Fight Aging! Newsletter, July 18th 2016

July 18th 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.

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  • October 2016: Longevity Day and the Eurosymposium on Healthy Aging
  • Michael Greve Pledges 10 Million to SENS Rejuvenation Research and Development
  • Human Telomere Dynamics and the Balance Between Cancer and Atherosclerosis
  • Recent Research on Aging and Regeneration in the Brain
  • Finally Signed Up for Cryopreservation: the Existence of a Fallback Plan is Great, but Only if You Actually Take Advantage of It
  • Latest Headlines from Fight Aging!
    • Gene Duplication and the Evolution of Longevity in Mammals
    • Longevity Does Not Equate to Overpopulation
    • Optic Nerve Regeneration and Partial Vision Restoration Achieved in Mice
    • Associating Biomarkers of Healthy Aging with Longevity Finds Only Small Effects
    • SENS Research Foundation Announces Project|21 Fundraising
    • Investigating the Mechanisms of Transthyretin Amyloid Aggregation
    • Education Correlates With Greater Longevity Consistently Over Time
    • Is Nuclear DNA Damage Responsible for Stem Cell Aging?
    • Calorie Restriction Reduces Inflammation in Human Practitioners
    • Studying Bacteria Provides Insight into the Origins of Aging


October 1st is the the UN International Day of Older Persons, and for the past few years the International Longevity Alliance has been campaigning to make it Longevity Day as well. This is an example of a longer-term, more subtle form of outreach to the public, most of whom never give much thought to aging, medicine, or what might be done at the intersection of those two fields in the near future. Improving the backdrop to the discussion is one way to help build greater support for treating aging as a medical condition to extend healthy life. A range of community events were held or started on Longevity Day last year, including the 2015 Fight Aging! SENS fundraiser. A number of conferences are held around that time of year, and in 2016 these include the Eurosymposium on Healthy Aging, hosted by the Healthy Life Extension Society, as well as the next conference of the International Society on Aging and Disease (ISOAD), both of which are scheduled for the end of September.

Longevity Day and Longevity Month - October 2016

Following the tradition of 2013, 2014 and 2015, as usual 3 months before October 1, there starts the organization of events and publications toward the "Longevity Day" (based on the UN International Day of Older Persons - October 1) in support of biomedical aging and longevity research. This has been a worldwide international campaign successfully adopted by many longevity activists groups. Last year, events, meetings, publications and promotions were organized in the framework of this campaign in over 40 countries. Some promotions reached hundreds of thousands of viewers. This campaign has also received factual endorsement and publicity from several internationally and nationally recognized scientific and advocacy associations.

Hopefully, this year, the campaign will be no less enriching, unifying and impactful. Though this year, it was suggested, while keeping the "longevity day" concept as would be desirable to particular groups and activists, rather to emphasize and organize the longevity promotion events in October in a new framework - as "The Longevity Month" - as usually the "longevity day" events spread through the entire month of October. Various "commemorative months" to support particular advocacy issues is a well established and effective practice, and a dedicated "month" can give people more flexibility and space to organize events and publications. This time it would even be endeavored to gain some official state-level recognition of this commemorative month campaign.

Eurosymposium on Healthy Aging

The Eurosymposium on Healthy Ageing (EHA) is a biannual conference organized for the first time in 2012. This meeting will highlight the cutting-edge of knowledge in the field of biogerontology and provide a unique opportunity for researchers, government officials, biotech executives, and advocates from around the world to meet, network, and forge new scientific collaborations.

The process of biological ageing is the root cause of all chronic age-related diseases and is inseparable from them. Worldwide, more than one hundred thousand people die every day from age-related diseases. So-called (healthy) or (normal) ageing should be seen as a presymptomatic stage for the appearance of severe and debilitating age-related conditions, such as Alzheimer's disease, most cancers, and cardiovascular disease. Ageing is a set of structural changes reducing the time until the individual suffers permanent functional decline and diminished health. Therefore, whether ageing in adults is viewed as a disease or a syndrome, it should be understood as potentially amenable to biomedical inteventions.

Addressing ageing-related debilitating processes through biomedical means should become a new and powerful approach to the prevention of non-communicable diseases which affect most people at the later stages of life. The purpose of preventive medicine for the elderly is to preserve the structure of an ageing individual so as to prevent functional decline.

International Society on Aging and Disease (ISOAD)

Despite dramatic improvement in average life expectancy, maximum documented lifespan in humans has remained at about 100-120 years throughout history. Most people do not live this long, however, because of disease (including age-related disease) and, perhaps also, physiological changes associated with "normal" aging. It has been proposed that such pathological and physiological factors may be interrelated, in that the aged are more prone to disease and have more limited adaptive capacity than younger adults. About 80% of older adults have age-related disorders like obesity, diabetes, hypertension, or heart disease, and 50% have at least two. Thus, aging has been described as a "risk factor" for various diseases, but the practical value of identifying such a non-modifiable risk factor - as opposed to modifiable risk factors like diet or hypertension - is unclear. Some have gone so far as to consider aging the "cause" of age-related diseases, although this does not explain why such diseases do not develop in everyone, nor why different individuals get different diseases. Aging (i.e., becoming chronologically old) is inevitable, but age-related diseases may not be.

A major goal of modern medicine is to preserve quality of life. Applied to the elderly, this translates into concepts like "successful", "healthy", or "optimal" aging, which are considered to comprise avoiding disease and disability, maintaining good cognitive and physical function, and remaining actively engaged in life. These objectives require the coordinated efforts and combined insights of scientists studying the basic biology of aging - gerontologists - and those focused on age related disease - geriatricians and others. The major goal of this society is to provide a platform that will help to fill the current gap between studies of the basic biology of aging and of aged-related disease.


Michael Greve is an internet entrepeneur turned venture capitalist with a long-standing interest in aging and longevity, and today he has pledged 10 million in support of SENS rejuvenation research: 5 million for the science, and a further 5 million to fund startups for clinical development. This money will help speed the development of therapies that can repair the forms of cell and tissue damage that cause aging, and thus prevent age-related disease, rejuvenate the old, and significantly extend healthy life spans. Michael Greve runs the Forever Healthy Foundation and the Kizoo venture fund, and has become ever more involved in the SENS rejuvenation research community over the past few years. If you attended any of the recent SENS conferences you might have met him. He was one of the generous matching fund donors for last year's Fight Aging! SENS fundraiser, and this year his venture fund has invested in companies Oisin Biotechnology and Ichor Therapeutics, both of which are carrying out the clinical development of biotechnologies relevant to the SENS approach.

I'm very pleased to see that Michael Greve has now joined the ranks of those who have committed a significant amount of funding to SENS research, alongside Aubrey de Grey, Peter Thiel, and Jason Hope. As more people in the venture community demonstrate their public, material support for this path forward, I think that we're going to see greater interest from that quarter. This is something that the SENS Research Foundation has been building towards since its inception, as it is no accident that the organization is headquartered in the Bay Area. The 5 million that Greve has pledged to research will be the founding donation for Project|21, which is the new SENS Research Foundation high-level fundraising program aiming to pull in exactly this sort of support: millions for specific programs, to complete the first prototype SENS rejuvenation therapies and push this industry into existence. You'll be hearing a lot more of this in the years ahead.

As you look at this important step forward in the movement to bring aging under medical control, consider that we all helped to make this happen, to persuade people like Michael Greve that this is the right place to invest in progress. Without the community of grassroots support and activism, without our voices and our own modest donations, without the writing and the crowdfunding and the discussions, without the simple step of talking to your friends about ending aging, we could never have gained the interest of people who can devote millions to the causes they believe in. A movement is a process, a collaboration. Today we can celebrate, and I think it is clear that this is but the start of far greater growth and success to come in the years ahead.

Michael Greve Commits 10 Million

German Internet Entrepreneur Michael Greve today announced that his Forever Healthy Foundation will be committing 5 million in philanthropic support over the next five years to the SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease. In addition Michael Greve's company KIZOO Technology Ventures will be committing seed investments of 5 million in startups focused on bringing rejuvenation biotechnology treatments to market.

"My goal is to provide support for the critical research of the SENS Research Foundation and to facilitate the development of the rejuvenation biotech industry and ecosystem. I think we should have more people contribute to the step-by-step creation of cures for the root causes of all age-related diseases. And we should have a whole rejuvenation industry based on the SENS treatment model including the self-accelerating feedback-loop of success stories and amazing opportunities for scientist, entrepreneurs and VC investors. This will truly accelerate both research and therapies. I have decided to lead by example and make this 10 million commitment," said Michael Greve.

Forever Healthy Foundation's initial donation will fund projects including Allotopic Expression of Mitochondrial Genes led by Dr. Matthew O'Connor at the SENS Research Foundation Research center and Pharmacological and/or enzymatic cleavage of glucosepane crosslinks led by Dr. David Spiegel at Yale University, SENS Research Foundation's Education Program led by Dr. Greg Chin and other SENS Research Foundation programs.

"Michael Greve's commitment shows that there is clear support for the critical work of the SENS Research Foundation. As the first donation in our Project|21 fundraising campaign, it will help enable us to build a bridge to the first human clinical trials of Rejuvenation Biotechnologies by 2021. This gift is an important cornerstone that we will be able to build upon," said Mike Kope, CEO, SENS Research Foundation.

SENS Project|21

Project|21 is a new initiative created by SENS Research Foundation to end age-related disease through human clinical trials, starting in 2021, through investment in rejuvenation biotechnology. We have all the pieces in place - core research groups, key players, shared knowledge, and underlying tools - for the creation of this industry.

Through three new programs, the Bridge fund, The Center of Excellence, and The Alliance Program, Project|21 will deliver the perfect environment for this fusion of opportunity and investment. With proper stewardship of this emerging industry, we can create an environment where the first damage repair interventions to address specific age-related disease will be brought to human clinical trials within five years.

50 million in total funding is required for Project|21, at least half of which will come from the members of SENS Research Foundation's Group|21. Group|21 will bring together 21 philanthropists, each donating between 500,000 and 5 million. Grants, grassroots efforts, and matching-fund strategies will provide the remaining support.


Today I'll point out a great open access paper on the evolution of human telomere dynamics: telomere length, how that length changes over time, and especially how it changes with aging. This makes a good companion piece to another paper from last week that covered the differences in telomere dynamics between mice and humans. This is quite important, since most of the work on this topic involves mouse studies, not human studies. As telomerase gene therapies continue to extend average telomere length and - in mice at least - also extend healthy life span, this is becoming a hot topic in the aging research community. It is increasingly a good idea to have a grounding of the basics and current scientific thinking on this portion of our biochemistry. Sooner or later someone will be selling telomerase gene therapies to the public as an alleged method to slow the progression of aging, and most likely selling these treatments well in advance of any comprehensive human studies or definitive answers as to their effectiveness. You will find yourself in the position of deciding whether or not to pay the price and undertake the therapies. Better to figure out your position and what would change your mind today rather than later.

Telomeres are repeating sequences of DNA that cap the ends of chromosomes. Their purpose is primarily to act as a part of the limiting mechanisms on cell replication: a little of the length is lost with each cell division, and when they become too short the cell self-destructs or becomes senescent, ceasing replication. For any given tissue the distribution of telomere length among cells is a function of how often new cells with long telomeres are created by stem cells, and how often cells divide. Stem cells maintain long telomeres through the use of telomerase, which adds more repeating sections to replace those lost to cell division. In humans only stem cells use telomerase, but in mice it has a much more widespread activity. Mice also have much longer telomeres than humans. All of this has everything to do with cancer, of course. The whole complicated arrangement of cells that are limited coupled to a much smaller number of cells that are privileged has evolved because it limits uncontrolled growth sufficiently well for evolutionary success. Without it highly structured and comparatively long-lived species such as our own couldn't exist.

Since stem cell activity declines with aging, it isn't surprising to see that measures of average telomere length also tend to do so - but this is a very poor measure of aging, and really only shows up in statistical studies across populations. There are too many other influences over the most commonly measured types of cell, such as immune cells. So average telomere length, much discussed this past decade, looks a lot like a measure of age-related damage, far removed from root causes. Given that, why does increased telomerase activity extend life in mice? Most likely for the same reasons that any method of spurring greater stem cell activity improves matters in an old individual: greater tissue repair and maintenance, a net benefit even if it is old and damaged cells that do the work. There are also other, less well explored activities undertaken by telomerase that might be beneficial, such as improvements in mitochondrial function. In mice at least it seems that these benefits come with no greater risk of cancer. It may be that improved immune function destroys more potential cancers than are created through greater activity in age-damaged cell populations, but that is pure speculation at this point. For humans the effects on cancer risk are much more of a question mark, though it is worth noting that stem cell therapies to date have exhibited far less risk of cancer than was expected at the outset.

Telomere Length and the Cancer-Atherosclerosis Trade-Off

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. Telomere length genetics should be considered in the context of evolutionary forces that have left their signature on the human genome. Inspection of the human genome reveals that of the approximately 22,000 currently annotated genes, 13,000 genes (about 60%) are linked to biological pathways of "cancer". These include genes engaged in growth, development, tissue regeneration, and tissue renewal, which heighten cancer risk due to increased cell replication, and genes that suppress cancer, including those that ultimately promote senescence and apoptosis. Central among cancer-protective pathways might be telomere-driven replicative senescence.

Stem cells are likely to undergo more replications in large, long-living mammals than in small, short-lived ones; this is because more replications are necessary for developing and maintaining a larger body size. More cell replication confers increased risk of cancer through accumulating de novo somatic mutations, which happen during successive DNA replications. This concept is supported by work showing that the risk of developing major human cancers is related to the number of stem cell divisions occurring in the tissues from which the cancers originated. Yet, large, long-living mammals generally display no increase in cancer risk compared to small, short-lived ones, a phenomenon known as Peto's paradox, suggesting that mechanisms have evolved to mitigate cancer risk in tandem with increasing body size and longevity. One such mechanism has been described in elephants. The elephant genome contains many more copies of TP53, a potent DNA damage response and tumor suppressor gene; p53-dependent apoptosis is thus triggered at a lower threshold of accumulating mutations, conferring cellular resistance to oncogenic transformation.

Similarly, a telomere-linked mechanism has been proposed in mammals based upon observations that telomerase activity in somatic tissues tends to be inversely correlated with body size while telomere length is inversely related to lifespan. Repressed telomerase and short telomeres would, therefore, limit replicative capacity in humans. In this way, short telomere length might curb the accumulation of de novo mutations and reduce the probability of oncogenic transformation in large, long-living mammals. Given the wide variation in telomere length across humans, might longer telomeres increase cancer risk? While initial studies were inconsistent (perhaps partially due to flaws in study design and small sample sizes), more recent studies show that in individuals of European ancestry, long telomeres, as expressed in leukocyte telomere length (LTL), are associated with increased risk for melanoma, adenocarcinoma of the lung, and cancers of the breast, pancreas, and prostate. Moreover, Mendelian randomization studies using leukocyte telomere length associated SNPs support the inference that having a longer LTL has a causal relation to cancer risk.

The cancer protection conferred by short telomeres could come with an evolutionary trade-off, namely, diminished proliferative activity of stem cells and consequently less regenerative capacity. This would manifest in age-dependent degenerative diseases. Some of the leading degenerative diseases in humans are related to atherosclerosis, and atherosclerosis is associated with short LTL. As cancer and atherosclerosis strongly impact longevity, the diametrically opposing roles of TL in these two disorders might be relevant to understanding the lifespan of contemporary humans and future trajectories in life expectancy. Notably, in evolutionary terms, this would probably have become more relevant when agrarian societies emerged over the past ten thousand years or so and lifespans increased considerably. In fact, evidence of atherosclerosis has been detected in ancient human Egyptian mummies.

Recent studies have used LTL genome-wide association study findings to generate "genetic risk scores" for cancers and for atherosclerosis insofar as it is expressed in coronary heart disease. These studies have shown that the same cluster of LTL-associated alleles is a risk indicator for melanoma, lung cancer, and coronary heart disease, such that when the joint effect of the alleles results in a comparatively long LTL, the risk for melanoma and lung cancer is increased, whereas the risk for coronary heart disease is diminished. The opposite holds when the joint effect of the alleles results in a comparatively short LTL, which engenders a higher risk for coronary heart disease and a lower risk for cancer. This cancer-atherosclerosis trade-off might principally apply to contemporary humans because they live so long, but not to ancestral humans. This trade-off has been principally established through the force of evolution. In contrast to cancer, which is associated with over ten thousand genes, only several hundred genes in the human genome have been shown to relate to atherosclerosis. Yet, atherosclerosis is a major determinant in the longevity of humans because of their relatively long lifespan, especially in high- and middle-income societies.


Today I'll point out a brace of recent research materials, all of which focus on the aging brain. A great deal of aging research is focused on the effects of aging in the brain, in part driven by the large level of investment in Alzheimer's disease research, and this overlaps with ongoing efforts to understand how the brain works: how it gives rise to the mind and how specific functional aspects of the mind work, all the way down to the level of proteins and intricate cellular structures such as synapses. While some researchers restrict themselves to investigation and observation, trying to fill in the large blank spaces on the map of the brain, others are working to find ways to repair some of the damage and reverse some of the declines. Forms of cell therapy are perhaps the closest to being broadly useful at the present time, but all sorts of ways to clear out cellular garbage and unwanted metabolic waste - such as the amyloid associated with Alzheimer's disease - are headed in the general direction of viability for clinical development.

Not this year, but certainly within the next decade, new classes of treatment will arrive, therapies that can at least partially address some of the fundamental causes of functional decline in the aging brain, rather than trying to patch over the consequences as so much of present day medicine does. Initially these therapies will be highly restricted, available only in trials, or for patients in the late stages of neurodegenerative conditions. That is the outcome that the current regulatory system forces upon us. There will be a mild but sweeping revolution then, I hope, as treatments for the causes of aging become a reality, that will tear down the ridiculous systems of regulation that stifle development, with the result that effective therapies will become far less costly and far more widely available. A treatment that can address the causes of age-related disease is a treatment that should be undertaken by everyone on a regular basis, not just those who are heavily damaged by the processes of aging, and not just those groups that unaccountable bureaucrats decide should gain access. Today, the foundations for that future are still being built, one incremental step at a time, but is never too early to plan ahead.

The brain needs to 'clean itself up' so that it can 'sort itself out'

When neurons die, their remains need to be eliminated quickly so that the surrounding brain tissue can continue functioning. A type of highly specialised cell known as microglia is responsible for this process which is called phagocytosis. Neurons are known to die during the convulsions associated with epilepsy. But contrary to expectations, in this condition the microglia are "blind" and incapable of either finding them or destroying them. Their behaviour is abnormal. And the dead neurons that cannot be eliminated build up and damage the neighbouring neurons further, which leads to an inflammatory response by the brain which harms and damages it even further. This discovery opens up a new channel for exploring therapies that could palliate the effects of brain diseases. In fact, the research group that authored this work is right now exploring the development of drugs to encourage this cleaning up process, phagocytosis.

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

The DNA damage response (DDR) is a complex biological system activated by different types of DNA damage. Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration, premature aging, and various types of cancers. Intriguingly, malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. For many years, brain degenerative disorders were thought to result from aberrant neural death. Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells (astrocytes, microglia, and oligodendrocytes). Impairment in the functionality of glial cells results in pathological neuro-glial interactions that, in turn, generate a "hostile" environment that impairs the functionality of neuronal cells. These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit.

Swapping sick for healthy brain cells slows Huntington's disease

Researchers have successfully reduced the symptoms and slowed the progression of Huntington's disease in mice using healthy human brain cells. The research entailed implanting the animals with human glia cells derived from stem cells. One of the roles of glia, an important support cell found in the brain, is to tend to the health of neurons and the study's findings show that replacing sick mouse glia with healthy human cells blunted the progress of the disease and rescued nerve cells at risk of death. Conversely, when healthy mice were implanted with human glia carrying the genetic mutation that causes Huntington's, the animals exhibited symptoms of the disease. The researchers believe that the healthy human glia were able to essentially stabilize and perhaps even rescue neurons by restoring the normal signaling function that is lost during the disease.

Cerebrovascular disease linked to Alzheimer's

While strokes are known to increase risk for dementia, much less is known about diseases of large and small blood vessels in the brain, separate from stroke, and how they relate to dementia. Diseased blood vessels in the brain itself, which commonly is found in elderly people, may contribute more significantly to Alzheimer's disease dementia than was previously believed, according to new study results. The study analyzed medical and pathologic data on 1,143 older individuals who had donated their brains for research upon their deaths, including 478 (42 percent) with Alzheimer's disease dementia. Analyses of the brains showed that 445 (39 percent) of study participants had moderate to severe atherosclerosis - plaques in the larger arteries at the base of the brain obstructing blood flow - and 401 (35 percent) had brain arteriolosclerosis - in which there is stiffening or hardening of the smaller artery walls.

The study found that the worse the brain vessel diseases, the higher the chance of having dementia, which is usually attributed to Alzheimer's disease. The increase was 20 to 30 percent for each level of worsening severity. The study also found that atherosclerosis and arteriolosclerosis are associated with lower levels of thinking abilities, including in memory and other thinking skills, and these associations were present in persons with and without dementia.

Adult Neurogenesis and Gliogenesis: Possible Mechanisms for Neurorestoration

The adult brain has some ability to adapt to changes in its environment. This ability is, in part, related to neurogenesis and gliogenesis. Neurogenesis modifies neuronal connectivity in specific brain areas, whereas gliogenesis ensures that myelination occurs and produces new supporting cells by generating oligodendrocytes and astrocytes. Altered neurogenesis and gliogenesis have been revealed in a number of pathological conditions affecting the central nervous system, indicating that modulation of the processes involved in adult neurogenesis and gliogenesis may provide a plausible strategy for treatment. Compared to neurogenesis, gliogenesis occurs more prevalently in the adult mammalian brain. Under certain circumstances, interaction occurs between neurogenesis and gliogenesis, facilitating glial cells to transform into neuronal lineage. Therefore, modulating the balance between neurogenesis and gliogenesis may present a new perspective for neurorestoration. These processes might be modulated toward functional repair of the adult brain.

New clues about the aging brain's memory functions

Researchers have shown that the dopamine D2 receptor is linked to the long-term episodic memory, which function often reduces with age and due to dementia. This new insight can contribute to the understanding of why some but not others are affected by memory impairment. In this study, a PET camera was used to examine individual differences in the D2 system in a group consisting of 181 healthy individuals between the age of 64 and 68. All participants also had to take part in an all-inclusive performance test of the long-term episodic memory, working memory and processing speed along with an MRI assessment (which was used to measure the size of various parts of the brain). Researchers could see that the D2 system was positively linked to episodic memory, but not to working memory or to processing speed by relating PET registrations to the cognitive data. Researchers could also see that the D2 system affects the functioning of the hippocampus in the brain, long linked to long-term episodic memory.


As regular readers will know, I've long considered the cryonics industry to be a sensible, necessary undertaking in an uncertain world. For those of us interested in longevity, the primary plan is to accelerate development of rejuvenation therapies to the point at which we can achieve actuarial escape velocity: that we'll benefit somewhat from the first generation of therapies, and thus survive long enough to benefit from the second, much better generation of therapies, and so on, until aging is comprehensively defeated and our remaining healthy, youthful, vigorous lifespans become indefinite in length. It is almost certainly the case that some people alive today will achieve that goal. The open question is whether or not that group includes you and I, and that isn't something that can be predicted at the present early stage of development, in which the first true rejuvenation therapies, capable of repairing the cell and tissue damage that causes aging, are not even in the clinics yet.

Uncertainty is one of the reasons why advocacy and fundraising is so important. It is also the reason why a backup plan is a good thing to have. The only viable backup plan for the foreseeable future is cryopreservation, which is to say the low-temperature storage of the brain following clinical death in the hope of future restoration. The evidence is good for vitrification of brain tissue to preserve the fine structure of tissue that encodes the mind, and while the process in practice can always be improved in quality and organization, the (currently unknown) odds of survival following cryopreservation are infinitely higher than those attending any other end of life choice. After the grave there is only oblivion, but for so long as the data of the mind is preserved, there is hope that sufficiently advanced medical nanotechnology will one day bring you back.

I have put off signing up for cryopreservation for a decade or so. This isn't uncommon; after all, it involves paperwork, adult responsibility, planning ahead, thinking about unpleasant events, and all that. People put off many other things for these and similar reasons. Writing wills, buying houses, getting married, starting companies, and so on. That doleful feeling of some unknown scope of paperwork that will have to be accomplished in the event that you do get your act together and set forth to be a responsible adult is ever a strong deterrent. Still, sooner or later all these tasks have to be carried out, and while no-one enjoys wading through legal documents, it is never as bad as you think it is going to be. If you are unfamiliar with the process of signing up for cryonics organization membership and cryopreservation, let me tell you that it is much less work than buying a house. It is about two and half times the work of getting a life insurance policy, if that helps calibrate things any better. Typically, it runs as follows:

1) Contact one of the established cryonics providers (Alcor or the Cryonics Institute in the continental US) and ask to join. They will send you a raft of paperwork typical of membership organizations, but since it involves the highly regulated area of end of life decisions you will have to have some of the documents witnessed and notarized. You are signing up to pay a monthly fee to help keep the lights on, and to donate your remains to the provider on death, but this is all provisional pending organization of payment.

2) Obtain life insurance to pay for your eventual cryopreservation. This is where you will want advice, as there are only a few life insurance companies that have experience with this sort of thing. I recommend chatting to Rudi Hoffman, who has acted as an insurance agent for for scores of people in the cryonics community. Paying for cryopreservation with life insurance involves establishing a policy that will pay out to the cryonics organization on death rather than to the more usual parties, such as family members. The matter of how large a policy to purchase is an interesting question, and I encourage you to read an earlier post that walks through that topic. The short of it is that more is generally better, as the future is uncertain. Life insurance companies will want to pick through your medical records, will send a nurse to check your vital signs, and will usually find some reason to charge a little more than the early, optimistic quote that was given sight unseen.

3) Then you wait for paperwork to cross the country back and forth, as everyone involved between you, the cryonics provider, the insurance agent, and the insurer has to sign everything. It might take a month or two, depending on how many of the end points are comfortable with electronic document exchange, but there is usually a lot of back and forth required. There is always time to stop and think about any particular choice.

4) With membership and contracts in hand, you should take care of a few other supporting legal documents. This means making a will that determinedly and in no uncertain terms states your wish to be cryopreserved, and just as importantly establishing what is known as a living will or advance healthcare directive, a declaration of who you want to have power of attorney in the case of your incapacity, and what actions they should take. That should obviously be someone you trust to ensure that you are cryopreserved, and who for preference has absolute no financial interest in the outcome one way or another. Because the contents of the will and living will are somewhat non-standard, you will probably have to make use of an actual living, breathing attorney rather than one of the very helpful standardized form legal services that have sprung up of late.

There are cautionary tales in the cryonics community regarding people who trusted their immediate family to ensure that they were cryopreserved, and those family members then sabotaged the arrangements in order to access the life insurance funds. This has happened on numerous occasions. Much as I might sound a misanthrope to say this, the best assumption to keep in mind when setting up the legal aspects of your cryopreservation is this: when on your deathbed, everyone not employed by the cryopreservation organization is a potential adversary, interested in the funds that they might be able to obtain for themselves at the cost of your survival. It doesn't matter how well you know people today, or the nature of your relationships with them. Cryopreservation is (hopefully) decades in your future, half a lifetime or more away: people change, and people who don't even exist today will be involved in your end of life care, having legally meaningful ties to you by kinship. Fortunately, it is possible to arrange matters to make it very hard for even family members to sabotage your arrangements, and most of these approaches are well documented by the cryonics providers.

For example, firstly you should ensure that no-one in your family is even named in the life insurance policy you are buying. It should pay out to the cryonics organization, and you might pick an entirely unrelated charity to benefit should you be unfortunate enough to die in a way that prevents your cryopreservation - thus the incentives align for the cryonics provider to try their best, as they get nothing if they fail, and your family has no interest in the outcome either way. Secondly, persuade as many close family members as possible to sign and have witnessed affidavits of support for your cryopreservation. Third, structure your will and living will to ensure that there are material incentives for your family in the event that you are successfully cryopreserved, and there are no material incentives for any of them to block that outcome. Fourth, record your determination to be cryopreserved, both in your will and in other media, and keep that reasonably up to date. Lastly for this list there is the matter of avoiding the unwanted attention of the state in the form of autopsy or other delays after death. The best methods here vary by jurisdiction, but in some states registering a religious objection can work well.

The best way to keep everyone on your side in the matter of cryonics is to ensure that all of the incentives align with the outcome of a successful cryopreservation, should it come to that. The moment that someone can benefit by making it hard to achieve that goal - that is when the problems start. Relying on the essential goodness of human nature has never been terribly effective when it comes to expecting people to follow through with something that they themselves do not support, or think is frivolous, or which requires them to sacrifice their own gain. If you are in the room and exerting your will, that is one story, but when you are gone, it is quite another.



Researchers here use some of the more recently sequenced mammalian genomes, of the majority eutherian branch that encompasses all of the mammals you might be familiar with, to investigate a potential role for gene duplication in the evolution of aging and longevity. This is a good example of much of the breadth of research into aging in that it is very far removed from any practical outcome: it is an unhurried process of mapping. Fundamental research is nonetheless essential despite - or arguably because of - the lack of a clear use for the knowledge gained.

One of the greatest unresolved questions in aging biology is determining the genetic basis of interspecies longevity variation. Within Eutherians, bowhead whales live more than 200 years, while short-lived rodents generally live up to 4 years. Gene duplication is often the key to understanding the origin and evolution of important Eutherian phenotypes. Many longevity-associated pathways evolved via gene duplication, and duplication can increase lifespan and impact the pathogenesis of various aging-related diseases. With the availability of genomes from long- and short-lived species and a set of hundreds of genes known to influence lifespan in model organisms, we thoroughly investigated the role that gene duplication played in the evolution of Eutherian longevity from a systematic perspective.

Longevity-associated gene families have a marginally significantly higher rate of duplication compared to non-longevity-associated gene families. Anti-longevity-associated gene families have significantly increased rate of duplication compared to pro-longevity gene families and are enriched in neurodegenerative disease categories. Conversely, duplicated pro-longevity-associated gene families are enriched in cell cycle genes. There is a cluster of longevity-associated gene families that expanded solely in long-lived species that is significantly enriched in pathways relating to 3-UTR-mediated translational regulation, metabolism of proteins and gene expression, pathways that have the potential to affect longevity. The identification of a gene cluster that duplicated solely in long-lived species involved in such fundamental processes provides a promising avenue for further exploration of Eutherian longevity evolution.

We can only speculate whether the inferred duplication patterns in this study could have impacted Eutherian longevity. In reality, longevity evolution is probably the result of many genes exhibiting small effect sizes, meaning that pinpointing the exact source of longevity determination will be extremely difficult to detect, even in large studies. Because we know that the environment and condition of an individual play a massive role on the proteins that are being expressed, perhaps the true meaning of the reason for duplicating these genes in long-lived species may not be fully understood from solely this perspective. However, subtle differences at the genomic level can exert a large phenotypic effect. It is possible that duplicating a small cluster of interrelated genes solely in long-lived species that have core functions involved in RNA and protein metabolism could have directly or indirectly impacted their longevity through their functions in gene and protein networks.


It cannot be stated too many times that extended life will not produce overpopulation or the sorts of resource shortages constantly feared by Malthusians. Even if it did, that would be a prompt to solve both the resource problem and the aging problem, not a prompt to condemn billions to death by relinquishing the clear path ahead to widespread, cheap rejuvenation treatments. Malthusian visions of any form are simply incorrect, however. They are based on a static view of the world in which the nature of resources doesn't change. Humans, however, are ingenious and motivated by the prospect of future scarcity and increased prices to develop new resources and new technologies. This has happened over and again, yet for some reason we still have Malthusians. There is some flaw in human nature that makes it hard to see that the world is being changed for the better even while we are in the midst of radical progress in science and technology.

A classic objection to the radical extension of life is: "But such an extension will lead to an overpopulation crisis!" We think this is important to refute that idea that longevity equates to overpopulation, because it is not a harmless idea. Actually, this formula is so widespread that it is used to stop investment of public money in longevity research, because people making decisions have serious reserves: nobody wants to invest money in a project that would lead to an overpopulation crisis! Therefore, it is important to avoid turning longevity into a scapegoat. In addition, if we knew how to live much longer in good health, it would not be very humane to force people to die at 80 in order to avoid some hypothetical overpopulation problems.

The fertility rate is the average number of children per woman in a given population. When this rate is around 2, the population is considered stable. Being overly concerned about life extension, while easily accepting a fertility rate slightly greater than 2, is simply not rational. Even if death disappears tomorrow morning, the resulting population increase would be smaller than the one observed during the baby boom. And should it happen in Sweden, then after 50 years, the population increase would only be 30%, which is within the limits of the population increases observed during the last century. Therefore, even after such an unlikely event (and assuming that it is a problem), we should have more than enough time to adapt. But we are far from being at this point: living 50 more years would already be a major scientific advance! There is no good reason to ban or to refuse to finance longevity research.

Last but not least, keep in mind that the context can radically change before life expectancy increases significantly. This has already been the case during the industrial revolution. We could discover new ways to provide shelter and food to more people at a smaller price, make new zones habitable, and even, in the long-term, colonize new planets. It is evident that a radical increase in population is not a "goal" in itself. But, assuming that it happens, it's consequences may be far less dramatic than what we imagine today, because the context will have evolved. In the previous century, some people thought that London would eventually be entirely covered with horse manure. Today, this idea makes people laugh! In past predictions, we always underestimated the increase of life expectancy and always overestimated population growth. Are we not making the same mistake again? Two centuries ago, Malthus (the most famous thinker of overpopulation) was making apocalyptic predictions based on the scale of one century. Today, the population has been multiplied by 8 and instead of collapsing, the standards of life have significantly increased.


In what seems an important incremental advance in nerve regeneration, researchers have demonstrated regrowth of damaged portions of the optic nerve in mice, and partial vision restoration as a result. Once past the initial point of provoking regeneration of nerve tissue, the challenge here is as much to identify the degree to which vision is restored as it is to actually repair damaged nerves. Mice cannot be walked through a standard eye exam, and they cannot tell you in detail just how good or bad their vision is. Determining how well they can see after the processes of damage and regeneration is a difficult undertaking, though clearly here there is a lot of room for improvement.

In experiments in mice, scientists coaxed optic-nerve cables, responsible for conveying visual information from the eye to the brain, into regenerating after they had been completely severed, and found that they could retrace their former routes and re-establish connections with the appropriate parts of the brain. The animals' condition prior to the scientists' efforts to regrow the eye-to brain-connections resembled glaucoma, the second-leading cause of blindness. Glaucoma, caused by excessive pressure on the optic nerve, affects nearly 70 million people worldwide. Vision loss due to optic-nerve damage can also accrue from injuries, retinal detachment, and other sources.

Retinal ganglion cells are the only nerve cells connecting the eye to the brain. Damage to mammalian retinal ganglion cells' axons spells permanent vision loss. Mammalian axons located outside the central nervous system do regenerate, though. And during early development, brain and spinal cord nerve cells abundantly sprout and send forth axons that somehow find their way through a thicket of intervening brain tissue to their distant targets. While many factors are responsible for adult brain cells' lack of regenerative capacity, one well-studied cause is the winding down, over time, of a growth-enhancing cascade of molecular interactions, known as the mTOR pathway, within these cells.

In the study, adult mice in which the optic nerve in one eye had been crushed were treated with either a regimen of intensive daily exposure to high-contrast visual stimulation, in the form of constant images of a moving black-and-white grid, or biochemical manipulations that kicked the mTOR pathway within their retinal ganglion cells back into high gear, or both. The mice were tested three weeks later for their ability to respond to certain visual stimuli, and their brains were examined to see if any axonal regrowth had occurred. Importantly, while retinal ganglion cells' axons in the crushed optic nerve had been obliterated, the front-line photoreceptor cells and those cells' connections to the retinal ganglion cells in the damaged eye remained intact.

While either visual stimulation or mTOR-pathway reactivation produced some modest axonal regrowth from retinal ganglion cells in mice's damaged eye, the regrowth extended only to the optic chiasm, where healthy axons exit the optic nerve and make their way to diverse brain structures. But when the two approaches were combined - and if the mouse's undamaged eye was temporarily obstructed in order to encourage active use of the damaged eye - substantial numbers of axons grew beyond the optic chiasm and migrated to their appropriate destinations in the brain. Tests of the mice's vision indicated that visual input from the photoreceptor cells in their damaged eye was reaching retinal ganglion cells in the same eye and, crucially, being conveyed to appropriate downstream brain structures essential to processing that visual input. In other words, the regenerating axons, having grown back to diverse brain structures, had established functional links with these targets. The mice's once-blind eye could now see. However, even mice whose behavior showed restored vision on some tests, including the one described above, failed other tests that probably required finer visual discrimination.


The past decade of genetic research into natural variations in human longevity have made it pretty clear that there are no large effects. Where genes influence longevity, they do so in later life, when individuals are damaged and health is failing, and individual effects per gene are both small and vary widely between study populations. This has long suggested to me that comparative genetics, examining long-lived and short-lived people, is not the place to find any sort of meaningful basis for a therapy to extend healthy life. The open access research linked below reinforces this point in a well-studied human population by associating longevity with genetic variants related to a number of biomarkers thought to reflect better health in old age. The individual associations found can be shown to explain only a small fraction of the observed variation in longevity:

Genetic studies have thus far identified a limited number of loci associated with human longevity by applying age at death or survival up to advanced ages as phenotype. As an alternative approach, one could first try to identify biomarkers of healthy ageing and the genetic variants associated with these traits and subsequently determine the association of these variants with human longevity. In the present study, we used this approach by testing whether the 35 baseline serum parameters measured in the Leiden Longevity Study (LLS) meet the proposed criteria for a biomarker of healthy ageing. We have previously proposed four criteria for a quantitative parameter that, we think, need to be fulfilled before being considered a biomarker of healthy ageing. In short, a biomarker of healthy ageing should show an association with (1) chronological age, (2) familial propensity for longevity, (3) known health parameters, and (4) morbidity and/or mortality. Thus far, biomarker research has identified several potential biomarkers of healthy ageing, such as glucose and free triiodothyronine (fT3) serum levels, CDKN2A (p16) gene expression, leukocyte telomere length (LTL), and gait speed.

By testing the four previously proposed criteria for biomarkers of healthy ageing in individuals from the LLS, we identified parameters involved in carbohydrate (glucose and insulin) and lipid metabolism (triglycerides) as biomarkers of healthy ageing. In addition, we showed that a relatively high proportion of the genetic variants previously associated with these parameters are also nominal significant in the largest genome-wide association study (GWAS) for human longevity to date. However, even in the largest GWAS for these parameters to date the explained variance is only 4.8% (glucose), 1.2% (insulin) and 2.1% (triglycerides), indicating that there is still a lot to discover. Nonetheless, we were able to find an enrichment of significant genetic variants, previously indicated to be involved in glucose, insulin and triglycerides regulation, in the longevity GWAS dataset. This indicates that the genetic component underlying these traits may also contribute to human longevity.


I mentioned Project|21 in yesterday's announcement of Michael Greve's 10 million pledge to SENS rejuvenation research and development, but I think it merits its own post. Not so very long ago the SENS Research Foundation engaged a specialist in high-end medical non-profit fundraising, and Project|21 is the outgrowth of that relationship, a program to raise the millions needed to take the first SENS therapies to readiness for human clinical trials over the next five years. To get to the point at which such a program is possible and practical required the years of groundwork and grassroots support that we as a community have provided: large donations always follow the crowd, and high net worth donors require advocates and thousands of supporters to light the way - and to continue those efforts. In effect, this launch of Project|21, alongside the advent of the first startups working on senescent cell clearance, marks a transition to a new stage of development for rejuvenation research following the SENS vision of repairing the cell and tissue damage that causes aging. Congratulations are due all round.

SENS Research Foundation today announced its Project|21 campaign to secure 50 million in private support from individual donors, foundations, and corporations. The goal of Project|21 is for SRF to partner with a new generation of visionary philanthropists, build the Rejuvenation Biotechnology industry, and bridge the most challenging gulf between research and treatment by enabling human clinical trials by 2021. Aubrey de Grey, founder and chief science officer of SENS Research Foundation said, "Ending aging will require large-scale investment to flow into a globally-recognized industry for rejuvenation biotechnology. Since we began in 2009, SENS Research Foundation has been putting all the pieces in place - core research groups, key players, shared knowledge, underlying tools - for the creation of this industry. The key programs funded by Project|21 can create an environment where the first damage repair interventions addressing specific age-related diseases will be brought to human clinical trials within five years."

The programs funded under Project|21 focus on three major barriers to the development of truly effective rejuvenation therapies. First, funding to convert promising basic research programs into solid investment candidates remains far too scarce. Second, there are too few opportunities for dynamic collaborations with mainstream regenerative medicine. Finally, there is little understanding of the regulatory pathways and clinical infrastructure these technologies will require. Project|21 addresses these three areas by creating a 15 million bridge fund to support promising early stage technologies; a center of excellence to deliver better opportunities for collaborative development of early stage programs; and a Rejuvenation Biotechnology Alliance Program to address challenges in regulation, manufacturing, and investment. The first donation received for Project|21 is a commitment from German internet entrepreneur Michael Greve's Forever Healthy Foundation for 5 million in philanthropic support over the next five years. In addition Michael Greve's company KIZOO Technology Ventures will be committing seed investments of 5 million in startups focused on bringing rejuvenation biotechnology treatments to market.


In transthyretin amyloidosis, also known as senile systemic amyloidosis when it occurs in the elderly, the protein transthyretin misfolds to precipitate into solid masses. This occurs to varying degrees over the course of aging for all of us, and it is becoming clear that these amyloid aggregates contribute meaningfully to the progression of heart disease, among other conditions. It also seems that transthyretin amyloidosis is what finally kills most supercentenarians, the oldest of people who evade every other fatal age-related condition.

There is a potential therapy to break down this form of amyloid that last year demonstrated very promising results in a human clinical trial, but it is currently locked into the slow regulatory path to availability; development has been ongoing for most of the last decade at a glacial pace. It is frustrating, given that this or a similar treatment should be used by pretty much everyone over the age of 40 every few years, and such a treatment should reduce the incidence of many fatal age-related conditions. Meanwhile, other research groups are continuing their investigations of the mechanisms of this form of amyloidosis and considering potential approaches to clearing transthyretin amyloid:

The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of TTR causes life-threatening transthyretin amyloidosis (ATTR) associated with three conditions traditionally known as senile systemic amyloidosis, familial amyloidotic polyneuropathy, and familial amyloidotic cardiomyopathy. Senile systemic amyloidosis is a late onset disease in which wild-type (WT) TTR aggregates, weakening the heart muscle. Senile systemic amyloidosis is usually diagnosed by post-mortem exams of patients over 80 years old. Familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy are hereditary conditions characterized by extracellular deposition of TTR amyloid fibrils in the peripheral nerves and heart, respectively, which leads to system failure.

Currently, there is no cure for transthyretin amyloidosis, and the treatment for familial cases of ATTR is liver transplantation. Tafamidis, a TTR tetramer stabilizer, has been recently approved in Europe; it delays progression of the disease. Several other therapeutics are currently in clinical trials, including other tetramer stabilizers such as diflunisal and RNAi therapies that cause a decrease in the production of TTR protein. Additional approaches are needed to prevent ATTR, and here we explore the use of peptide inhibitors that block aggregation of TTR.

Several models of the TTR amyloid spine have been proposed, but the aggregation-prone segments of the protein remain uncertain. Based on the studies of crystal structures of amyloid-driving segments, our group has proposed that fibrils can form through intermolecular self-association of one to several fibril-driving segments. Identical segments from several protein molecules stack into steric zipper structures, which form the spine of the amyloid fibril through tightly interdigitated β-sheets. Here we identify two segments of TTR that drive protein aggregation by self-association and formation of steric zipper spines of amyloid fibrils. Based on the amyloid structure of these two segments, we designed two peptide inhibitors that halt the progression of TTR aggregation.


It is known that greater levels of education correlate with greater life expectancy, but the novelty in the research here is a matter of just how far back in history this correlation can be shown to exist - it isn't dependent on access to very modern medicine. This is a part of a web of correlations between social status, intelligence, wealth, and education, all of which associate with modestly greater longevity. The underlying mechanisms and their relative importance remain debated; it seems easy to argue for wealth to grant relatively greater access to medicine, for example, but there is also evidence to link intelligence with greater physical robustness. Ultimately the point of building rejuvenation therapies is to make all of this irrelevant, however: for everyone to be able to live for as long as desired in perfect health, regardless of the hand dealt by chance and genetics.

By using historical data on about 50,000 twins born in Sweden during 1886-1958, we demonstrate a positive and statistically significant relationship between years of schooling and longevity. This relation remains almost unchanged when exploiting a twin fixed-effects design to control for the influence of genetics and shared family background. This result is robust to controlling for within-twin-pair differences in early-life health and cognitive ability, as proxied by birth weight and height, as well as to restricting the sample to monozygotic twins. The relationship is fairly constant over time but becomes weaker with age.

Literally, our results suggest that compared with low levels of schooling (less than 10 years), high levels of schooling (at least 13 years of schooling) are associated with about three years longer life expectancy at age 60 for the considered birth cohorts. The real societal value of schooling may hence extend beyond pure labor market and economic growth returns. From a policy perspective, schooling may therefore be a vehicle for improving longevity and health, as well as equality along these dimensions.


Researchers here cast doubt on nuclear DNA damage as a primary cause of decline in the stem cell population that is responsible for creating immune cells and blood cells. All cell populations accumulate random mutations in nuclear DNA over the course of aging. It is well proven that this causes a rise in cancer risk, though as noted in the paper here that isn't a simple linear relationship. The consensus position is that this damage also contributes to degenerative aging in the form of increased disarray in cell operations, but there is no solid evidence to demonstrate that this is in fact so, nor to show the degree to which it is a cause of aging in comparison to other forms of damage. There are opposing viewpoints from those who suggest that nuclear DNA damage isn't in fact significant in aging beyond the matter of cancer, at least over the present human life span.

The mammalian blood system consists of many distinct types of differentiated cells with specialized functions like erythrocytes, platelets, T-and B-lymphocytes, myeloid cells, mast cells, natural killer cells and dendritic cells. Many of these mature blood cells are short-lived and need thus to be replaced at a rate of more than one million cells per second in the adult human. This continuous replenishment depends on the activity of hematopoietic progenitor cells (HPCs) and ultimately hematopoietic stem cells (HSCs).

HSCs numbers and HSCs potential are controlled via complex regulatory mechanisms involving tight molecular and cellular control of quiescence, self-renewal, differentiation, apoptosis, and localization as well as cell architecture. Under steady state conditions, HSCs are a largely quiescent, slowly cycling cell population, where only 8% of cells enter the cell cycle per day. However, in response to stress, HSCs exit quiescence and expand and differentiate. The mostly quiescent status of HSCs is thought to be a protective mechanism against endogenous stress caused by reactive oxygen species and DNA replication. In contrary to a common assumption that cell loss is tightly associated with aging, the number of phenotypic HSCs actually increases in both mouse and humans. In the aged bone marrow, there are two- to ten-fold more HSCs present when compared to young. Aged HSCs show under stress, like for example in serial transplantation assays, a diminished regenerative potential as consequence of a lower long-term self-renewal capacity. Aging-associated changes can be attributed at least in part to aging of HSCs. Aged HSCs are deficient in their ability to support erythropoiesis and show a markedly decreased output of cells from the lymphoid lineage, whereas the myeloid lineage output is maintained or even increased compared to young HSCs.

A controversially discussed cell-intrinsic factor driving HSC aging is DNA damage. HSCs are responsible for maintaining tissue homeostasis throughout a lifetime. It is therefore critical for HSCs to maintain their genomic integrity to reduce the risk of either BM failure or transformation. The paradigm of the DNA damage theory of stem cell aging states that aging-associated changes in the DNA repair system in HSCs, together with changes in cell cycle regulation due to increased DNA damage with age, are thought to result in elevated DNA mutations, which then causally contribute to the decrease in HSCs function with age. However, genetic engineering of mutations in most of the genes linked to DNA damage response so far did not result in the "aging-characteristic" initial expansion of the number of phenotypic HSCs, rendering a central role for these genes and the pathways they represent with respect to physiological aging of the hematopoietic system not likely.

Data confirms a mild 2-3 fold aging-associated increase in the mutation frequency in hematopoiesis, the increase though is linear and not exponential with respect to age, rendering a cause-consequence relationship to the exponential increase of leukemia upon aging unlikely. Modeling of aging of HSCs populations based on evolutionary theories also demonstrates that accumulation of genetic changes within HSCs are not sufficient to alter selectivity and fitness of HSCs, and identified non-cell autonomous mechanisms, aka changes in the stem cell niche, as the major selective driving force for aging-associated leukemia. Such conclusions are also supported by the observation that while a 22-fold increase in the mutational load initiated cancer, a modest 2-3 fold increase in mutational load did not result in leukemia initiation. Finally, novel data from our laboratory demonstrated that the quality of the DNA damage response in HSCs does not change upon aging.

Since the accumulation of DNA mutations in HSCs upon aging might not be directly linked to the functional decline of HSCs with age and an aging-associated exponential increase in the incidence of leukemia, what other mechanisms might contribute to these phenotypes? It could already be shown that aging of the HSCs niche and environment plays an important role in selecting and expanding normal and pre-leukemic HSC and HPC clones upon aging. Thus the concept of adaptive landscapes has been recently developed. In this concept, the niche environment of HSCs changes upon aging, influencing the functionality of HSCs. The mutations acquired over time might not influence the HSC per se. In addition to extrinsic factors also intrinsic alterations that are not mutations in DNA might ultimately contribute to HSCs aging. We have recently reported that HSCs change their polarity upon aging, both in the cytoplasm and the nucleus. It might thus be possible that also changes in the general architecture of the cell might contribute to HSC aging. Changes in the 3D arrangement of epigenetic marks and structural proteins might influence for example cell divisions in a way that reduces potential in daughter stem cells, contributing to intrinsic HSC aging. In summary, multiple mechanisms might contribute to aging of HSCs, and ultimately depend on the interplay between cell extrinsic and cell intrinsic factors.


It is known that the practice of calorie restriction, reducing calorie intake while still obtaining sufficient micronutrients, reduces inflammation in animals. This is one of many beneficial changes in the operation of metabolism observed to result from calorie restriction, and this intervention is well documented to extend life spans in short-lived species. Here researchers show that the same effects on inflammation occur in our species. Chronic inflammation rises with aging as the immune system becomes ever more dysfunctional, and contributes to the progression of all of the common age-related diseases. Inflammation is also produced by visceral fat tissue, however, which is one of the reasons why being overweight lowers life expectancy and increases risk of suffering age-related disease. Reduced amounts of visceral fat are probably an important cause of lower inflammation due to reduced calorie intake.

Restricting calories by 25 percent in healthy non-obese individuals over two years, while maintaining adequate protein, vitamin, and mineral intake, can significantly lower markers of chronic inflammation without negatively affecting other parts of the immune system. "Previous studies in animals and simple model organisms over the past 85 years have supported the notion that calorie restriction can increase the lifespan by reducing inflammation and other chronic disease risk factors, but with mixed results about whether it has a negative or null effect on cell-mediated immune responses. This is the first study to examine these effects over two years on healthy, normal- or slightly over- weight individuals and observe that caloric restriction reduces inflammation without compromising other key functions of the immune system such as antibody production in response to vaccines."

After six weeks of baseline testing, which included metabolic measurements to determine their total daily energy expenditure, and blood collection to evaluate inflammation and cell-mediated immunity markers, 220 eligible individuals were randomized into two groups and further stratified by site, sex, and body mass index. The control group maintained their normal diet for the duration of the study, while the test group was provided with support to maintain a high-satiety diet that restricted their calories by 25 percent including customized behavioral guidance. The test group was also given multivitamin and mineral supplements to prevent micronutrient malnutrition. To maintain a 25 percent reduction in calories the test group's calorie prescriptions were reduced three times through the two-year study to coincide with their weight loss based on body fat, and muscle mass calculations.

The research team found that the test group had a significant and persistent reduction in inflammatory markers with no discernible difference in immune responses from the control group at the end of 24 months. However, while reduction in weight, fat mass, and leptin levels were most pronounced at 12 months they were not accompanied by the significant reduction in C-reactive protein and TNF alpha, both indicators of inflammation, until 24 months. This delay suggests that long-term calorie restriction, at least 24 months, induces other mechanisms that may play a role in the reduction of inflammation.


Aging came into being very early in the history of life, resulting from the evolution of strategies to deal with the inevitable accumulation of metabolic waste and damaged molecules in single-celled organisms: operating any sort of machinery produces wear and byproducts, and this is just as true of biological machinery. This can be seen in bacteria today, where cell division can shift most or all of the damage onto one of the daughter cells, using reproduction as a way to dilute waste and damage to maintain a core population that is pristine. The cost is a secondary population that is aging, becoming more damaged over time. These strategies were inherited by multicellular organisms, and show up in, for example, stem cell populations that must maintain themselves for long periods of time. There is a clear spectrum of collective action in mechanisms relevant to aging that reaches from the bacterial collaboration observed in the research here to the highly organized behavior of tissues and their stem cells in our species. At root, it is all about how to deal with damage, and aging is absolutely a matter of damage accumulation.

Microorganisms like bacteria reproduce by growing and dividing into two new bacteria. The older the bacteria, the more defects they have accumulated. When bacteria divide, the two new bacteria look the same, but the question is whether the defects are divided equally between the two new individuals. The researchers performed experiments in the laboratory and made model calculations. They wanted to investigate what was best for the bacterial community. Would it be best to have a colony that was aged to the same degree? Or would it be better for the colony to have the aging defects accumulate in some individuals, while others were free of aging defects and were thus younger?

In the laboratory they studied the bacterial colonies under different conditions and influences. The measurements showed that when a colony was left in peace, the bacteria shared almost symmetrically, so the new individuals were fairly similar with the same number of defects. However, if they exposed the colony to 'stress' in the form of heat or bacteriostatic compounds, cell division was asymmetrical. Now the defects gathered in one bacterium, which then aged and also grew at a slower rate. "What we have found is that the asymmetry of cell division is not controlled genetically. It is a process that is controlled by the physical environment. Through collective behaviour, the bacterial colony that is exposed to stress can stay young, produce more offspring and keep the colony healthier." This is a process that is probably universal and applies to cells in many organisms, including for stem cells. A single individual cell cannot overcome the damage, but the group of cells can do so together. The strength lies in the collective behaviour.


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