus evolved programs cause accumulations of cellular and molecular damage, which goes on to create further harm.

This is exactly backwards from the more mainstream view in the research community, and how I myself see the balance of evidence, which is that cellular and molecular damage accumulates through the normal operation of metabolism. That damage causes increasingly large reactions in evolved biological systems, few of them good, as their operating parameters and local environment become ever more dysfunctional. Damage causes more damage, and the process accelerates rapidly in later life, just as in any complicated machine. One of the most fascinating things about aging research at the present time is that biology is so fantastically complex that there is room enough yet to argue over whether damage causes change or change causes damage. There is so much left unknown and fuzzy still at this stage, despite the mountains of knowledge accumulated, that researchers still have great latitude to theorize and rearrange the chunks of what is known.

The end result is a lot of theorizing, as is always the case in any territory where much is left to be mapped. This will continue until enough proof arrives to settle the debate. In the case of the most important debate in aging research, which is between programmed aging and aging as damage, the most rapid and cost-effective way to settle this would be to implement initial prototypes of the SENS proposals for rejuvenation treatments. These are based entirely on the view of aging as damage accumulation, and involve the repair of specific forms of cellular and molecular damage thought to be fundamental, caused by the ordinary operation of metabolism rather than by some other form of damage. If aging is programmed then SENS will not work well at all, producing only fleeting benefits before the programs assert themselves to create more damage. If aging is damage, then SENS prototypes will greatly extend healthy life spans in laboratory animals such as mice. The cost of producing these prototypes is probably in the vicinity of $1-2 billion and 10-20 years, which is less than the cost for a Big Pharma entity to develop a single drug these days.

One of the originators of the hyperfunction theory of aging is very much in favor of manipulating mTOR, mechanistic target of rapamycin as a way to treat aging. He is a prolific author on this topic, and feels that work on rapamycin - and related drug candidates such as everolimus - in recent years goes a long way towards bolstering his case for mTOR as a master regulator of the aging process. If you are an adherent of the programmed aging viewpoint then altering metabolic operation, such as by dialing up or dialing down circulating levels of specific proteins, is exactly the approach that should be taken to treat aging. Restore something that looks more like youthful metabolism and damage will be repaired to at least some degree, depending on how far things have gone. If you follow the aging as damage viewpoint, on the other hand, then altering metabolic operation is a matter of rearranging deckchairs on the Titanic: it fails to address the underlying cause of frailty, degeneration, and disease, and therefore can only produce poor or fleeting benefits.

I think you'll find this an interesting piece, being almost exactly reversed in many of its viewpoints from much of the research I point out. All groups have their triumphalism, and one can appreciate a well conducted expression of that urge even when fairly certain that the author is wrong in his or her big picture view of the science:

Rejuvenating immunity: "anti-aging drug today" eight years later

Until recently, aging was believed to be a functional decline caused by accumulation of random molecular damage, which cannot be prevented. Breaking this dogma, hyperfunction theory described aging as a continuation of growth, driven by signaling pathways such as TOR (Target of Rapamycin). TOR-centric model predicts that rapamycin (and other rapalogs) can be used in humans to treat aging and prevent diseases. In proper doses and schedules, rapamycin and other rapalogs not only can but also must extend healthy life-span in humans. This theory was ridiculed by opponents and anonymous peer-reviewers. Yet, it was predicted in 2008 that "five years from now, current opponents will take the TOR-centric model for granted". And this prediction has been fulfilled.

Currently, humans and animals (in protected environment) die from age-related diseases, which are manifestation of aging. By slowing aging, rapamycin and calorie restriction can delay age-related diseases including cancer. They extend life span. Yet, the causes of death seem to be the same. Or not? Why is this important? Consider an analogy. 300 years ago in London, 75% of people died from external causes (infections, trauma, starvation) before they reached the age of 26. So only a few died from mTOR-driven aging. Only when most external causes have been eliminated, people now die from mTOR-driven age-related diseases. Similarly, if TOR-driven aging would be eliminated by a rational combination of anti-aging drugs, even then we still would not be immortal. There will be new, currently unknown causes of death. I call this post-aging syndrome. We do not know what it is. But we know that accumulation of molecular damage or telomere shortening (as examples) eventually would cause post-aging syndrome.

Even in the ancient world, when most people died from "external causes", symptoms of mTOR-driven aging were well known. In contrast, we do not know symptoms of post-aging syndrome. Aging is quasi-programmed and is not accidental. Although its rate varies among individuals, the chances to outlive aging and to die from post-aging syndrome are very low. Still, we may identify these symptoms in humans over 110 years old and especially in animals treated with rapamycin (and other anti-aging modalities). Inhibition of mTOR may extend life span, thus revealing post-aging syndrome. How will we know that we observe post-aging syndrome? There are potential criteria: Animals and humans die from either unknown diseases, unusual variants of known-disease and rare diseases. Or at least, the range of age-related diseases is dramatically changed. As discussed in 2006, causes of post-aging syndrome may include accumulation of random molecular damage, telomere shortening, selfish mitochondria and so on.

While gerontologists were studying free radicals and anti-oxidants, the TOR-centric (hyperfunction) theory revealed anti-aging drugs such as rapamycin and metformin. There are several potential anti-aging drugs in clinical use. Combining drugs and modalities, selecting doses and schedules in clinical trial will ensure the maximal lifespan extension. Simultaneously, medical progress improves aging-tolerance. Aging tolerance is the ability to survive despite aging. For example, bypass surgery allows patients with coronary disease to live, despite aging-associated atherosclerosis. Gerontologists do not need to catch the train that has already departed. No need to study rapamycin, which already entered the clinic. This is now a merely medical task. Gerontologists may continue to study free radicals and accumulation of random molecular damage as a potential cause of post-aging syndrome (not aging). It is important to study post-aging syndrome, to be ready to fight it, when medical progress with rapamycin will allow us to reach post-aging age: perhaps 50 years from now.

A Brief Introduction to Model Organisms in Aging Research
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The varied approaches to research developed over past decades by the aging research community are driven by two things: firstly that we live for a long time, and secondly the absence of a way to accurately determine an individual's biological age. The only way to measure the effects of potential treatments is to carry out life span studies, and in humans that is impractical to say the least. Thus research into aging and longevity starts with short-lived animals such as nematode worms and flies: exploration and experimentation takes place using these species because life span studies can be carried out in a suitably short period of time to make progress. Promising work moves to mice, where life span studies can last for five years and cost millions. Only later do potential treatments make it to human clinical trials, if at all. This is all much the same as most modern medical research; the process of discovery and development moves incrementally from a state of being far from human biology and cheap to work on to a state of being close to human biology and very expensive to work on.

To a surprising degree the fundamental biology of cells, regulation of metabolism, and mechanisms of aging are similar in even very widely separated species. Aging and many of its interesting epicycles such as the calorie restriction response appeared very early in evolutionary history, a long way down in the tree of life. Thus research in lower animals can still be relevant to human cellular biochemistry, and provide insight into human aging. Nonetheless, worms are not mice and mice are not people. The cost of investigative research that starts with other species is that there is a fair degree of failure when translating promising work over to mammals, and yet more failure when moving from short-lived mammals such as mice to long-lived mammals such as humans. That is acceptable given that the alternative is no research at all, as all studies would be prohibitively expensive to carry out.

Another aspect of research into aging and its associated medical conditions is that genetically altered lineages of laboratory animals are frequently employed. The reasons for this are again economic at root. If you want to study a specific condition, such as old age for example, it is more cost-effective to work with mice that suffer from a DNA repair deficiency that mimics some aspects of accelerated aging than it is to work with normal mice. More research can be carried out more rapidly with accelerated aging mice, even when accounting for the fact that a significantly greater fraction of the results will be irrelevant to normal aging. The same applies to the many different animal models of specific age-related diseases: these are all loose replicas intended to share some characteristics of the disease as it occurs in humans, but under the hood they are not the same thing at all. Animal models are a way to make progress in a cost-effective manner, not an accurate rendition. These things are always worth bearing in mind when reading research results based on animal studies.

Do Model Animals Tell Us Anything about Human Aging?

Using model animals in gerontological studies has yielded an enormous wealth of useful information about the mechanisms of human aging and longevity. Animal models were crucial in identifying the conserved pathways that regulate human aging. Model organisms are fundamental for aging research, because there are serious limitations of using human subjects, such as the length of lifespan, genetic heterogeneity and vast differences in environmental influences. The shape of survival curves represents the health of the organism over time. Model organisms display significantly different lifespans, however the survival curves resemble those of humans quite remarkably.

Yeast S.cerevisiae

Yeasts have been instrumental in identifying the major conserved aging pathways shared among a large variety of species. Despite the fact that yeast is a unicellular organism that has significant differences in its genetic pathways with humans, the advantages of using yeast as an aging model include their fast growth, low cost and easy storage and maintenances of organism strains. Over the years researchers have developed a broad variety of genetic manipulations that make yeast a powerful tool in the hands of an aging biologist.

Nematode C.elegans

The roundworm Caenorhabditis elegans is a powerful model for studying aging due to its short lifespan. It is easy to culture and maintain strains because nematodes can be kept frozen and suffer no apparent damage upon thawing. The animals are optically transparent and can be used in high-throughput automated experiments, which makes them a perfect tool for answering the most pressing questions in biology of aging. However, there are obvious drawbacks of using C. elegans as a model for human aging. They are evolutionary distant from humans, lack tissues like brain, blood, they don't have internal organs and are post-mitotic, meaning that nematodes lack the ability to regenerate their tissues and are limited in serving as a model of aging of highly proliferative tissues.

Fruit fly D.melanogaster

Fruit flies have many advantages as a model system for aging studies. They have a relatively short lifespan of 60-80 days, which is more than that of a nematode, but compared to them drosophila have more distinct tissues and organs including the brain, eyes, kidney, liver and heart. Fruit flies have proliferating stem cell populations in their guts. Flies share about 60% of disease-related genes with humans, which makes them a desirable model also given their low cost and easy handling. However, maintaining a transgenic strain is more costly and labor-heavy, since whole flies cannot be frozen and thawed without damage.

Hydra

Hydra is definitely not the most popular model organism, but it might be overlooked quite groundlessly. Hydras are notorious for their negligible senescence. This very fact makes them a very desirable system to study. In fact, there is no apparent senescence in asexually reproducing hydras, yet the signs of aging can be seen after the organism reproduces sexually. Another overlooked fact is that hydras share 6071 genes with humans, whereas fruit flies have 5696 genes in common with humans, and nematodes - only 4751. Among the known human aging-related genes at least 80% are shared with hydra.

Fish

The most widely used fish model is the zebrafish D.rerio. It lives for about 2-3 years, which is not particularly beneficial, because its lifespan is similar of rodents, but it is more evolutionary distant from humans. Nonetheless, zebrafish has a remarkable ability to regenerate its tissues, which is an advantage for elucidating the mechanisms of tissue regeneration and longevity. Another fish may be a more promising laboratory model for aging - turquoise killifish Nothobranchius furzeri. Killifish is one of the shortest-lived vertebrate with a lifespan of only 13 weeks. Its small size and high fecundity offer a considerable advantage in terms of reducing laboratory costs on housing and maintenance.

Rodents

Mice are invaluable in aging research. There are approximately 99% of human orthologs in mice, which is a significant advantage compared to invertebrate models. Mouse lifespan is approximately 2-3 years depending on the strain, which makes them a more expensive tool in the arsenal of an aging biologist. Inbred mice have been studied very extensively and a large body of knowledge about aging mechanisms, age-related diseases and existing and potential therapies was created using this model. Using inbred lines is a double-edged sword: on one hand, genetic differences between animals are virtually non-existent, however this is not representative of human population and it is not clear to what extent the results can be transferred to humans.

Naked mole rats

Heterocephalus glaber, the naked mole rat, is the most long-lived rodent with a maximum life span of approximately 30 years. Naked mole rat exhibits negligible senescence, virtually no age-related increase in mortality and high reproduction levels until death. They have several signs of age-related pathology similar to humans, such as osteoarthritis and degeneration of the retina. Naked mole rats can provide clues to mechanisms of longevity and potential therapies in humans, and hence are an extremely valuable model animal. There are several disadvantages of using them as laboratory animals, however, including specific housing conditions like low light levels, high temperature and humidity. Very long lifespan poses an obvious limitation on the variety of experiments suitable for this model.

Primates

Rhesus macaques have been used in various types of research, however there are not too many studies of age-related mechanisms in primates. The main reasons for that are their long lifespan, which is more than 30 years, their size and weight, which complicate housing and maintenance and make this model an expensive and hard to handle. However, there are several distinct advantages of using non-human primates for studying age-related pathologies, such as Alzheimer's disease and other neurodegenerative diseases that can't be recapitulated in mouse models.

Metchnikoff Day, an Opportunity to Promote the Study of Aging and Longevity
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√Člie Metchnikoff was a noted figure in the first days of modern immunology, with much of his most important work carried out in the closing decades of the 19th century. He is credited with coining the term gerontology for the study of aging, and was the author of The Prolongation of Life: Optimistic Studies - which through the miracles of modern technology one can now read online for free. I strongly recommend perusing the section entitled "Should We Try to Prolong Human Life?" as it shows how little arguments over the use of medicine to enhance human longevity have changed in the past century:

Although the duration of the life of man is one of the longest amongst mammals, men find it too short. From the remotest times the shortness of life has been complained of, and there have been many attempts to prolong it. Ought we to listen to the cry of humanity that life is too short and that it would be well to prolong it? Would it really be for the good of the human race to extend the duration of the life of man beyond its present limits? Already it is complained that the burden of supporting old people is too heavy, and statesmen are perturbed by the enormous expense which will be entailed by State support of the aged.

If the question were merely one of prolonging the life of old people without modifying old age itself, such considerations would be justified. It must be understood, however, that the prolongation of life would be associated with the preservation of intelligence and of the power to work. In the earlier parts of this book I have given many examples which show the possibility of useful work being done by persons of advanced years. When we have reduced or abolished such causes of precocious senility as intemperance and disease, it will no longer be necessary to give pensions at the age of sixty or seventy years. The cost of supporting the old, instead of increasing, will diminish progressively.

If attainment of the normal duration of life, which is much greater than the average life to-day, were to over-populate the earth, a very remote possibility, this could be remedied by lowering the birth-rate. Even at the present time, while the earth is far from being too quickly peopled, artificial limitation of the birth-rate takes place perhaps to an unnecessary extent.

Members of the energetic European grassroots community of longevity advocates propose to celebrate Metchnikoff's anniversary each year, and given his views and his work in medicine rightfully so, I say. That date is May 15th, and this year marks the 170th anniversary of Metchnikoff's birth. This initiative joins many others from past years, such as working to make celebrate the UN International Day of Older Persons as Longevity Day, all of which aim to raise awareness and build support for serious scientific efforts to treat and control degenerative aging.

Good advocacy is made up of many varied initiatives, year after year, for who knows which approach will go on to become a great success. Good advocacy is a matter of continually and inventively striving to deliver our message to ever more listeners, to persuade that next supporter, to raise that next dollar to fund the research that matters. The more that is done the easier it becomes: success attracts success, and every small gain matters.

May 15, 2015 - 170th anniversary of √Člie Metchnikoff - the founder of gerontology

There is a tradition to celebrate the anniversaries of great persons (scientists, artists, writers, politicians, generals) to promote the area of their activity and popularize their ideology. It may be hoped that, in this year, the anniversary of Metchnikoff will serve to promote and popularize the science and ideology of healthy life extension, including the state level. The "Metchnikoff Day" can provide an impulse for organizing topical meetings and conferences, a stimulus for research, and publications in the media, dedicated to Metchnikoff's legacy and continuation of his life work - the study of aging and longevity. This may play a positive role not only for the advancement and popularization of research of aging and healthy longevity, but also for the promotion of optimism, peace and cooperation.

In view of the immense significance of degenerative aging processes for the emergence of virtually all diseases, both communicable and non-communicable, and in view of the accelerating development of potential means to intervene into and ameliorate these processes for the sake of achieving healthy longevity, Metchnikoff's pioneering contribution to this field assumes an ever greater global significance. The world is rapidly aging, threatening grave consequences for the global society and economy, while the rapidly developing biomedical science and technology stand in the first line of defense against the potential threat. These two ever increasing forces bring gerontology, describing the challenges of aging while at the same time seeking means to address those challenges, to the central stage of the global scientific, technological and political discourse. At this time, it is necessary to honor Metchnikoff, who stood at the origin of gerontological discourse, not just as a scientific field, but as a social and intellectual movement.

Currently events in honor of the Metchnikoff Day are being planned in Kiev, Ukraine, on behalf of the Kiev Institute of Gerontology of the Ukrainian Academy of Medical Sciences; St. Petersburg, Russia, on behalf of the Gerontological Society of the Russian Academy of Sciences and I.I. Mechnikov North-Western State Medical University; in Moscow on behalf of the National Research Center for Preventive Medicine of the Ministry of Healthcare of the Russian Federation and the Russian Longevity Alliance; Larnaca, Cyprus, on behalf of the ELPIs Foundation and the Cyprus Neuroscience and Technology Institute; Oxford, UK, on behalf of the Oxford University Scientific Society and Biogerontology Research Foundation; in Ramat Gan, Israel, on behalf of the Israeli Longevity Alliance and the International Society on Aging and Disease (Israel). It may be hoped that, following these examples, more events and publications will be held around the world in honor of this day.

Protein Modification as a Biomarker of Aging
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The development of fairly consistent, accurate means to measure biological age - as opposed to chronological age - from a tissue sample is an important thread in aging research. Aging is a process of damage accumulation, and rejuvenation would be achieved through damage repair. Research and development aimed at significant extension of healthy life span can only become cost-effective given good ways to measure damage, however. There must be some reliable means to quickly assess the results of a treatment that claims a degree of rejuvenation through the partial repair of a specific form of cellular or molecular damage. In some cases this might seem easy. Take senescent cell clearance, for example: you run the therapy in mice, and compare a range of measures known to scale by senescent cell count in tissue samples before and after the treatment regimen. However, all that really tells you is how well the therapy clears senescent cells. All aspects of biology interact with one another, and age is a global phenomenon. To determine how aged an individual is and how effective a treatment might be when it comes to the practical outcome of additional healthy life span added there is presently little to be done other than wait and see.

The biggest challenge in the development of life-extending therapies is funding and cost. On the one hand there is far too little funding directed towards finding ways to treat aging. On the other hand effectively evaluating an alleged means of treating aging currently requires life span studies, and even in mice that takes far too long and costs far too much to be done casually. If there were standardized, quick and easy markers of physiological age that could be assessed before and after a treatment, then this research and development might be able to proceed ten times as rapidly, and evaluation of possible therapies would be open to far more research groups. There are many, many more laboratories with the capacity and funding to carry out a speculative $100,000 study versus a speculative $1,000,000 study.

All of this is to explain why there is considerable interest in developing a cheap biomarker of aging that can reliably assess physiological age from a tissue sample. No-one wants to run a five year mouse study if there is a ten minute alternative that produces an answer of about the same accuracy. That ten minute alternative doesn't yet exist, but some lines of research seem promising, such as work on DNA methylation patterns that appear to be fairly consistent between individuals over the course of aging. There is also the suggestion that the approach should be to measure the fundamental forms of damage thought to cause aging - but all of them, not just the one being treated by the therapy under consideration. At the present time that might be more onerous than finding a good set of secondary consequences that are reactions to damage, such as epigenetic changes.

The open access paper linked below covers a fairly wide range of topics. The structures of our cells and tissues are built of proteins, and these proteins are constantly damaged and replaced. Many varied mechanisms toil constantly to remove proteins and cellular components as soon as they show damage or dysfunction. Nonetheless the difference between young tissue and old tissue is that old tissues have far more damage: misfolded proteins, malfunctioning structures inside cells, metabolic waste products such as advanced glycation endproducts (AGEs) gumming together structures in between cells, and on and so forth. The damage leaks through, and even damage repair mechanisms are not invulnerable; they falter with age due to much the same set of issues as causes dysfunction elsewhere. In the future repair technologies, such as those outlined in the SENS proposals, will bring about rejuvenation by reversing these forms of damage. Since these issues are a part of full set of causes of aging they are also potential markers of aging.

Protein modification and maintenance systems as biomarkers of ageing

Changes in the abundance and post-translational modification of proteins and accumulation of some modified proteins have been proposed to represent hallmarks of biological ageing. Non-enzymatic protein glycation is a common post-translational modification of proteins in vivo, resulting from reactions between glucose or its metabolites and amino groups on proteins, this process is termed "Maillard reaction" and leads to the formation of advanced glycation endproducts (AGEs). During normal ageing, there is accumulation of AGEs of long-lived proteins such as collagens and several cartilage proteins. AGEs, either directly or through interactions with their receptors, are involved in the pathophysiology of numerous age-related diseases, such as cardiovascular and renal diseases and neurodegeneration.

Beside protein glycation, it is also well known that levels of oxidised proteins increase with age, due to increased protein damage induced by reactive oxygen species (ROS), decreased elimination of oxidized protein (i.e. repair and degradation), or a combination of both. Since the proteasome is in charge of both general protein turnover and removal of oxidized protein, its fate during ageing has received considerable attention, and evidence has been provided for impairment of the proteasome function with age in different cellular systems. Thus, these protein maintenance systems may also be viewed as potential biomarkers of ageing.

It is expected that a combination of several biomarkers will provide a much better tool to measure biological age than any single biomarker in isolation. For the most part, the markers based on proteins and their modifications that have been chosen are directly related with mechanistic aspects of the ageing process. Indeed, they are relevant to such important physiological features such as protein homeostasis and glycoprotein secretion that have been previously documented as being altered with age. Therefore, it is expected that they may be less influenced by other factors not necessarily related with ageing.