Fight Aging! Newsletter, April 11th 2016

April 11th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe please visit:


  • Fight Aging! Migrated to WordPress, Tire-Kicking is Almost Complete
  • A Book from Cryonics Provider Alcor: Preserving Minds, Saving Lives
  • Senescent Cell Clearance and a Focus on Delaying Skin Aging
  • A Few Recent Omics Studies in Extremely Old Individuals
  • The Actuarial Press Interviews Aubrey de Grey
  • Latest Headlines from Fight Aging!
    • DNA Methylation with Aging in Skin Tissue
    • Hair Follicles from Old Tissue Rejuvenated When Placed into Young Tissue
    • Induced Stem Cells that Build Tissue
    • Results from a Trial of a Cell Therapy for Heart Failure
    • CXCL5 Levels Correlate with Progression Towards Coronary Artery Disease
    • Stem Cell Therapy in Rats with Heart Failure Normalizes Heart Function
    • Progress in Understanding the Genetics of Organ Regeneration
    • Average Telomere Length is a Terrible Measure of Aging
    • Low Dose Lithium Extends Life in Flies
    • Influences on Longevity: Genetics or Lifestyle?


The big move of platform finally happened for Fight Aging! this past weekend. I've been putting this off for quite the while, five years at least. For the past twelve years, Fight Aging! ran on the Movable Type blog platform, and now it is on WordPress. While I have no regrets regarding missing out on the early and chaotic years of WordPress, picking Movable Type was certainly one of the more personally consequential wrong choices on technology I've made over the years. Sadly, it is never easy to pick the platform that will turn out to succeed, or at least the one that won't collapse into unsupported irrelevance all too rapidly, as was the case for Movable Type. Hence, a decade down the line, I had to run a large migration of years of encrusted features and additions, approaching a rewrite in places, fleeing a platform that has so fallen out of favor that even the migration tools have vanished or no longer work. There is probably a metaphor for aging and the human condition as it stands today buried in there somewhere.

The purpose of my sharing this is primarily to note that a lot of work has been done under the hood in order to, ideally, keep everything much the same at the surface. Near everything has changed. The tires have been kicked, and numerous last-minute problems identified and fixed, but ideally you should see few differences. I've rearranged some of the site sections and most of the URL paths have changed, yes, but all of the old URLs should automatically redirect to the new locations. This should also be true for those of you using the content feeds in various ways. They should all continue to just work, though you might consider updating the URLs at some point. If anyone finds broken links, broken pages, or other things that are not as they should be, please do let me know. This is a site of, at this point, more than 12,000 posts, so it is hard to check them comprehensively, even with automation. Beyond the posts, the site is something of an iceberg; the pages you see are generated and served by about a tenth of the code that is actually important and in use under the waterline.

It has to be said that security is an increasingly important concern on any modern platform. Being on Movable Type was very constraining from the point of view of adding features, true, but it at least provided the benefit of being a small target, the recipient of little in the way of automated attacks and spam. WordPress, in comparison, is arguably one of the biggest targets online today thanks to its popularity as a platform. Glancing at the metrics, the defenses put in place have blocked something like 3,000 drive-by spam submissions in the past day or two, and the intrusion logs are just as voluminous. One of the time-consuming parts of this migration was the need to lock things down to a much greater extent than was the case in the past. WordPress is a palace of a thousand doors, half of which are hidden away, all of which need their locks and guards, and few of which are either locked or guarded when set up out of the box. While that does to a certain extent mean that you only have to run a bit faster than the other guy to stay ahead of of the proverbial bear, it is still necessary to do it right and plug all of the holes.

As a final note, the real benefit of this migration is that I'm now in a far better position to tinker and change and update Fight Aging! in ways both small and large. If you have ideas or features you'd like to see, this would be the time to mention them. I make no promises that any particular change will definitely happen, or that it will happen rapidly, but much more is now possible than was the case last week.


Today I'll point out the availability of Alcor's book Preserving Minds, Saving Lives, a collection of some of the better writing on cryonics set down over the years. Much like research into rejuvenation therapies after the SENS model of repair of molecular damage, it is sadly the case that cryonics receives neither the attention nor the funding it merits given the plausible scope of benefits that might be realized. This is slowly changing in both cases, but much faster for rejuvenation research after the SENS model. Bootstrapping cryonics from its present state of a small non-profit industry and tiny scientific community into a much larger, capable, and more mainstream concern is proving to be a slow process indeed, but I think it will have its own tipping point in the years ahead.

Cryonics is, in short, the low-temperature preservation of at least the brain as soon as possible following clinical death. With the use of cryoprotectants, a glass-like state of vitrification is achieved in which ice formation is minimal to non-existent, cell damage is minimal, and the fine structure of the brain is preserved. It is a reasonable assumption that, if performed well, this also preserves the data of the mind, which present evidence strongly suggests is encoded somewhere in the dendrites and synaptic structures linking neurons. Lower animals have shown signs of retaining memory following vitrification and revival, and initial proof of concept experiments have demonstrated that internal organs can be vitrified and restored for transplantation, though currently the best restoration methodologies are fragile and failure-prone, still many years from clinical use. Still, it is through the organ transplant industry that cryonics will likely reach its tipping point: there is growing interest in the use of vitrification to store donated organs, or the seed tissues that grow into organs. When reversible vitrification of donor organs is possible, then preservation of the brain, the mind, and the self is a logical next step. For so long as the mind remains intact, the possibility remains for future restoration in a time of more capable medical technology. Death is not absolute or irreversible until that structure is gone.

This is why cryonics is important. It, like rejuvenation research, is all about saving lives, stemming the flood of death that passes us by every day. We live in a madhouse world in which more than 150,000 lives end daily, each one an invisible tragedy, while billions more march to an oblivion that might be avoided. Most are unaware of the alternative offered by cryonics, and of those who have heard of cryonics or given it some thought, most reject it out of hand. As a species, and judging by our actions, we are not as much in love with life as might be thought given our conversations and literature.

Preserving Minds, Saving Lives

Cryonics is an experimental medical procedure that uses ultra-low temperatures to put critically ill people into a state of metabolic arrest to give them access to medical advances of the future. Since its inception in the early 1960s, the practice of cryonics has moved from a theoretical concept to an evidence-based practice that uses emergency medical procedures and modern vitrification technologies to eliminate ice formation.

Preserving Minds, Saving Lives offers an ambitious collection of articles about cryonics and the Alcor Life Extension Foundation. From its humble beginnings in 1972, and its first human cryonics patient in 1976, Alcor has grown to a professional organization with more than 1,000 members, more than 140 human patients, and more than 50 pets, all awaiting a chance to be restored to good health and continue their lives.

This 570-page book presents some of the best cryonics writings from Cryonics magazine from 1972 to 2012. There are clear expositions of the rationale behind cryonics, its scientific validation, and the evolution of Alcor procedures. Also covered are repair and resuscitation scenarios, philosophical issues associated with cryonics, and debates within the cryonics community itself.

Why you want to read Alcor's new book

So perhaps you're fairly new to Alcor and cryonics. You're pretty sure this technology might be worth investigating; maybe you've even gotten signed up. But there's a lot you don't know. When your friends and relatives ask you those awkward questions about WHY you're doing this and what makes you think it will work, you haven't figured out solid answers yet. Especially if you live in an area without many other people involved in cryonics, you may really need solid ideas. You may even wish you have a book you could hand some of them, something that might make all of these ideas clear.

We have that book - Preserving Minds, Saving Lives: The Best Cryonics Writings from the Alcor Life Extension Foundation. We have been working on those answers for more than 35 years, often in the pages of our magazine, Cryonics. This book takes many of those great answers and puts them together in one volume for you. Why do we preserve patients in liquid nitrogen? How might that change in the future? What is the difference between freezing and vitrification? Why is vitrification better? How did this odd idea get started in the first place? What has Alcor gone through to get to this point? What mistakes were made along the way and how do we know cryonicists have learned from those mistakes? Why the heck isn't cryonics wildly popular? It's all here, along with many other discussions, by the best writers Alcor has had to offer for more than three decades. There are a handful of technical articles, because we want to make sure that the bases for this technology are readily available for future researchers. But most of the articles are accessible to anyone.


Skin aging is a fixation in the broader community beyond the sciences, perhaps the more so because there is no effective treatment to slow or turn back skin aging. Life-long exercise and calorie restriction are the only thing that works. When looking at what you can go out and buy, all that does exist are a few marginal cosmetic approaches that don't address the actual underlying processes, and beyond that a very large number of people lying through their teeth about what their products are capable of achieving. An enormous amount of money changes hands on the basis of those lies, enough to sustain sizable industries. The degree to which people know they are being taken and are engaged in purchasing "anti-aging" products for reasons other than believing it will do any good is an open question. Still, this is a great example of the way in which outright fraud can become both respectable and sizable enough to solidify a place in society, which in turn is one of the many reasons why we should question everything around us rather than taking any it for granted. Change is coming in this case, however, in the form of therapies that do in fact address the underlying root causes of skin aging, and will be capable of actually, measurably, undeniably rejuvenating old skin.

If we look at the root causes of aging, assembled from the gathered evidence of dozens of fields of research and expressed as the SENS research proposals, those most relevant to the aging of skin appear to be (a) declining stem cell function, (b) the formation of persistent cross-links in the extracellular matrix, and (c) growth in the number of long-lasting senescent cells. However, no-one today can tell you which of those is most important, nor the relative levels of importance. The only practical way to find out is to fix one of those problems and see what happens. They are all fairly independent of one another, and will be addressed by entirely different research groups and sections of the research and development communities. If pushed for an educated guess, I'd say that we'd have heard by now if it was the case that stem cell infusions produced noticeable differences in skin in older individuals, so beyond wound healing this seems likely to be a smaller effect than the other two. As for the ordering of those other two, I really have no idea and no intuition. One could argue coherently for either: the extracellular matrix is the basis for skin elasticity, and cross-links definitively affect that elasticity, but senescent cells cause a very wide range of harms, and are thought to exist in aged skin in sizable numbers.

Cells become senescent in response to internal damage or a toxic environment, among other reasons. This shift in state removes them from the cycle of cell division, and it is thought that this is primarily an evolved defense against cancer, blocking the most vulnerable cells from running amok should they suffer just the wrong combination of mutational damage. Most senescent cells destroy themselves via programmed cell death mechanisms, or immune cells are drawn to the secreted signals of senescent cells and dismantle them. Some senescent cells linger indefinitely, however, and over a lifetime substantial fractions of many tissues become composed of cells in this state. A study some years back found as many as 20% of the cells in aged baboon skin showed signs of senescence, for example. These lingering cells generate a mix of signals called the senescence-associated secretory phenotype, which boosts inflammation, can harm the surrounding tissue structures, and make nearby cells more likely to become senescent themselves. In turn higher levels of chronic inflammation contribute to the progression of all of the common pathologies of aging.

The present state of ignorance on the relevance of senescent cells in skin aging won't last much past the next two years. Two companies are presently working on senescent cell clearance therapies, Oisin Biotechnologies and UNITY Biotechnology. In the former case, the technology has been demonstrated in rats. I have to imagine that for both companies, somewhere on the to-do list is the simple experiment in which one administers the treatment to aged animals and then measures the effects on skin elasticity and other physical measures impacted with age. That would be well within the capabilities of the Major Mouse Testing Project as well, using the recently discovered senolytic drug combinations if nothing else. If an approach can clear even a quarter of senescent cells in skin, that should be enough to draw conclusions on the impact to skin function. Beyond the knowledge gained, I can think of little better bait for publicity or potential funding from the big names in cosmetic science.

In the open access review linked below, the authors cover the approaches of destroying or altering the biochemistry of senescent cells as a class of approaches that could be used to delay skin aging. These researchers are associated with some of the existing groups working on the harmful biochemistry of senescent cells, as well possible methods to remove those cells or alter that biochemistry, such as the Buck Institute, and so they scrupulously avoid use of the word "rejuvenation." Removal of senescent cells is absolutely a very narrow form of rejuvenation, however. The presence of senescent cells is one of the defining features of old tissue, and they contribute to many of the processes of degenerative aging: inflammation, remodeling of surrounding tissues, failing tissue function, and so forth. Remove those cells and it is not unfair to say that the tissue in question is now closer in character to young tissue - a degree of rejuvenation has occurred, in other words. Of course that tissue still has amyloids, cross-links, failing stem cell populations, cells overtaken by damaged mitochondria, and so forth, but that is why we need a toolkit of various rejuvenation therapies, not just one tool.

Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review

Cellular senescence is a tumor-suppressive mechanism wherein cells are permanently growth arrested. Cells are induced to senescence by a wide variety of cellular perturbations, including nuclear DNA damage and mitochondrial dysfunction. Senescent cells are characterized by the secretion of several proinflammatory factors, a phenomenon called senescence-associated secretory phenotype (SASP). The accumulation of senescent cells with age is thought to contribute to impaired tissue homeostasis and to different age-related diseases. Lack of cell proliferation in senescent cells hampers the ability of tissues to regenerate after chronic and persistent injury, resulting in tissue damage. The proinflammatory and tissue-remodeling activities of the SASP also create chronic inflammation and alter tissue structure, which are the two main causes of age-related pathology. One fascinating hypothesis is that senescent cells might contribute in a cell and non-cell autonomous fashion to skin aging. Skin aging is associated with several pathologies, including lower protection from pathogens, increased irritation, loss of insulation, delayed wound healing and susceptibility to cancer, among others. Here, we summarize the evidence of the presence of senescent cells in the skin, and the potential for pharmaceutical interventions that eliminate the negative effects of senescent cells as methods to delay skin aging.

The impact of senescent cells on animal pathology was directly demonstrated when eliminating senescent cells through a suicide gene in a premature aging mouse model reduced selected age-related pathologies such as sarcopenia, cataracts, and loss of subdermal adipose tissue. Interfering with senescent cells may be beneficial for the overall health of the animal, and the development of specific interventions that target senescent cells may serve as a therapy to delay aging, including skin pathologies. This strategy can be achieved using three different approaches: (1) selective induction of cell death; (2) improvement of the immune system, and (3) inhibition of the SASP. The decline in immune function with age is consistent with the high number of senescent cells at old age, supporting the idea that the immune system may limit the number of senescent cells through clearance of these cells. Hence, it may be worth developing a strategy that boosts the immune cells capable of specifically eliminating senescent cells.

Removal of senescent cells and reducing the SASP are being considered as therapeutic strategies to delay the onset of age-related pathologies. Several drugs have already been identified that selectively target senescent cells. Some of them might have toxic effects when administered systemically for a long period of time: for example, ABT263 can cause thrombocytopenia in patients treated with an oral form of the compound. However, the toxicity might be highly reduced by developing drugs for topical treatment, an approach that would be suitable for skin interventions. The contribution of senescent cells to skin function is complex because they may be both beneficial and detrimental depending on the context; it is still unclear whether senolytic drugs will delay skin aging. Senescent cells are important for proper wound healing through their secretion of the SASP factor PDGF-AA and through their capacity to limit fibrosis, while chronic induction of cellular senescence through mitochondrial dysfunction may contribute to stem cell loss with age. Hence, proper testing of dosage and timing must be investigated to determine if these drugs would indeed reduce the negative impact on skin aging. Nonetheless, the possibility of selectively targeting senescent cells through pharmacological interventions posits a potential new solution to the functional decline associated with skin aging.


Below you'll find linked a few papers on the biochemistry of extremely old individuals, those who are in the portion of life in which they are heavily damaged by the processes of aging, most of their former peers are dead, and genetic variations become significant in determining quality of life and remaining life expectancy. A great deal of data is arriving on the biochemistry of the aged. The capacity of the research community to accumulate data on molecular biochemistry, in genetics, in epigenetics, and in the growing diversity of "omics" fields, of which genomics was only the first and least specialized, has for years greatly exceeded the capacity to analyze that data. Those fractions of the community concerned with making sense of it all will be playing catch-up for decades, I believe, given the pace of growth in data on the operation of human cellular metabolism - and given that productive and useful analysis is fundamentally a harder, more expensive, and more uncertain problem than collecting the data in first place. The ongoing revolution in biotechnology means that mountains of omics data are assembled today, and there is every sign that tomorrow's mountains will be an order of magnitude larger. So when you pick papers to read from the ongoing river of new studies that build upon human metabolic data, bear in mind that if the influx of new data stopped tomorrow, there would probably still be enough to productively occupy the research community for years yet. It is an interesting situation, to be sure.

When it comes to aging, it all becomes deeper and more uncertain, of course. Researchers still have a long way to go to completely fill in the high level sketch of how human metabolism works in an ordinary, healthy adult, to turn that high level sketch into a comprehensive accounting of living molecular biology at the detail level. The task of understanding how that vastly complex and poorly understood system then changes over time, and how it goes wrong, and how it behaves in the seemingly endless variety of damaged states that accompany aging rather than in its normal, proper modes of operation in youth ... well, that is a much bigger project. The sheer complexity of our biochemistry is why researchers have struggled to produce safe and effective ways to alter cellular metabolism to slow aging, even when the goal is replicate aspects of well-known and easily studied states such as the responses to exercise or calorie restriction. Producing a slow-aging human by following this path is not a project for our era, but something that will require the far greater resources of biotechnology and computation that will emerge much later this century. Even then, why do this? Aging more slowly because you have a better biochemistry is not rejuvenation, and it doesn't much help those already old and damaged.

Thus to my eyes the best way to look upon the study of human longevity and human genetic and metabolic diversity is as an interesting but presently less important field of scientific endeavor. Extension of healthy life will not come from these studies, but rather from efforts to repair and reverse the molecular damage that causes aging. Given therapies that can achieve that goal sufficiently comprehensively, people will not enter the state of being very damaged and frail, and age-related diseases will not arise. The study of the resilience of some older people in the face of frailty will become a historical curio, in the same way as there is little study of the impact of genetic variations on smallpox survival rates today. That is the future we want to see, and it is one that researchers can work towards today, given present knowledge of the causes of aging, sidestepping our ignorance of the intricate chain of cause and effect linking root cause molecular damage to end result age-related disease. Just as the Romans could use engineering and empiricism to build imposing and functional structures that lasted for centuries, without modern materials science and computational modeling, in a state of comparative ignorance, the very same conceptual approach can be applied to rejuvenation therapies: revert the well-known and well-cataloged differences between old and young tissues, and observe the results, adjusting course as needed.

A Stress-Resistant Lipidomic Signature Confers Extreme Longevity to Humans

Plasma lipidomic profile is species specific and an optimized feature associated with animal longevity. In the present work, the use of mass spectrometry technologies allowed us to determine the plasma lipidomic profile and the fatty acid pattern of healthy humans with exceptional longevity. Here, we show that it is possible to define a lipidomic signature only using 20 lipid species to discriminate adult, aged and centenarian subjects obtaining an almost perfect accuracy (90%-100%). Furthermore, we propose specific lipid species belonging to ceramides, widely involved in cell-stress response, as biomarkers of extreme human longevity. In addition, we also show that extreme longevity presents a fatty acid profile resistant to lipid peroxidation. Our findings indicate that lipidomic signature is an optimized feature associated with extreme human longevity. Further, specific lipid molecular species and lipid unsaturation arose as potential biomarkers of longevity.

Improved lipids, diastolic pressure and kidney function are potential contributors to familial longevity: a study on 60 Chinese centenarian families

Last year, we managed to recruit 60 longevity families from Hainan province, a well-known longevity region in China, and performed a complete physical examination on all subjects. Based on this population, we found that the thyroid function was associated with longevity and could be heritable. In this study we expanded the study by investigating associations of the rest blood parameters with age, and associations between generations, aiming to seek candidate factors associated with familial longevity. Associations of blood parameters in centenarians (CEN) with their first generation of offspring (F1) and F1 spouses (F1SP) were analyzed.

In this study, using association and further comparison analyses we identified several blood parameters that may contribute to longevity. First, total cholesterol (TC) and triglyceride (TG) increased with age until 80 years, but decreased in centenarians, indicating that lipid metabolism was improved in the oldest old. A similar trend was observed for LDL-C, although it was not associated with age before 80 years. The changes in lipid levels were consistent with that in other studies. Increased TC, TG and LDL-C concentrations are the most important independent risk factors for cardiovascular disease, the leading cause of adult death worldwide. In this regard, we can assume that the CEN may be less susceptible to cardiovascular disease, and hence, live longer. To understand why the CEN have such a favorable lipid profile, we analyzed the expression of genes involved in lipid metabolism and found some differentially expressed genes between the CEN and F1SP. Based on their known functions, they may confer both beneficial and detrimental effect on regulating lipid profiles, suggesting there is a balance in the regulation of the lipid metabolism in the longevity subjects. However, the overall outcome seemed to reduce lipid levels and thus accounted for the favorable lipid profile in centenarians.

More importantly, we observed for the first time that diastolic blood pressure rather than systolic pressure was improved in CEN compared to the elderly. Blood pressure is a well accepted cause for age-related diseases, not only for the cardiovascular disease, but also for cerebrovascular and/or neurodegenerative diseases, such as cerebral hemorrhage and senile dementia. Indeed, a number of studies have noticed that diastolic blood pressure exerts stronger influence than systolic blood pressure on the occurrence and development of cardiovascular and cerebrovascular diseases. Our results expand the knowledge by extending the age range to over 100 years. Likewise, we managed to identify several candidate genes associated blood pressure. Of notice is the CST3 gene, it has the most significant difference between the CEN and F1SP, and it codes a protein called cystatin c which has been positively associated with systolic pressure but inversely with diastolic pressure, which was well consistent with our observation.

Methylomic predictors demonstrate the role of NF-κB in old-age mortality and are unrelated to the aging-associated epigenetic drift

Changes in the DNA methylation (DNAm) landscape have been implicated in aging and cellular senescence. To unravel the role of specific DNAm patterns in late-life survival, we performed genome-wide methylation profiling in nonagenarians (n=111) and determined the performance of the methylomic predictors and conventional risk markers in a longitudinal setting.

The consequences of aging-accompanied DNAm alterations for late-life health and functional abilities are largely unknown. A recent epigenome-wide association study (EWAS) demonstrated that the association between age-related DNAm changes and healthy aging phenotypes in individuals 32-80 years of age is negligible. The results of this study also reveal that the DNAm regions associated with aging phenotypes are distinct from those associated with chronological age. These findings suggest that the CpG sites involved in health-related outcomes in later life are largely regulated by sites other than the established age-related DNAm regions. In addition, using an EWAS approach, we have recently demonstrated that the CpG sites that are associated with aging-related inflammation are largely different from the sites associated with age. This phenomenon is also observable in regard to gene expression profiles and old age mortality. We have previously demonstrated that the genes exhibiting aging-related changes in expression levels are predominantly different from those that predict mortality in late life. These findings underscore the complexity and unknown nature of the genomic factors that control the human health span and late-life events.

Nevertheless, the mortality-predicting genes in our previous study were found to be functionally connected to the nuclear factor kappa B (NF-κB) complex, which is a central mediator in immunoinflammatory responses and has been advocated as the culprit in aging and cellular senescence. Aberrant activation of NF-κB has been reported in various age-associated conditions, such as neurodegeneration, immunosenescence, inflammaging, sarcopenia and osteoporosis, whereas studies involving mouse models have observed that NF-κB activation is a key determinant of accelerated aging and longevity. The results of this study corroborate the role of NF-κB in all-cause elderly mortality; the molecular network constructed from the genes harboring the mortality-associated CpG sites displayed the NF-κB complex as a central mediator. We hypothesize that our findings could relate to the recent observation of a programmatic role of hypothalamic NF-κB and IκB kinase-β activation in the control of the life span in experimental mouse models. Adhering to the conclusion of this mouse study that the decisive role of hypothalamic NF-κB is exerted systemically level through immune-neuroendocrine crosstalk, we suggest that our findings on immune cells might represent the peripheral correspondence of hypothalamic NF-κB activation. However, establishing the systemic-level events that connect NF-κB function to all cause-mortality in aged humans will require further research.


An interview with Aubrey de Grey of the SENS Research Foundation appears in the latest edition of the Actuary. This is in connection with forthcoming appearances at actuarial conferences, something that has long been a regular occurrence in de Grey's schedule as one of the more important advocates for rejuvenation research. The actuarial community is a good target for all advocacy relating to aging research, not least because they are already half-way bridging the gap with their own projects, aiming to better quantify the prospects for extended life spans through progress in medical science.

The profession of actuary is a node that connects medicine as practiced today, medical research and development for tomorrow, and the staggering sums of money that move through the global insurance and pensions industries. They are among the most ready to hear the story that great uncertainty lies ahead for the trend of increasing life expectancy, with the potential for radical gains should rejuvenation research programs like SENS move to the next stage of funding and pace of progress. SENS or something like it will happen, but the timing is very uncertain because the bootstrapping process that ends with taking over the medical mainstream is still in its early stages. At this point a couple of rejuvenation technologies are in early commercial development, but research funding is sparse for the rest and they remain years away from realization even if all goes well. The other uncertainty is that no-one has yet deployed SENS-like therapies based on repair of damage in humans: the effectiveness of the first of these, such as senescent cell clearance, at the outset, or five years in, or after a decade of improvements, is a question mark. One of them could add five or ten years to human life expectancy, a very large outcome for a treatment undertaken every few years, or it could improve health but do nothing meaningful to life span because other causes of aging lead people to die on about the same schedule.

While far from all actuaries are paragons of rationality when it comes to rejuvenation research and the prospects for change, a sizable fraction have become increasingly willing to hedge their predictions over the past decade, and industry voices have warned that a time of uncertainty lies ahead. Technological progress, and the great sweeping change now underway in the research community, from trying to patch over the consequences of aging to trying to repair the causes of aging, will make twenty year and longer life expectancy trend predictions meaningless. Actuaries have been speaking on this topic for some time now, but it isn't a message happily received in all quarters. Change in the insurance industry will come but slowly, and there will no doubt be entirely unnecessary chaos and destruction as we progress towards the medical control of aging and the greatly increased healthy longevity that will accompany it. No tears should be shed for that outcome, achieved by those betting against progress, save for the fact that losses will no doubt be socialized and the taxpayers will wind up footing the bill.

Lifelong learning

Dr Aubrey de Grey is a prominent biomedical gerontologist and chief science officer of the SENS Research Foundation. He is editor-in-chief of Rejuvenation Research, a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organisations. "You know, people have this crazy concept that ageing is natural and inevitable, and I have to keep explaining that it is not." His views on ageing are simple. "The human body is a machine with moving parts and like a car or an aeroplane, it accumulates damage throughout life as a consequence of normal operation."

Historically, efforts to postpone the ill health of old age have focused on finding ways to clean up our metabolism so that we accumulate damage to the body more slowly. About 15 years ago, de Grey had a 'Eureka!' moment upon realising that the most practical way to achieve this would be to find ways to repair the damage rather than looking to slow it down. "I realised we can classify different types of genetic damage into seven major categories, for each of which there is a different repair approach". This is the focus of the SENS Research Foundation. "We have all these diverse projects across various strands of research that we think need to be done, and because we are an independent non-profit charity, we have the luxury of being able to work on the hardest problems."

Although some of his views are met with scepticism and disbelief, he feels that the scientific community is become more accepting of his ideas, citing a recent breakthrough publication in one of the world's leading scientific academic publications. "As time goes on, our progress becomes more significant in proving the feasibility of my ideas. When I first started talking about these, people found them heretical and there was a lot of denigration from the scientific community, but I've gradually won them over. Other people are also making progress in actually implementing what we're doing. Just recently, an important US paper came out that showed you could extend the lifespan of mice using a particular type of damage repair that we'd been talking about for a decade."

If de Grey's predications are solid, what does he think this means for the actuarial profession? "I sympathise with the actuarial profession, because the fact is, the people who pay you to do your jobs really don't want to know the truth." Obviously, if his predictions come to fruition, there would be enormous implications for our industry; life and pensions in particular. Giant changes in life expectancy are likely to spark a renegotiation of pension contracts, as well as the way we approach our healthcare system, state benefit system and provide insurance. De Grey refused to be drawn on the wider impact that successfully achieving his goals could have, commenting: "I think it is foolish to speculate on what society is going to be like, even in 20 years, let alone 200 years from now. So many things are going to be different. The only thing we can do is prepare for as many alternative possibilities and consider how we might minimise any problems that might be created as a consequence of solving the problem of ageing." He believes dwelling on the bioethical considerations is missing the point: "We have to recognise that the problem we have today is enormous. Therefore it's critical not to be intimidated by the prospect that we have too many people, or living longer might be boring, and not let those considerations actually slow us down in terms of the development of medicines that get ageing under control."

De Grey readily admits that the likelihood of his research successfully extending his own lifetime is low. "As for any pioneering technology, the timeframe is extraordinarily speculative. Nobody has the faintest idea how long it's going to take. I put it at 20-25 years from now when we have a 50-50 chance of getting to a decisive level of comprehensiveness that works, which I've called longevity escape velocity. If we do get there by then, I've got a fair chance of benefiting. But I have absolutely no doubt there's at least a 10% chance we won't get there for another 100 years because we hit new problems that we haven't thought of. So if I look at my own personal prospects, or the prospects of any other particular person, the timelines and uncertainty result in this all being very speculative."



DNA methylation is a form of epigenetic alteration to DNA, influencing the rate at which specific proteins are produced from their blueprint genes. The pattern of methylation shifts constantly in response to circumstances, but since the damage that causes aging is much the same in everyone, it is possible to identify patterns that correlate well with age. Here researchers investigate DNA methylation changes in aging skin:

Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age-related changes in DNA methylation at the genome scale have been termed 'epigenetic drift', but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age-related epigenetic changes because of its substantial cell-type homogeneity and its well-known age-related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array-based profiling of 450,000 methylation marks in various age groups. Data analysis confirmed that age-related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy.

In agreement with our previous studies that were carried out either at lower resolution or with smaller sample sizes, we find that age-related methylation changes appear rather moderate and do not compromise the overall integrity of the epidermis methylome. Nevertheless, we identified a variety of specific age-related methylation changes. In contrast to prior work by others, where whole-blood samples and different tissues were used to develop a predictive signature of biological age, we achieved significantly improved prediction accuracy by training the prediction algorithm on epidermis samples. In agreement with previous analyses, we observed a significant age-related hypermethylation of CpG island-associated probes. Interestingly, this effect was strongly enriched during two specific age windows, at 40-45 and 50-55 years. Considering that our samples were exclusively derived from female volunteers, it seems reasonable to link the latter window to menopause, which is also known to distinctly accelerate skin aging. The high temporal and spatial specificity of these methylation changes suggests that defined signaling pathways, such as estrogen signaling, may be involved in their establishment.

Our results also describe an age-related erosion of DNA methylation patterns that is characterized by two distinct features: (i) While the topology of young methylomes is characterized by sharply demarcated regions of (almost) complete and (almost) absent methylation, old methylomes appeared to be less clearly defined, which is reflected by the significantly reduced variance and spatial correlation within methylomes. (ii) While young methylomes are highly similar among each other, old methylomes appeared to be substantially more heterogeneous. Hence, while methylation patterning within an individual becomes more homogeneous with age, the differences between individuals increase. The effects of age-related methylation changes on gene expression patterns have been analyzed in several previous studies. Somewhat surprisingly, however, no global correlations could be established and methylation-related expression changes generally appeared very limited. These findings support the notion that age-related methylation changes function to stabilize pre-existing gene expression patterns. Alternatively, age-related gene expression changes might also be too subtle to achieve statistical significance in classical differential expression analyses. The analysis of gene co-expression networks provides an opportunity to analyze transcriptional deregulation at a higher level of complexity, and our findings demonstrate a reduced connectivity of gene expression in old samples. These results are in agreement with earlier findings in aging mice and suggest that the age-related erosion of methylation patterns is accompanied by a reduced fine-tuning in the transcriptional circuitry, possibly through methylation-dependent changes in transcription factor binding.



Experiments based on exposing old tissue to a young environment, and vice versa, have been gaining much more attention in recent years. The most common are the heterochronic parabiosis studies in which the circulatory systems of an old and a young individual are linked, with the result that the older individual benefits in a modest reduction in many measures of age-related decline, such as stem cell activity. This has led research groups to focus on the effects of signal molecules in the bloodstream as a proximate cause for some age-related changes in biochemistry. There are many other approaches to mixing old and young biochemistries, however, and in this open access paper the authors report on the results of taking an easily transplanted structure within skin, the hair follicle, and moving it between old and young individuals:

Recently, parabiosis experiments pairing old and young mice have suggested that some features of aging organs in old mice, in particular stem cells, can be reversed by factors in blood of young mice, including brain, spinal cord, and heart. The hair follicle, which cycles through telogen (resting), anagen (growing), and catagen (regression) throughout the life of mammals, undergoes obvious age-related changes including hair loss. The hair follicle contains hair-follicle-associated pluripotent (HAP) stem cells, which may also deteriorate during aging. Instead of using complex parabiosis surgery, we used hair-follicle subcutaneous transplantation in order to determine if the hair follicle, including its ability to produce hair shafts, and its HAP stem cells, can be rejuvenated.

We transplanted young hair follicles subcutaneously into both young and old nude mice. We also transplanted old hair follicles into young and old nude mice. In young nude mice, the transplanted young hair follicles started to establish blood vessel connections and hair shafts began to grow by week 2. The old hair follicles transplanted to young nude mice also established blood vessel connections by week 2. The growth rate of old hair follicles in young nude mice was somewhat slower than young hair follicles. In contrast, in old nude mice, both transplanted young and old hair follicles failed to regrow extensive hair shafts. At week 2 and week 4, both the young and old transplanted hair follicles had less blood vessel connections with old host mice, in contrast to blood vessel connections in young mice.

Therefore, our results showed that both young and old hair follicles can regrow extensive hair shafts when transplanted to young nude mice, while neither young nor old hair follicles can regrow extensive hair shafts when transplanted to old nude mice. These results suggest that young nude mice can provide a more suitable environment to subcutaneously-transplanted hair follicles, both young and old, than old nude host mice. These results also suggest a large influence of the host nude on the donated hair follicles, due to the fact that both young and old hair follicles fail to regrow long hair shafts in old host mice. Old hair follicles had the capability to regrow long hair shafts when transplanted to young host mice, suggesting that old hair follicles can be rejuvenated by young host mice. In young nude host mice, HAP stem cells in the transplanted follicle were active throughout the 8-week experimental period as can be seen by their expression of nestin-driven green fluorescent protein (ND-GFP). ND-GFP expressing cells were widely distributed in both young and old hair follicles transplanted to young host nude mice. HAP stem cells were located in various areas of the follicle, including the follicle sensory nerve, hair matrix bulb and outer-root sheath. HAP stem cells surrounded the hair bulb at week 8 suggesting their role in hair-shaft regrowth. In old hair follicles of old nude mice, most of the ND-GFP expressing cells were located in the attached sensory nerves but not in the center of the hair follicle as they were in old follicles transplanted to old mice. Thus the subcutaneous environment has a strong influence on the HAP stem cells of young and old hair follicles.



A group of researchers is claiming the creation of induced stem cells reprogrammed from adult somatic cells that, unlike the current standards for stem cell therapies, create daughter cells that participate in building tissue rather than affecting regeneration through signaling only. The claim is that this method recapitulates one of the primary mechanisms of limb regeneration seen in salamanders, in which which ordinary adult cells dedifferentiate to become multipotent stem cells capable of constructing multiple tissue types. The paper is to the point, but the publicity materials indicate that the authors think this is a very big deal. Given that they've not completed animal studies to prove the point, this may be premature, but we shall see.

Stem cell therapies capable of regenerating any human tissue damaged by injury, disease or ageing could be available within a few years. "This technique is a significant advance on many of the current unproven stem cell therapies, which have shown little or no objective evidence they contribute directly to new tissue formation. We are currently assessing whether adult human fat cells reprogrammed into induced multipotent stem cells (iMS) cells can safely repair damaged tissue in mice, with human trials expected to begin in late 2017. This technique is ground-breaking because iMS cells regenerate multiple tissue types. We have taken bone and fat cells, switched off their memory and converted them into stem cells so they can repair different cell types once they are put back inside the body."

The technique involves extracting adult human fat cells and treating them with the compound 5-Azacytidine (AZA), along with platelet-derived growth factor-AB (PDGF-AB) for approximately two days. The cells are then treated with the growth factor alone for a further two-three weeks. AZA is known to induce cell plasticity, which is crucial for reprogramming cells. The AZA compound relaxes the hard-wiring of the cell, which is expanded by the growth factor, transforming the bone and fat cells into iMS cells. When the stem cells are inserted into the damaged tissue site, they multiply, promoting growth and healing. The new technique is similar to salamander limb regeneration, which is also dependent on the plasticity of differentiated cells, which can repair multiple tissue types, depending on which body part needs replacing.

Along with confirming that human adult fat cells reprogrammed into iMS stem cells can safely repair damaged tissue in mice, the researchers said further work is required to establish whether iMS cells remain dormant at the sites of transplantation and retain their capacity to proliferate on demand.



Results were recently published for a trial of ixmyelocel-T, a therapy consisting of the delivery of a mix of cell types generated from a patient sample, including mesenchymal and immune cells. This produced modestly promising results in a trial for limb ischemia a few years back, and here the focus is on heart failure, with a similar modestly promising outcome. To take a glass half empty view, the results suggest that in advanced cases of disease the present generation of regenerative therapies are too little, too late. Far greater rebuilding and reconstruction will be needed to do more than slow the decline, but equally these same present generation therapies would no doubt achieve more if used earlier and more often in the disease process, all the way back to preclinical stages. That would require something of a paradigm shift in the way mainstream medicine is practiced, however. The idea of treating people for prevention with therapies of this sort is not yet a popular one, sad to say, and the state of regulation makes it hard to start down that path within the bounds of the system.

Among 109 patients randomized to receive the cell therapy or a placebo, those receiving the cell therapy, which involved extracting stem cells from a patient's own bone marrow, showed a 37 percent lower rate of the trial's primary endpoint, a composite of deaths, cardiovascular hospitalizations and clinic visits for sudden worsening of heart failure symptoms, over a 12-month period. "To date, this is the largest double-blind, placebo-controlled stem cell trial for treatment of heart failure to be presented." The study was a phase 2 clinical trial for a new stem cell therapy known as ixmyelocel-T. Using this technique, a doctor extracts a sample of bone marrow from a patient, processes it for two weeks to "enhance" it by increasing the number of beneficial stem cells, and then injects the processed bone marrow product into the same patient's heart muscle. The goal of the procedure is to strengthen the heart by increasing the number of functioning heart muscle cells, an approach known broadly as regenerative therapy.

The trial enrolled 109 patients with class III or IV heart failure resulting from ischemic cardiomyopathy, a type of heart failure that is related to restricted blood flow from a heart attack or coronary artery disease. Roughly half, 58 patients, were randomly assigned to receive intramyocardial ixmyelocel-T treatment, and 51 patients were assigned to receive a placebo. Patients in the control group underwent a bone marrow extraction and received a placebo injection two weeks later. Among patients given stem cell therapy, 3.4 percent died and 37.9 percent were hospitalized with cardiovascular problems, as compared to 13.7 percent and 49.0 percent, respectively, in the placebo group. Patients given stem cell therapy also had, on average, a longer amount of time until their first adverse event. Other measures of heart function and quality of life, including a walking endurance test and a measurement of the amount of blood pumped out of the left ventricle with each contraction, also suggested improvements in the group receiving ixmyelocel-T.



Researchers have recently provided evidence for a correlation between levels of CXCL5 and progression towards coronary artery disease in aging. The more CXCL5 present, the better the state of the arteries in the study group:

For many people, coronary artery disease (CAD) - the buildup of plaque in the heart's arteries - is an unfortunate part of aging. By studying the genetic makeup of people who maintain clear arteries into old age, researchers have identified a possible genetic basis for the disease, as well as potential new opportunities to prevent it. "Our main goal was to try to understand why some people develop CAD and some people with similar risk factors do not, and we found that older people give us a great model to understand the natural disease process." Researchers analyzed blood samples and heart scans from 143 people over age 65 who were referred for cardiovascular screening. The analysis revealed that people with clear arteries had markedly higher levels of a protein called CXCL5, as well as genetic variants near the CXCL5 gene, compared with people with more plaque.

Previous studies linked CXCL5 with inflammation, leading some researchers to assume the protein was harmful. But recent research in mice suggested the protein could help limit plaque buildup by changing the composition of fat and cholesterol deposits in the arteries. The new finding offers the first evidence that CXCL5 could play a protective role in people, at least in the context of CAD. In addition to offering clues about how CAD develops, the study opens new possibilities for prevention and treatment. For example, it may be possible to develop a drug that mimics the effects of CXCL5 or that increases the body's natural CXCL5 production to help prevent CAD in people at high risk. The protein could even potentially be leveraged to develop a new, nonsurgical approach to help clear clogged arteries. One limitation of the study is that because all participants were referred for a heart scan, the study did not include healthy patients. Further research is needed to confirm the role of CXCL5 in CAD and explore drug development opportunities.



Starting with the earliest efforts to produce stem cell therapies, repairing damage and dysfunction of the heart has always been a primary goal. At present only very partial repair is possible in human cell therapies, for reasons that include the fact that cell therapies cannot address the buildup of important metabolic wastes such as cross-links, but improvement towards more optimal outcomes in this class of therapy is an incremental process of finding and refining methodologies of production and delivery of cells. With this in mind, researchers have recently achieved a very promising result in an animal study:

A new study shows that weeks after infusions of cardiosphere-derived cells (CDCs), the heart-pumping function returned to normal in laboratory rats with hypertension and diastolic heart failure. Formerly known as diastolic heart failure, the diagnosis now called heart failure with preserved ejection fraction is a condition in which the heart muscle becomes so stiff that its pumping chambers cannot properly fill with blood. Even though the heart's ability to pump blood to the body remains normal, its inability to fill with blood over time can lead to fluid buildup. This affects other body organs and causes fluid congestion, especially in the lungs. The hard-to-treat condition leads to extreme fatigue and difficulty breathing.

In the new research study, 34 laboratory rats with hypertension and heart failure with preserved ejection fraction were given infusions of cardiac stem cells. A second group of 34 laboratory rats were given a placebo. Four weeks later, the rats in the stem cells group had normalized heart function and their hearts were able to fill normally. Those in the placebo group became progressively sicker and died prematurely. "When patients with preserved ejection fraction get sick, they might be hospitalized and they might be prescribed medications like diuretics, which reduce the buildup of fluid in the lungs. The patients might get better symptomatically, but we haven't really treated the underlying condition. This research suggests that cardiac stem cells could be effective as a therapeutic agent, and there is a specific treatment we can try when everything else has failed." On the basis of these findings, the researchers have recently obtained clearance from the FDA to use cardiospheres to treat humans with heart failure with preserved ejection fraction. These stem cells, manufactured by Capricor as their product CAP-1002, have already been used in other human clinical trials.



Despite some promising results, such as the one linked here, it remains an open question as to whether the mechanisms necessary for regeneration of limbs and organs, a feat that species such as salamanders and zebrafish are capable of, also remain buried in mammals, such as mice and humans. Have we lost that ability entirely over the course of evolutionary history, did our branch of the tree of life never have it, or does it remain, dormant, and possible to reactivate? Since mice, humans, salamanders, and zebrafish all grow from embryos, and since the process of organ regrowth at least superficially resembles embryonic development, there is hope that the third option is in fact the case, and that this is a path to enabling profound regeneration in our species.

"We want to know how regeneration happens, with the ultimate goal of helping humans realize their full regenerative potential." Over the last decade, researchers have identified dozens of regeneration genes in organisms like zebrafish, flies, and mice. For example, one molecule called neuregulin 1 can make heart muscle cells proliferate and others called fibroblast growth factors can promote the regeneration of a severed fin. Yet what has not been explored are the regulatory elements that turn these genes on in injured tissue, keep them on during regeneration, and then turn them off when regeneration is done. In this study, researchers wanted to determine whether or not these important stretches of DNA exist, and if so, pinpoint their location. It was already well known that small chunks of sequence, called enhancer elements, control when genes are turned on in a developing embryo. But it wasn't clear whether these elements are also used to drive regeneration.

First, the researchers looked for genes that were strongly induced during fin and heart regeneration in the zebrafish. They found that a gene called leptin b was turned on in fish with amputated fins or injured hearts. They scoured the 150,000 base pairs of sequence surrounding leptin b and identified an enhancer element roughly 7,000 base pairs away from the gene. They then whittled the enhancer down to the shortest required DNA sequence. In the process, they discovered that the element could be separated into two distinct parts: one that activates genes in an injured heart, and, next to it, another that activates genes in an injured fin. They fused these sequences to two regeneration genes, fibroblast growth factor and neuregulin 1, to create transgenic zebrafish whose fins and hearts had superior regenerative responses after injury. Finally, the researchers tested whether these "tissue regeneration enhancer elements" or TREEs could have a similar effect in mammalian systems like mice. They attached one TREE to a gene called lacZ that produces a blue color wherever it is turned on. Remarkably, they found that borrowing these elements from the genome of zebrafish could activate gene expression in the injured paws and hearts of transgenic mice.

Eventually, the researchers think that genetic elements like these could be combined with genome-editing technologies to improve the ability of mammals, even humans, to repair and regrow damaged or missing body parts. "There may be strong elements that boost expression of the gene much higher than others, or elements that activate genes in a specific cell type that is injured. Having that level of specificity may one day enable us to change a poorly regenerative tissue to a better one with near-surgical precision."



Here I'll point out one of numerous studies providing evidence to illustrate that telomere length isn't all that useful as a biomarker of aging. Telomeres cap chromosomal DNA, a length of repeated sequences that shortens every time a cell divides. This forms a part of the limiting mechanism that stops ordinary somatic cells from dividing indefinitely. Stem cells and cancer cells maintain their ability to divide by periodically extending their telomeres via various mechanisms. At present telomere length is usually measured from a blood sample, taking the average of lengths in immune cells. This will reflect some combination of cell division rates, cell replacement rates, and the immune status of the individual.

Statistically, considered over large populations, average telomere length in immune cells trends downward with aging, indicating that cell populations are dividing more frequently, or not receiving as great an influx of new cells with long telomeres as they were in youth, or both. The latter is a part of the well-known decline of stem cell activity with age. Unfortunately telomere length is nonetheless a terrible measure of biological age on a practical, individual basis, as the correlation just isn't that good, and measures can vary greatly over time for reasons that have little to do with aging, such as ill health due to infectious disease. This all ties in with the idea that the age-related statistical trend towards diminishing telomere length in cell populations is a reflection of the effects of damage on other processes, as well as the influence of numerous other environmental circumstances, and not a cause of aging in and of itself.

Advances in technology allow scientists to measure intricate details about the human body that greatly enhance understanding of health, disease and aging. Yet, when it comes to predicting death, more rudimentary measures - like a person's age or a person's ability to climb stairs or walk a short distance - are much more powerful predictors of survival than certain biomarkers. Using data from the United States, Costa Rica and Taiwan, researchers compared a broad set of predictors of death - like age, smoking habits and mobility - with the length of telomeres, DNA sequences that generally shrink with age.

Decades ago, researchers discovered that telomeres - which are protective caps on the ends of our chromosomes - act as a 'molecular clock' in human cells. Every time cells divide, telomeres shorten until they become critically short and signal the cell to stop dividing. Telomere length is typically measured in white blood cells (leukocytes), and shorter leukocyte telomeres have been associated with disease, aging and death. For these reasons, there has been great interest in the ability of this biomarker to predict mortality.

After evaluating data, the research team found that using telomere length to predict a human's death was only marginally better than a "coin toss." Chronological age was, by far, the single best predictor of death in all three countries. "Scientific evidence on telomere length has been sensationalized and, in some cases, exaggerated by the media and by companies that have capitalized on the research to market products that may promise more than they can deliver. This is what fueled our research. We wanted to determine whether telomere length could predict mortality better than other well-established predictors of survival, most of which are less invasive and much less costly to measure."

The researchers note some potential limitations of the findings. People who are critically ill might exhibit changes in the distribution of different types of leukocytes that makes their telomeres appear longer. In this study, telomere length is measured in leukocytes, which is common across most research. But some types of leukocytes tend to have longer telomeres than others. "Telomere length tends to be longer in the type of leukocyte that becomes more dominant when a person is ill. Therefore, a sick person might appear to have 'longer' telomere length, but that is deceptive. In fact, these critically ill individuals may be much more likely to die in the short-term despite the appearance of 'longer' telomeres."

It also is plausible that telomere length is a better predictor of long-term mortality, compared to short-term survival, since it reflects the gradual process of cellular aging. "Alternatively, telomere length might be a predictor of mortality only for certain groups of patients, such as those with cancer. An interesting possibility is that telomere length might not be a good predictor of mortality, but it could be a good predictor of healthy aging. Increasing evidence demonstrates that shorter telomeres are associated with cardiovascular disease, but additional research is needed to clarify the association between telomere length and other diseases of aging such as cancer."



Low doses of lithium have been shown to modestly extend life in nematodes, and a Japanese study suggested a correlation between human life expectancy and natural variations in lithium in tap water - a small and uncertain effect, as are most when it comes to human longevity. So it is interesting to find a similar outcome in flies, and here researchers have linked the effects of lithium intake to genes that are already targets of interest in aging research, NRF-2 and GSK-3, involved in regulation of cellular responses to stresses:

Fruit flies live 16% longer than average when given low doses of the mood stabiliser lithium. When the scientists investigated how it prolongs the lives of flies, they discovered a new drug target that could slow ageing - a molecule called glycogen synthase kinase-3 (GSK-3). The team found that lithium delays ageing by blocking GSK-3 and activating another molecule called NRF-2, which is found in worms, flies and mammals (including humans) and is important for defending cells against damage. According to the scientists, GSK-3 could be a target for drugs to control ageing. The study shows that male and female flies live longer than average when given low doses of lithium during adulthood or later in life, regardless of their genetic make-up. At low doses, few adverse effects were seen in the flies as they continued to feed normally and produce healthy offspring.

Different doses of lithium chloride were given to 160 adult flies to measure the effect on lifespan. Higher doses reduced lifespan but lower doses prolonged life by an average of 16% and maximum of 18% compared to a control group given sodium chloride. The benefits of lithium were also seen when it was used as a transient and one-off treatment. Flies that received a one-off dose near the end of their lives lived a maximum of 13% longer and young flies given low doses of lithium chloride for 15 days before switching to a control for the remainder of their lives also lived longer. "We studied the responses of thousands of flies in different conditions to monitor the effects of lithium and how it extends life. We found low doses not only prolong life but also shield the body from stress and block fat production for flies on a high sugar diet. Low doses also protect against the harmful effects of higher, toxic doses of lithium and other substances such as the pesticide paraquat."



The conventional wisdom is that common genetic variations have only a very small impact on mortality and health across the majority of the present human life span, but as the molecular damage of aging accumulates in later life, a time of frailty, disability, and high risk of age-related disease, genes make an increasingly significant contribution to determining remaining life expectancy. Here is a very readable open access paper on this topic, covering at a high level a range of the mainstream work on genetics, lifestyle, and aging from the past few decades:

Before the 1990s it was largely considered that aging is ineluctable and that genetics does not control it. It was important, in this view, the idea that aging occurs after reproduction, and then there is no need, but also no opportunity, for selection to act on genes that are expressed during this late period of life. Thereafter studies clearly demonstrated that genetic variability could indeed affect lifespan. This triggered many studies in model organisms in order to disentangle the different biochemical pathways which could affect lifespan, and to highlight the genes coding for the proteins involved in such pathways.

It is of note that some authors suggested the molecular mechanisms modulating lifespan could be due to a pleiotropic effect of genes which have evolved for different purposes (such as the genes in the IGF-1 pathway which have evolved to face presence/absence of nutrients) but can, ultimately affect lifespan; others proposed that some genes may have evolved to program aging and avoid "immortality", as this would hamper the continuous substitution of old subjects with new, younger, ones. It was obviously inevitable that the research of the genetic basis of longevity turned to human beings and investigated whether the common genetic variability of human populations could affect inter individual differences in lifespan but also whether the genes found to prolong lifespan in model organisms, on turn, were correlated to human lifespan.

As to the first question (does common genetic variability affect lifespan, and in particular does it affect longevity?), this has been studied by two approaches. The first one was the reconstruction of the sibships of long-lived subjects and the comparison of their survival curves with those of the birth cohorts born in the same geographical area. This approach demonstrated that brothers and sisters of the long-lived subjects had a clear survival advantage (at any age) with respect to the general population. The second approach, with intrafamily controls, was started in order to distinguish the genetic from the "familiar" effect. Researchers compared the survival function of brothers of centenarians with those estimated for their brothers in law, that is with the men who married their sisters; these men were supposed to share with the brothers of the long lived subjects the familiar environment. By using this second approach, it has been found that the survival advantage of siblings of long-lived subjects was not completely shared by their brothers in law, despite they shared the same environment for most of their life. This suggested that beyond the family environment, there are genetic factors influencing survival and, consequently, lifespan. The genetic component of lifespan in humans has also been analyzed by comparing the age of death of monozygotic and dizygotic twins. This has allowed the estimate that about 25% of the variation in human longevity can be due to genetic factors and indicated that this component is higher at older ages and is more important in males than in females.


Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.