Fight Aging! Newsletter, December 18th 2017

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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  • Asking the Right Question: Do You Want to Live Longer, if Good Health is Guaranteed?
  • An Interview with Doug Ethell of Leucadia Therapeutics
  • Idle Thinking on the Outcome when the Political Establishment Notices that Rejuvenation Therapies are Imminent
  • Working on a More Detailed View of Muscle Stem Cell Aging
  • Vote for SENS Rejuvenation Research at Project for Awesome this Weekend
  • Mutational Damage in Long-Lived Brain Cells Correlates with Age
  • Young Plasma Improves Liver Function in Old Rats by Boosting Autophagy
  • Yet More Evidence for Impaired Drainage of Cerebrospinal Fluid in Aging
  • Death Receptors as Biomarkers for Cardiovascular Mortality
  • A Discussion of Cellular Senescence in Age-Related Macular Degeneration
  • Cellular Senescence as a Failed Anti-Cancer Strategy
  • Modest Physical Activity in Old Individuals Correlates with Reduced Cardiovascular Disease Risk
  • The SENS Research Foundation Comments on Calico's Research into Apparent Rejuvenation in Oocytes
  • Pineapple Fund Donates 1 Million in Bitcoins to the SENS Research Foundation
  • Cellular Senescence and Stem Cell Decline in Age-Related Cardiac Hypertrophy Caused by Hypertension

Asking the Right Question: Do You Want to Live Longer, if Good Health is Guaranteed?

Historically, the public at large has shown themselves to be quite disinterested in living longer. Over the years I've been aware of the longevity science movement, it has always been a challenge to expand the community towards greater acceptance, support, and funding. As an example of attitudes we observe, you might look at the Pew survey of attitudes to life extension from a few years back, in which the people surveyed generally agreed that they wanted to live a few years longer than their peers - in the same sort of way as a house should be just a little bit larger than those of the neighbors, to make the point, but not so much so as to be gauche. Humanity is ever petty in the details when conducting any of its grand madnesses; we can see that in even a cursory glance across a lengthy history of what is, by modern standards, a series of sweeping, cruel insanities. Yet we will be judged just as harshly by those yet to come.

Are we asking the right questions? It has long been thought in our community, though gathering supporting evidence for this hypothesis is ever a difficult proposition, that people are on the whole unenthused by the prospect of longevity because they instinctively feel that a longer life would mean becoming ever more decrepit and sick. They think that superlongevity would mean a collapse into an exaggerated caricature of a wizened elder, unable to do anything other than suffer ever more bitterly. This hypothesis for the public rejection of longevity science for so many years was outlined more than a decade ago, and brought up again at the time of the aforementioned Pew study.

Yet "older for longer" is not the outcome that rejuvenation therapies will achieve. It was never the plan, and no researcher has ever claimed to be working towards that end. Functional, working rejuvenation biotechnologies based on periodic repair of the cell and tissue damage that causes aging will instead postpone aging in the young, and restore health and youthful ability to the old. They will turn back age-related disease. The future is not being older for longer, but rather being younger for longer. This has proven to be a very difficult message to deliver; it has been repeated over and again, and never seems to stick.

Yet in the past few years, a few small surveys have shown that if you ask the right questions in the right context, then ordinary, everyday people will say that they want greater longevity. The right question is whether or not one would want to live longer if health is guaranteed for those additional years. Focus on the health, and people inch towards wanting more time. We have yet to collectively figure out how this should translate into our advocacy for rejuvenation research - it isn't quite as straightforward as one would hope. After all, the message we have delivered for years is exactly that we want to extend health as well as overall life span, and that in fact the only practical way to achieve longevity is to provide greater and longer-lasting health.

People say they want to live longer - if in good health

Longevity is a such a pervasive goal in public health policy and even popular media, but individually most people only want to live long lives if they will be healthy, according to a new study. "People in three cultures from around the world are reluctant to specify their desired longevity. To me this is interesting because longevity is such a valued public health objective, but at the individual level, longer lives are a goal 'only if' I remain healthy."

The results of these interviews reinforce previous findings from this research group that revealed many older adults - in various cultures - think of life as not a smooth continuum of time but segmented into different states. The researchers refer to four "ages" or stages of life, including the third age, which is an active retirement where people leave traditional work and family roles, followed by the fourth age. "People seem to view one part of the future as wanted and another as not wanted, typically the 'fourth age' which is basically the period when one might experience a disability or a potential health decline."

For this study, the researchers interviewed 30 people in each country, and they recruited the sample with sex and age quotas to reflect a range of experience with retirement. About one-third of respondents did not express aspirations for a longer life. "Some felt their lives had already reached a stage of completion, and others as a form of fate acceptance." A larger number of respondents did mention they wanted to extend their lives. Yet less than half of that group noted a specific amount of time they desired to live. The strongest opinion among that group was the desire to live longer only if they maintained their current or what they deemed to be acceptable levels of health.

Is longevity a value for older adults?

The human desire to prolong life and postpone death has a long history. In modern times, population longevity, as measured by the statistical estimate of life expectancy, is taken as a measure of nations' progress and development. The promotion of longer lives, principally through reduced mortality at younger ages, is a prominent goal of public health policy and research. Academic units concerned with gerontology have been adding the term longevity to their titles - a center for longevity, a longevity institute. Presumably, this skirts the negative connotation of aging and aligns the organization with a desirable end. Longevity can be an organizational mission in a way that aging cannot.

At the same time, longevity is not without shadows because modern medical care can maintain lives that are felt to be too long. At the population level, rising numbers of long-lived persons can pose societal challenges. Sheer longevity is also qualified by the age from which it is projected, for the hope of a long, full life is one thing at age 10 or age 20, but another in the seventh, eighth, and further decades of life. This latter stretch is the concern of our paper.

Longevity counts time from some point forward but it is also an individual perception about time left before the ultimate deadline of death. Deadlines are motivators and none more so than death. The question about future time left and one's goals can be reshuffled to ask another question: whether time left is itself a goal. Do older people value longevity for themselves? That is the focus of our analysis, based on conversational interviews with older adults in three cultures. The study of "desired longevity" (vs. expected longevity) has been quite limited, which is particularly puzzling given such theoretical interest in the end of life and gerontology's tacit assumption that most people want to live a long life. On the one hand, the modern promise of increasing health and vitality predicts an embrace of longevity. On the other hand, worries about late-life frailty and illness may make people hesitate to welcome extended lives.

Survey techniques have been used to ask adults about desired longevity, this in order to examine the distribution of replies (always contingent on respondents' ages) as well as associated factors that may explain the replies. One feature of these findings is a curious amount of non-response (refused to answer, don't know) to questions about desired longevity. Distributions of numerical answers about desired longevity also display another pattern: the "age heaping" of replies at five-year intervals, such as 80, 85, 90, etc. Taken together, approximate-age replies along with nontrivial amounts of response refusal suggest that older adults' longevity goals may not be sufficiently measurable by survey techniques.

In this study, we asked people in an open-ended way about their desire for longer life: Would you like to have more time? What age would you like to become? This was something more specific than asking about a preference for survival without reference to any length of time; about one's plans for the future; or whether people see the future as open or limited, as in studies of future time perspective. Our attempt was to discover whether there were preferred temporal spans with which older adults framed their futures and plans.

The two-question series about extra years and desired age ("How old would you like to become?") was designed to generate talk about extended life. Free to answer the questions in their own way, participants could say any number of things about longer life during the interviews. Amid these responses, our analysis capitalized on a pattern that was strongly apparent. When it came to desired longevity, most people did in fact want to live longer, but few supplied a numerical answer that was not also conditional on the maintenance of continued good health. The majority preference was for longer life but "only if."

The health stipulation was cited by three-quarters of the 57 cases who desired longer lives. This stance was a prominent pattern, and in the replies to our questions there were certain similarities: the conditional expressions (if, as long as, it depends), the anecdotes about others in poor health, and the reference to medical discourse about quality of life. The bundling of longevity desires with a health stipulation was common to all three research sites. Such similarities suggest to us that longevity expectations, while personal expressions, are also generated from social discourse of a kind that exists in the three cultures and that yields shared styles of talk about extended life. We posed questions to individuals and each replied in his or her own way, yet there was a consistent, cultural convention favoring health-qualified longevity.

An Interview with Doug Ethell of Leucadia Therapeutics

Leucadia Therapeutics is a startup company focused on Alzheimer's disease, noteworthy for being one of the few ventures to depart from the orthodoxy of immunotherapy to clear amyloid and tau protein aggregates. The Leucadia staff are working on the establishment of a faster and cheaper path to an effective therapy for Alzheimer's that nonetheless still addresses the deeper causes of the condition.

Leaving the mainstream is perhaps more of a challenge in the Alzheimer's research community than elsewhere; the US National Institute on Aging has for years been primarily an Alzheimer's concern, and the biggest of Big Pharma entities have made equally large investments in the field over that same period of time. As a result there is a great deal of institutional inertia to continue to push forward with large and costly amyloid clearance strategies that are only incremental improvements on those that have failed by the dozen in the past. Publicly advocating any other path can have a negative impact on career prospects when embedded in such a large and structured system. However, going on for two decades in to these efforts, and with no practical therapy yet to show for the billions spent, the Alzheimer's heretics are starting to become more organized and influential.

It is undeniably the case that protein aggregates of amyloid and tau are important in Alzheimer's, and if they were removed safely and efficiently, patients would benefit. But these forms of metabolic waste are not the whole story; how is it that their presence only grows in the aging brain? Is some combination of declining immune function and persistent microbial infection a significant source of protein aggregates, for example? The evidence for that hypothesis is quite compelling. And in the case of Leucadia's work, are protein aggregates observed in the aged brain there due to a failure of drainage systems? The cerebrospinal fluid is thought to carry these aggregates away for disposal elsewhere in the body, but the pathways used fail with age. Thus the slow buildup of amyloid and tau with age might be thought of as a progressive failure of clearance of these waste products, a structural and fluid flow problem, rather than a cellular problem of greater production.

This is an attractive hypothesis, not least because testing it should be a comparatively low-cost, rapid effort - very far removed from the vast expense of current amyloid clearance approaches. Leucadia is the company formed to carry this initiative forward, now that the research and evidence gathered to date has reached the point of making that leap. The Methuselah Fund and a number of other angels and organizations have invested in Leucadia Therapeutics to date, Fight Aging! among them. Since the latest round of funding is now complete, I recently had the chance to talk to founder Doug Ethell and ask some questions about the company and the approach to Alzheimer's disease.

How did Leucadia come about? What led you down this interesting path of research and development?

I'd been undertaking Alzheimer's disease research as a medical school professor for well over a decade and I gave a talk at the Rejuvenation Biotechnology Conference in 2015. David Gobel, director of the Methuselah Foundation, was in the crowd and we got to talking at a poster session later that day. Dave said the foundation would like to fund some of my Alzheimer's research, if I wanted to start a company with that money. I founded Leucadias Therapeutics a few months later and the Methuselah Foundation made an equity investment.

If you could provide an overview for the audience here of the Leucadia approach to Alzheimer's disease and the underlying rationale?

Our approach to Alzheimer's disease has been to take a step back from molecular interactions and see where we are in the forest. The 'Peculiar disease of the cerebral cortex,' that Alois Alzheimer described over a hundred years ago is notable because a significant part of the pathology forms between cells in what is called interstitial spaces. In the brain, those spaces are filled with cerebrospinal fluid, or CSF, that clears away metabolites and debris that won't go blood vessel walls. We are interested in how CSF clears away regions of the brain where Alzheimer's disease starts first, with the idea that those routes are breaking down.

Think of it a small creek in the forest. Oak trees overhand the creek and occasionally a leaf falls in and gets carried away. In late summer, before the leaves change, the creek starts to dry up and leaves are carried away slower and slower, until a threshold is reached where they form a mat and then none of them are carried away. The plaques in Alzheimer's disease are mats of amyloid-beta. As it turns out, Alzheimer's disease pathology appears first in older parts of the cerebral cortex, called allocortex, where CSF is handled very differently than in the neocortex. The allocortex is intimately connected to the olfactory system and CSF that clears interstitial spaces in the allocortex drain from the brain to the nasal cavity thorough a porous bone called the cribriform plate.

With age apertures in the cribriform plate become occluded, and that can be accelerated by life events such as head injuries and broken noses. The net effect of those occlusions is an age-dependent slowing of CSF outflow, resulting is less efficient CSF-mediated clearance of the allocortex. Those leaves (the amyloid) start to accumulate and gum up the works, leading to in the accumulation of factors that cause Alzheimer's disease pathology. At Leucadia Therapeutics, we're developing a way to restore the clearance of CSF from those areas, with a product we call Arethusta. The name is derived from Greek mythology; the water nymph Arethusa was being pursued by the river god, Alpheus. Artemis let her her escape by helping her turn into a hidden underground creek. Arethusta creates a hidden stream so people can escape Alzheimer's disease.

You just raised your first round; what will be achieved with the funding now in hand?

This raise provides a tremendous boost as it allows us to hire more people, expand on our intellectual property, resolve engineering and manufacturing issues, and refine our regulatory strategy. Our goal is to start clinical trials in 2019 so there is plenty to do. The raise adds quite a bit of momentum.

In recent years I recall some independent research from other groups to support drainage issues as a significant cause of protein aggregation in the brain. Which of these results do you think add the most weight to your work?

That work involves CSF uptake from surface of the neocortex by structures that have been called glymphatics. Very interesting stuff, but a bit different than that allocortex and cribriform plate system we focus on. I published a hypothesis paper about the CSF clearance and Alzheimer's disease connection in a 2014 paper in the Journal of Alzheimer's Disease, after 2 years of editorial review. I first reasoned this mechanism in 2010. In comparison, the first glymphatic paper appeared in 2013.

A lot of alternative theorizing on the causes and progression Alzheimer's is taking place these days, people challenging the primacy of the amyloid hypothesis. Have any of these caught your eye as compelling?

Amyloid deposits (plaques) are a definitive feature of Azheimer's disease pathology, so it is certainly involved. The question is, are those deposits cause or effect? The amyloid hypothesis states that amyloid accumulations cause Alzheimer's disease, but my perspective is that plaques are simply effects, manifestations if you will, of an underlying condition that allows them to form. Ten billion has been spent on many failed clinical trials that centered on the amyloid hypothesis, and some are still ongoing, but none of them addressed the underlying cause of amyloid accumulation. Even if they were successful in clearing some plaques, they'll come right back. Leucadia's approach is to treat the underlying cause and let the brain take care of amyloid clearance by itself.

I feel that the long absence of tangible process towards therapies for Alzheimer's disease has led people to fixate on tiny gains rather than the goal of a cure. But what does realistic success look like in the fight against Alzheimer's over the next decade or so?

I spent over a decade looking at amyloid effects on neuronal death and neuroimmune interactions. Over that period, it got to be more and more depressing to watch an unbroken string of failed clinical trials up-close, played out in slow motion. The ball was pushed down the field a few yards at a time. It didn't go anywhere ... not for 25 years. There was a concerted effort by funding agencies to keep everyone viewing Alzheimer's disease research the same way. Neitzsche had it right when he wrote that the prevailing interpretation is a question of power and not truth.

What the Alzheimer's field desperately needed, and still needs, is dissenting voices that say, "There's something we're missing here. Something big." I'm one of those voices and let me tell you, when you rock the boat by challenging dogma, well-connected people whose livelihoods are built on that dogma take great offense, even if they've been proven wrong time and again. As for progress over the next decade, advances won't come in dribs and drabs but in bursts of activity. At Leucadia, we're developing a very significant advance that takes the field in an entirely different direction.

If this all works out well, and the Leucadia therapy does produce the desired outcome in patients, where next?

We are absolutely focused on slowing the relentless progression of Alzheimer's disease pathology. That's a pretty tall order, and once we get there, then we'll see about setting some new goals.

Idle Thinking on the Outcome when the Political Establishment Notices that Rejuvenation Therapies are Imminent

The political establishment is a plague upon the land; this is generally true of any era. We are fortunate to live in an age in which the level of impact is less brutal and more bureacratic than it has been, and in a region in which the level of wealth is high enough to allow most people to live comfortably despite the constant wars and vast waste of the powers that be. There is, importantly, sufficient space in our society left unpillaged and uncontrolled for technological development to take place at a fair pace. Technology determines near everything about our lives, the degree to which they are worth living, the shape of our societies, and the pace at which we age to death. Faster progress is a great and wondrous thing. Yet, sooner or later, new technologies become promising enough to come to the attention of the political establishment, at which point the challenges of development turn into the challenges of fending off various genteel and less genteel forms of banditry and sabotage.

I noticed the article below in the political press today; it is surprisingly informed in its details, if not some of its premises, given the source. Political journalism is just about the worst of the press industry, and "worst" in this context has become a very low bar of late; the stentorian propaganda of the past has given way to a sort of tawdry crab bucket mass hysteria. As to the article here - should we start to see more of this sort of thing, repeated more often, that might mark the beginning of an interventionist establishment in the matter of longevity science. This probably isn't something to be welcomed: the first instinct of that establishment is to put a halt to any form of change, the second is to tax every new thing regardless of the damage done, and the third is to restrict and control access, limiting it to those with connections.

Where the attention of the establishment results in funding wrestled from the pool generated by involuntary taxation and devoted to a specific cause, such funds are invariably largely diverted into useless activities and waste, or used to prop up unrelated activities carried out by the politically connected. Look at just how little the US National Institute on Aging has accomplished over the last twenty years: so much funding, so many studies, so many programs, and yet where are the results in terms of years of human life span gained? Remaining life expectancy at 60 has moved very slowly upward in a trend unrelated to public research expenditure. The future of additional years of healthy life will be enabled by philanthropy, charities, and startup companies using a tiny fraction of the NIA budget, based on science that was sufficiently explored to get started thirty years ago.

Meanwhile, the first instinct of the propagandists of the political press is to ask how any improvement to the suffering of the elderly might affect the balance of votes or entitlement payments or political parties or current regulations. One gains the distinct impression that people, that suffering, that death really don't matter all that much in their eyes, save for how they are seen at a distance from the city on the hill. It is ugly, I think.

We could do worse than to shun all politicians and their creatures, and work on doing the good that we want to see in the world ourselves. The political establishment exploits and thrives by co-opting our worst instincts, however, and as the present state of the world demonstrates, this strategy is highly effective. As a choice in life, I'd advise reading more Thoreau and Spooner and less of the press as it stands today - advice that was no doubt just as relevant a few centuries past as today. Engaging with the political establishment is a poisoned chalice, one that drags down the productive and ensnares them in a system that does little but generate waste and mockery. The real work is done elsewhere.

Why a drug for aging would challenge Washington

What if you could live to 85, 90 or even 100 with your mental faculties intact, able to live independently without debilitating conditions until the last year of your life? What if just one medical treatment could stave off a handful of terrifying ailments like heart disease, cancer, and Alzheimer's? The idea of a pill for aging sounds like science fiction or fantasy. But the hunt is increasingly real. The leading approach even has a name: senolytic drugs. The science is still far from proven, but the prospect of a drug for healthier aging has already attracted significant investment from well-known drug companies, and the first human studies of anti-aging drugs are getting underway. If the results pan out, the first drugs could be available in as little as a decade.

As the research moves forward, however, it is raising a series of new questions that both medicine and regulators will need to confront. And the most complex questions arise around exactly the issue that makes the field so exciting: The notion of treating the aging process itself. There's never been a drug for aging in part because "aging" isn't considered a disease by the FDA. Should it be? What signs and symptoms of aging is it OK to medicalize? And if a drug were approved for aging - something that every human experiences - who would bear the costs for a pill that potentially could be prescribed for every person alive? And those aren't the only questions. It turns out that evaluating the science is also complex, partly because it's hard to measure whether a drug is fundamentally changing the course of human aging. It's also ethically fraught: Aging is a normal human process, so testing a drug for "aging" means that otherwise healthy people would be subjected to its inevitable side effects, for unproven benefit. How long a trial would even be needed? Regulators aren't close to answering this kind of question.

So far scientists are tiptoeing around many of these complicated issues by testing these drugs only in very sick people, studying to see if they help treat deadly diseases with few other treatment options. The idea is to get a potential anti-aging drug approved first under more traditional protocols without having to tackle the thornier, longer-term questions raised by the idea of treating "aging." However, doctors are unlikely to wait for answers to the larger questions around these drugs before they begin to prescribe them to patients. As soon as a senolytic or other anti-aging drug is approved for any purpose, physicians are allowed to start prescribing them to their patients for any condition they want, and likely will.

Anti-aging science has long been viewed with skepticism, a "soft" science more often the province of quacks selling dubious potions than serious medical researchers. But senolytic drugs are changing that. The idea behind them is to attack senescent or "zombie" cells - cells that have stopped dividing, but aren't dead. Senescent cells release toxic and inflammatory compounds that impair the function of healthy cells, and scientists believe they help drive the decline of important body tissue, like organs. Scientists have found that the number of senescent cells increases with aging in mice, monkeys and humans; they're associated with chronic conditions like diabetes, heart disease, cancer, arthritis and overall frailty. In small mammals, scientists have found that killing senescent cells delays and prevents many age-related conditions and diseases. In animal testing, senolytic agents have also successfully treated conditions including heart dysfunction, lung diseases, diabetes, osteoporosis, and damage induced by radiation. Clearing senescent cells from adult mice has even been shown to increase median lifespan.

Interpreting results of human anti-aging studies won't be easy. To prove that a drug prevents aging, companies will ultimately have to find changes in people that aren't known to be affected by disease. For example, skin gets lined and wrinkled and loses elasticity over the years - but that doesn't cause illness. Muscle mass also decreases with age. If a company could show that the drug alters these changes, "that's a pretty good argument that you are affecting aging." But the potential for approving anti-aging drugs on the basis of these signposts is already triggering the alarm bells of bioethicists. They fear companies' pressure to approve these medicines quickly could lead to patients being exposed to medicines that offer only superficial benefits - and possibly hidden harm. This concern over "indication creep" - the tendency for drugs to be prescribed for problems they weren't approved to treat - is another trigger for ethicists. Many of the companies testing the first senolytic drugs aren't trying to get them approved for aging but instead are targeting diseases where they believe senescent cells play a role.

Because of the enthusiasm around the drugs, researchers are already concerned about anecdotal stories of people wanting to use the medicines to treat aging before they're ready for prime time. Paul Robbins of the Scripps Institute said some senolytics are natural products or older chemotherapy drugs. He's heard of clinics already being set up overseas to provide drugs like these as anti-aging treatments, even without evidence they work, or data on the right dosage. The hype is dangerous, warns James Kirkland, whose employer, the Mayo Clinic, is investing in senolytics. "Anything can go wrong along the way. If you could caution your readers, tell them absolutely not to take these drugs until trials are done, because this is a new way of doing things. We don't know if they are going to work and we don't know what the side effects are."

"If you demonstrate that these drugs work, probably everybody is going to want to take the drugs. So then the question becomes a question of cost," said Steven Austad, scientific director of the American Federation for Aging Research. A high-priced drug taken by everyone could place a burden on an already strained health care system, which presumably would have to pay for everyone to take the drug for many decades. And the longer people live, the longer they will draw from government benefit programs. "Politically, this is a hot topic," said Laura Niedernhofer of the Scripps Research Institute. "Someone who does not dig in deeply thinks immediately, 'Oh my God, lifespan is going to extend and Social Security is already in bad shape, and so how are we going to handle this'?" Niedernhofer is an optimist, however, arguing that the costs of anti-aging therapies will more than pay for themselves, their costs offset by the fact that healthier people will require less medical care in the final years of their lives.

Another concern, said University of Minnesota bioethicist Leigh Turner, is pushing resources toward an unproven idea, instead of toward tried-and-true public health programs that have already been proven to extend lives and improve health, like providing clean drinking water or better waste management. But "nothing in our world is equitably distributed - not money, not food, not water," counters S. Jay Olshansky, who studies aging at the University of Illinois at Chicago School of Public Health. These inequities aren't an excuse to stop pursuing an idea that could improve health for everyone. And the potential high cost shouldn't stop the research, he says: Richer countries have pursued a lot of expensive health interventions that were at first not affordable, or are still not affordable to parts of the developing world.

Working on a More Detailed View of Muscle Stem Cell Aging

The population of stem cells that supports muscle tissue is one of the better studied classes of such cell. Stem cells enable tissue maintenance and regeneration by delivering a supply of new daughter somatic cells that can multiple to make up losses, and through signaling that alters cell behavior. This activity declines with advancing age, however, with stem cells spending ever more of their time in a quiescent state. This is thought to be a response to rising levels of cell damage and tissue dysfunction, behavior that evolved because it serves to reduce the risk of cancer over a period in which our ancestors were under selection pressure for greater longevity. Cancer is a numbers game: more damage, more cell replication, and more cells all raise the odds of a cancerous mutation taking place.

Up close, the dynamics of stem cell behavior within the trend of age-related decline are anything but simple and uniform. The more data that researchers obtain, the more complexity they uncover. Biology is rarely as simple as the present understanding, and never as simple as would be convenient for the development of new therapies. Nonetheless, reliable manipulation of muscle stem cells is an important goal because it should enable some degree of reversal of age-related loss of muscle mass and strength, the condition known as sarcopenia.

There are many different layers of muscle biology at which benefits might be obtained. These range from the brute force approach of myostatin blockade, to put a thumb on the higher level controlling mechanisms that govern when muscle growth takes place at all, to adjusting the internal behavior of stem cells to make them more readily active, to repairing the underlying cell and tissue damage that causes stem cells to retreat from youthful levels of activity. Some of these methodologies are closer to realization than others; as a general rule, therapies that bypass the need for more detailed knowledge of these stem cell populations can make it to the clinic more rapidly.

Researchers Track Muscle Stem Cell Dynamics in Response to Injury and Aging

"Our study is one of the first to look at muscle stem cells in their native tissue with resolution at the level of a single clone. This allowed us to probe the dynamic heterogeneity of the cells, a measure of their flexibility to respond to exercise, injury, and the normal wear and tear that occurs with aging. Using this approach, we found surprising differences in the degree to which stem cells can maintain this heterogeneity, depending on what they are asked to do."

Adult muscle stem cells are essential for repairing and regenerating muscle throughout life. These cells are located between muscle fibers and exist as a heterogeneous population that need to "self-renew" to maintain the stem cell population, as well as differentiate into myogenic cells that proliferate, differentiate, and fuse to create new muscle fibers. "Here, we focused on studying how the pool of muscle stem cells responds to age or after an injury to the muscle. Our goal is to understand how stem cells uniquely cope with or yield to these different pressures. Then, we can use this information to create new approaches designed to specifically prevent muscle stem cell loss and/or dysfunction linked to sarcopenia or in association with muscle diseases that are characterized by chronic tissue damage, such as dystrophies."

The research team followed the self-renewal capacity and range of progeny produced by individual stem cells. "The results were quite different from what we expected - aged muscle stem cells maintained a diverse assortment of cells in the overall pool, despite being less able to proliferate and multiply sufficiently. The outcome was flipped when we caused an injury and watched how the pool responded to tissue damage. In the case of injury, the stem cell pool becomes less diverse, but maintains its proliferative capacity. Our findings lead to several interesting questions about the potential causes of these observed differences."

Muscle Stem Cells Exhibit Distinct Clonal Dynamics in Response to Tissue Repair and Homeostatic Aging

Emerging evidence supports a significant functional heterogeneity in adult stem cell compartments. Single-cell studies in several tissues have revealed a range of behavioral capacities with regard to proliferation, self-renewal, and differentiation potential. This heterogeneity has been proposed as a beneficial feature of stem cells, which must rapidly adjust to the changing demands of their host tissue. By maintaining a spectrum of functional abilities, stem cells are better prepared to respond to various tissue repair scenarios while contributing to homeostatic turnover.

Single-cell lineage tracing offers a powerful means of studying functional heterogeneity in stem cells. Prior lineage tracing studies in vivo have demonstrated a broad array of clonal histories in different tissues. Modeling efforts leveraging these clonal datasets have begun to describe the dynamics of stem cell hierarchies. Intriguingly, several groups have described a loss of clonal complexity, or the diversity of stem cells in a pool or niche with distinct clonal origin, with accumulated stem cell activity. However, much of this work has taken place during youthful tissue homeostasis, and thus, little is known about how different environmental settings may alter the rate of this decline over time, including aging or wound healing. Moreover, the impact that reductions in clonal complexity may have on functional heterogeneity and stem cell behavior is still unclear.

To answer these questions, it is critical to study both aspects of individual stem cell behavior as part of the greater whole, particularly within a readily manipulated host tissue. To this end, skeletal muscle is well suited to examine changes in stem cell heterogeneity in response to disruptive or pathological settings. Skeletal muscle contains a bona fide stem cell population, termed muscle stem cells (MuSCs) or satellite cells, distributed throughout the tissue in their niche, where they remain poised to activate and contribute to cellular turnover.

To determine the impact of homeostatic aging and tissue repair on MuSC clonal complexity, we longitudinally assessed individual MuSC fate over time using in vivo multicolor lineage tracing. Surprisingly, we demonstrated that clonal complexity is largely preserved with homeostatic aging despite reductions in proliferative heterogeneity. Conversely, biostatistical modeling revealed that MuSCs undergo symmetric expansion and stochastic cell fate acquisition specifically during tissue repair, predicting neutral competition between clones resulting in clonal drift, or an increasingly small number of dominant clones. Accordingly, we observed that sustained regenerative pressure resulted in a progressive reduction in clonal complexity. Overall, this work establishes the importance of context in defining the principles underlying stem cell dynamics in skeletal muscle.

Vote for SENS Rejuvenation Research at Project for Awesome this Weekend

This year's Project for Awesome runs from December 15th to 17th. It is a short and energetic festival of fundraising and video creation in which people give and vote on which causes to distribute the funds to. The event has been growing from its modest start for the past decade. The world could use more such initiatives, and I encourage you to join the festivities and vote for videos that take your fancy at Project for Awesome before the end of the week.

The very first Project for Awesome was organized in 2007, and has been held each December since. This year, Project for Awesome is December 15th (beginning at 12:00pm EST) to December 17th (ending at 11:59am EST). During Project for Awesome, thousands of people post videos about and advocating for charities that decrease the overall level of world suck. As a community, we promote these videos and raise money for the charities. In 2016, the community raised over 2,000,000, including several generous matching donations. The donations were split between two organizations chosen by John and Hank along with twenty charities chosen by the online video community.

This year supporters of the Life Extension Advocacy Foundation and SENS Research Foundation have assembled a fair few video submissions to put forward the case for charitable funding of rejuvenation research programs. Vote for them! This continues a fine tradition for our community, as the best of the organizations involved in advocacy and research to have emerged over the past twenty years were built atop the collaborative philanthropy of ordinary folk. Great progress has been achieved because we came together to give individually modest amounts, and then persuade others to do the same and more. We have led the way. The reason that we can celebrate sizable donations to the cause of defeating age-related disease, such as the one announced earlier today, is that our activity has made this a plausible and noted cause.

The defeat of aging makes sense. The overwhelming majority of the pain, illness, and death in the world is caused by aging: more than 100,000 lives lost every day, while tens of millions more suffer with little hope of help. Beyond the human toll, the economic cost of this constant, massive wave of debility and loss is staggering. Our societies tie themselves in knots attempting to pay the vast sums it would require to merely cope with the consequences of aging - not do anything about it, just cope. Yet for less than the cost of a sports stadium, or the latest stealth bomber, or twelve months of the US National Institute on Aging budget, a complete set of biotechnologies to control aging by repairing its causes could be realized in just a handful of years. This is the promise of the SENS rejuvenation research programs, a very cost-effective approach to the problem of aging. Take the known causes of aging, the cell and tissue damage that causes aging and age-related disease, and repair them.

We would be foolish not to work towards this goal.

Mutational Damage in Long-Lived Brain Cells Correlates with Age

Is random mutational damage to nuclear DNA a sizable cause of aging? The consensus in the scientific community on that question is that it is an important cause, with the theory being that this results in sufficient change in protein production and cellular behavior to produce degraded function. That consensus is challenged, however, and at present there is a distinct lack of supporting evidence for either position, even given a few intriguing studies from recent years. It is well known that mutation level correlates with age, and methods of slowing aging also slow the increase of mutational damage. So every aspect of aging does in fact tend to correlate with mutation load, but that doesn't necessarily tell us anything about cause and effect - and that is the case here.

Aging in humans brings increased incidence of nearly all diseases, including neurodegenerative diseases. It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. Markers of DNA damage increase in the brain with age, and genetic progeroid diseases caused by defects in DNA damage repair (DDR) are associated with neurodegeneration and premature aging. While analysis of human bulk brain DNA, comprised of multiple proliferative and non-proliferative cell types, revealed an accumulation of mutations during aging in the human brain, it is not known whether permanent somatic mutations accumulate with age in mature neurons of the human brain. Here, we quantitatively examined whether aging or disorders of defective DDR results in more somatic mutations in single postmitotic human neurons.

Somatic mutations that occur in postmitotic neurons are unique to each cell, and thus can only be comprehensively assayed by comparing the genomes of single cells. Therefore, we analyzed human neurons by single-cell whole-genome sequencing (WGS). Since alterations of the prefrontal cortex (PFC) have been linked to age-related cognitive decline and neurodegenerative disease, we analyzed 93 neurons from PFC of 15 neurologically normal individuals from ages 4 months to 82 years. We further examined 26 neurons from the hippocampal dentate gyrus (DG) of 6 of these individuals because the DG is a focal point for other age-related degenerative conditions such as Alzheimer's disease. Finally, to test whether defective DDR in early-onset neurodegenerative diseases is associated with increased somatic mutations, we analyzed 42 PFC neurons from 9 individuals diagnosed with the progeroid diseases Cockayne syndrome (CS) and Xeroderma pigmentosum (XP).

Our analysis revealed that somatic single-nucleotide variant (sSNVs) accumulated slowly but inexorably with age in the normal human brain, a phenomenon we term genosenium, and more rapidly still in progeroid neurodegeneration. Within one year of birth, postmitotic neurons already have ~300-900 sSNVs. Three signatures were associated with mutational processes in human neurons: a postmitotic, clock-like signature of aging, a possibly developmental signature that varied across brain regions, and a disease- and age-specific signature of oxidation and defective DNA damage repair. The increase of oxidative mutations in aging and in disease presents a potential target for therapeutic intervention. Further, elucidating the mechanistic basis of the clock-like accumulation of mutations across brain regions and other tissues would increase our knowledge of age-related disease and cognitive decline. CS and XP cause neurodegeneration associated with higher rates of sSNVs, and it will be important to define how other, more common causes of neurodegeneration may influence genosenium as well.

Young Plasma Improves Liver Function in Old Rats by Boosting Autophagy

In the research here, injections of blood plasma from young rats are shown to improve autophagy and liver function in old rats. This is interesting given the so far mixed evidence for young to old plasma transfer to be beneficial. There is, however, a history of research to show that increased levels of the cellular maintenance processes of autophagy can improve liver function in old rodents. Autophagy normally declines with age, and this appears to contribute to a variety of issues, such as loss of stem cell activity. You might recall that increasing the number of receptors on lysosomes in old rats can improve liver function; lysosomes are the portion of the autophagic infrastructure that break down damaged proteins and structures, and they function more effectively when equipped with more receptors.

The young to old plasma transfusion strategy is an outgrowth of parabiosis research in which the circulatory systems of a young and old individual are linked. This worsens measures of aging in the younger individual and improves them in the older individual. Current opinion in the research community is divided between the hypothesis that factors in young blood improve cell and tissue function, or that factors in old blood harm cell and tissue function. There is evidence for both sides, and the balance has swung back and forth over the past few years.

The study here adds something new, meaning the evidence for beneficial effects of plasma transfer to be primarily mediated by increased autophagy, at least in the liver. This has been demonstrated for calorie restriction and a number of related methods of modestly slowing the aging process in laboratory species - autophagy is clearly important in the hierarchy of biological systems that determine the relationship between environmental circumstances and natural variations in the pace of aging. Given that those approaches fail to extend life in humans and other long-lived species to anywhere near the same degree as occurs in short-lived species, one might speculate that the same unfortunate relationship will apply here. Parabiosis might turn out to be just another way of manipulating some of the beneficial cellular reactions to calorie restriction, achieving the same poor results on life span in humans, but possibly still a useful degree of other benefits to health.

Recent studies showing the therapeutic effect of young blood on aging-associated deterioration of organs point to young blood as the solution for clinical problems related to old age. Given that defective autophagy has been implicated in aging and aging-associated organ injuries, this study was designed to determine the effect of young blood on aging-induced alterations in hepatic function and underlying mechanisms, with a focus on autophagy.

Aged rats (22 months) were treated with pooled plasma (1 ml, intravenously) collected from young (3 months) or aged rats three times per week for 4 weeks, and 3-methyladenine or wortmannin was used to inhibit young blood-induced autophagy. Aging was associated with elevated levels of alanine transaminase and aspartate aminotransferase, lipofuscin accumulation, steatosis, fibrosis, and defective liver regeneration after partial hepatectomy, which were significantly attenuated by young plasma injections.

Young plasma could also restore aging-impaired autophagy activity, while inhibition of the young plasma-restored autophagic activity abrogated the beneficial effect of young plasma against hepatic injury with aging. In vitro, young serum could protect old hepatocytes from senescence, and the antisenescence effect of young serum was abrogated by 3-methyladenine, wortmannin, or small interfering RNA to autophagy-related protein 7. Collectively, our data indicate that young plasma could ameliorate age-dependent alterations in hepatic function partially via the restoration of autophagy.

Yet More Evidence for Impaired Drainage of Cerebrospinal Fluid in Aging

Leucadia Therapeutics is one of the young companies shepherded by the Methuselah Fund, in this case working on an Alzheimer's treatment predicated on a theory of the disease that views impaired drainage of cerebrospinal fluid as an important cause. Alzheimer's disease is a condition characterized by a build up of protein aggregates, and one of the ways in which the brain normally removes these aggregates is through drainage of cerebrospinal fluid out into the body. The passages for that drainage, like most other bodily systems, fail over time. An increasing amount of supporting evidence for this to contribute to age-related disease has emerged in recent years.

In the example here, researchers arrive at the consideration of failing cerebrospinal fluid drainage from a quite different position, the study of hydrocephalus, or excess accumulation of cerebrospinal fluid in the brain. This is not uncommon in older individuals, and there is a noted overlap with Alzheimer's disease - it is not hard to join the dots between these two areas of research. Evidence for one tends to support the other, and the various research groups exploring the physiology of drainage in the brain may well wind up converging on the same destination.

Syndromes of progressive neurological disturbances in the setting of normal cerebrospinal fluid (CSF) pressure have been termed as "normal pressure hydrocephalus" (NPH). Patients without known precipitating factors are diagnosed with idiopathic NPH (iNPH), the mechanism of which remains largely unknown. However, the steep increase in the incidence of iNPH in individuals who are 60 years of age or older suggests an association with aging. Some recent studies have emphasized on the primary role of abnormal water/blood drainage or viscoelasticity changes in the brain parenchyma as the likely mechanisms underlying age-related development of the disease.

Nevertheless, since the initial reports, the immediate improvement in symptoms following removal of CSF through a lumbar tap has not only been useful for clinical purposes, but has also suggested abnormal perfusion as the direct cause of clinical manifestations. Despite the body of evidence demonstrating changes in blood flow following the "tap test" (TT), there are no established diagnostic criteria based on blood flow imaging. It is critical that iNPH be diagnosed sufficiently early to enable CSF diversion using a shunt where appropriate to prevent irreversible damage. Thus, there is a need for novel, non-invasive techniques to assess this condition in the elderly population.

Recently, mapping the low-frequency phase in a blood oxygenation level-dependent (BOLD) signal time-series has been proposed as a clinically useful biomarker in cerebrovascular diseases. In the present study, we acquired resting-state BOLD magnetic resonance imaging (MRI) scans before and after a spinal TT, and compared the BOLD lag maps to evaluate the effect of treatment on brain perfusion in subjects with iNPH.

We observed an abnormal phase in the periventricular region where the deep veins converge. Under healthy conditions, the phase or relative drainage time in this region consistently exhibited a late venous phase. This abnormally long drainage or "wash-out" time in iNPH was normalized by TT, while the global mean of the phase remained stable. Collectively, these results permit an interpretation that a part of the deep venous system is drained by collaterals in iNPH instead of the normal route via the internal cerebral veins. The broad change after TT may reflect the normalization of this state, involving a change in the drainage pattern. Altered venous drainage has been observed in chronic NPH and the periventricular area may be one of the commonly affected sites of this venous inefficiency.

The fact that both normal aging and abnormalities in iNPH (which is corrected by TT) involve deep venous insufficiency may have etiological implications, as this suggests altered venous drainage in the absence of pathological ventricular dilation. Accordingly, for example, a causal relationship between hydrocephalus and periventricular edema may be questioned. It can also imply an initiating role of venous congestion in brain compliance reduction which develops during both pathological and aging processes. Although the concept of venous inefficiency as the cause of hydrocephalus is not new, it has not been linked to aging. Although the role of CSF in the mechanism cannot be inferred from the present data, it is interesting that affected areas encompass regions related to CSF turnover.

Death Receptors as Biomarkers for Cardiovascular Mortality

Researchers here present evidence for the appropriately named death receptors to be biomarkers for cardiovascular disease risk, an indirect measure of the damage accumulating in the vascular system over the course of aging, and its effects on cellular biochemistry. The research community is very interested in establishing reliable, easily measured biomarkers that relate to age-related disease, mortality, and known mechanisms of aging. The more that exist, the more likely it is that these biomarkers can be combined in some algorithmic way to generate a more precise overall biomarker of biological age - something that can be used to rapidly assess the performance of the first rejuvenation therapies, as they arrive, and to steer their development.

Death receptors are activated, for example, in the case of infections when white blood cells that have combatted a virus are to be removed. It was previously known that death receptors in the blood can be measured, but not whether an elevated level was linked to increased cell death in type 2 diabetes and arteriosclerosis. The aim of the study was therefore to investigate whether "death receptors" could be used as a marker that could be linked to ongoing tissue damage and if this could be used to predict the risk of developing diseases. The results show that increased cell death can be linked to increased levels in the blood of three different members of the same "death receptor family" (TNFR-1, TRAILR-2 and Fas). Increased cell death is seen in type 2 diabetes as well as arteriosclerosis.

High blood sugar and blood fats (low levels of HDL, "the good cholesterol") subject the body's blood vessels and insulin-producing beta cells to stress. Long-term stress damages the cells and can cause the death receptors on the surface of the cell to trigger a cell suicide program within the cell. "When the beta cells are damaged, the production of insulin decreases, which increases the risk of diabetes. The damage activates repair processes in the blood vessels. If these are not properly resolved, this usually leads to the development of plaque in the blood vessels (arteriosclerosis). The formation of cracks in this plaque is the primary cause of myocardial infarction and stroke."

The study also looked at the connections between different risk factors - age, BMI, blood fats, blood sugar and blood pressure - and the death receptors TNFR-1, TRAILR-2 and Fas in blood samples from 4,742 people who are part of the population study Malmö Diet Cancer. Samples from the 1990s were compared with the risk of suffering from diabetes, heart attack, and stroke in the coming 20 years. The results show clear links between the level of death receptors in the blood and the different risk factors. High levels of death receptors were common in diabetics which indicates increased cell stress and risk of damage to different organs. Among non-diabetics, high levels of death receptors were linked with an increased risk of developing diabetes and cardiovascular diseases. This indicates that the level of death receptors in the blood reflects the damage that the risk factors cause in different organs.

A Discussion of Cellular Senescence in Age-Related Macular Degeneration

Cellular senescence is one of the root causes of aging. A small fraction of the large number of cells that become senescent every day fail to self-destruct, and instead linger in tissues to secrete a mix of inflammatory and other harmful signals. This behavior is known as the senescence-associated secretory phenotype, or SASP. The sizable numbers of senescent cells in old tissues have been implicated as a contributing cause of numerous age-related conditions, from lung disease to cardiovascular issues to forms of arthritis. More causal links will be discovered: this is a newly energetic field of research.

As an example of the sort of thinking presently taking place, researchers here discuss a potential role for cellular senescence in macular degeneration, a progressive blindness caused by destruction of retinal tissue. While it seems fairly likely that senescent cells are involved, the question is always whether or not they are involved to a sufficient degree to be an important cause. That seems plausible based on what is known, but it isn't an open and shut case. There is considerable uncertainty, based on the existing evidence. Fortunately, now that senolytic therapies to clear senescent cells are a going concern, there is a fairly rapid way forward to learning more: remove senescent cells in aged animal models of macular degeneration, and see what happens. Someone will get around to that in the next few years, I'd imagine.

Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor, but it is a complex disease in which both genetic and environmental factors play a role. The exact mechanism of its pathogenesis is unknown. Oxidative stress, protein aggregation, and inflammation play a central role in AMD development. Early dry AMD is hardly detectable and usually asymptomatic. Its advanced form, called geographic atrophy (GA), is associated with a massive loss of photoreceptors that evokes central visual loss. A clinical hallmark of wet AMD is the presence of neovascular vessels sprouting from the choriocapillaris into the retina.

It has been proposed that cellular senescence of RPE cells plays a role in the etiology of AMD. It seems that many studies on the role of cell senescence in organismal aging and age-related pathologies support this idea. The exposure of cells to recurrent or chronic nonlethal stress might contribute to an increase in the accumulation of stress-induced senescent cells, thereby accelerating tissue aging. A growing body of evidence proves that persistent DNA damage, especially double-strand breaks (DSBs) and DNA damage response (DDR), are closely associated with cell senescence. Evidence also links DNA damage with inflammation and disease, particularly age-dependent diseases. This is sort of a vicious cycle as DNA damage-dependent senescence can lead to secretion of molecules, which can reinforce senescence and can induce DNA damage and DNA damage-dependent bystander senescence.

Retinal pigment epithelial (RPE) cells in the central retina are quiescent, and when damaged, they can be replaced by their proliferating counterparts at the RPE periphery. Oxidative stress can induce senescence in RPE cells and result in inability of peripheral RPE cells to rescue their central RPE counterparts, which can lead to a massive loss of RPE cells observed in clinically detected AMD. If most of macular peripheral RPE cells are affected by senescence, this mechanism can fail leading to AMD. Senescent RPE will be the source of pathology and have a detrimental impact on surrounding tissue through the senescence-associated secretory phenotype (SASP).

We believe that senescence associates with autophagy and DDR. All these three effects, senescence, autophagy, and DDR, can be provoked by oxidative stress, which is a major factor in AMD pathogenesis. Moreover, aging is the main risk factor of pathogenesis of AMD and can be related to oxidative stress. Inflammation associates with oxidative stress, aging (inflammaging), and AMD. Therefore, it is logical and justified to hypothesize that senescence can play a role in AMD and this process can be influenced or regulated by autophagy and DDR. Consequently, GATA4, as an identified factor to be involved in cell senescence, autophagy, DDR, and inflammation, seems to be a natural candidate to play a major role in the proposed mechanism of AMD pathogenesis. However, this is only a hypothesis, which should be verified, but we tried to show some arguments that this subject is worth further study and development.

Cellular Senescence as a Failed Anti-Cancer Strategy

The evolution of multi-cellular life is in essence the story of a tooth and nail struggle with cancer, one that continues even now. Complex structure, regeneration, and growth are all required in higher forms of life, but that combination means that any sort of sustained breakdown in control over cell proliferation tends to be fatal because it disrupts necessary structures. Multiple layered systems, within cells and outside them, have evolved to try to block damaged cells from uncontrolled proliferation, ranging from tumor suppressor genes to the surveillance of the immune system and its destruction of potentially cancerous cells. Cellular senescence is one of these strategies, and like all of them, it is only somewhat successful. With only a few rare exceptions, evolution has curbed cancer risk to the minimum degree needed for a species to survive, no more than that.

Cellular senescence is, of course, one of the causes of aging. Cells become senescence in response to damage, a toxic environment, or at the end of their replicative life span, and near all destroy themselves or are destroyed by the immune system. Enough linger to cause problems, however, producing the senescence-associated secretory phenotype (SASP) that disrupts tissue structure and function. Cellular senescence is an anti-cancer strategy because senescence locks down a cell to prevent replication - so it should function to remove the most at-risk cells before they can run off the rails. Indeed, this works in the early stages of life. But with enough senescent cells lurking in a tissue, the SASP changes the environment to make it much more amenable to cancer: inflammatory, pro-growth, with increased levels of cell damage. Ultimately, cellular senescence becomes an enabler of cancer.

Cellular senescence describes an irreversible growth arrest characterized by distinct morphology, gene expression pattern, and secretory phenotype. The final or intermediate stages of senescence can be reached by different genetic mechanisms and in answer to different external and internal stresses. It has been maintained in the literature but never proven by clearcut experiments that the induction of senescence serves the evolutionary purpose of protecting the individual from development and growth of cancers. This hypothesis was recently scrutinized by new experiments and found to be partly true, but part of the gene activities now known to happen in senescence are also needed for cancer growth, leading to the view that senescence is a double-edged sword in cancer development.

In current cancer therapy, cellular senescence is, on the one hand, induced deliberately in tumor cells, as thereby the therapeutic outcome is improved, but might, on the other hand, also be induced unintentionally in non-tumor cells, causing inflammation, secondary tumors, and cancer relapse. Importantly, aging leads to accumulation of senescent cells in tissues and organs of aged individuals. Senescent cells can occur transiently, e.g., during embryogenesis or during wound healing, with beneficial effects on tissue homeostasis and regeneration or accumulate chronically in tissues, which detrimentally affects the microenvironment by dedifferentiation or transdifferentiation of senescent cells and their neighboring stromal cells, loss of tissue specific functionality, and induction of the senescence-associated secretory phenotype, an increased secretory profile consisting of pro-inflammatory and tissue remodeling factors.

These factors shape their surroundings toward a pro-carcinogenic microenvironment, which fuels the development of aging-associated cancers together with the accumulation of mutations over time. Among well-documented stress situations and signals which induce senescence, oncogene-induced senescence and stress-induced premature senescence are prominent. New findings about the role of senescence in tumor biology suggest that cancer therapy should leverage genetic and pharmacological methods to prevent senescence or to selectively kill senescent cells in tumors.

Modest Physical Activity in Old Individuals Correlates with Reduced Cardiovascular Disease Risk

The study noted here can be added to the list of those that find modest activity to associate with reduced risk of cardiovascular disease risk in old people. This sort of finding is a comparatively recent development in epidemiology because it relies upon the use of accelerometers, of the sort found in every mobile device these days. Before the advent of low-cost accelerometers, studies of exercise and health relied on self-reporting, which is simply not accurate enough to identify effects resulting from low levels of everyday physical activity such as gardening, cleaning, and so forth. The current consensus on this sort of data is that activity causes health benefits and reduced mortality, not that people who are healthier tend to undertake more activity. This is based on a smaller amount of human data in which effects can be observed over years based on earlier levels of exercise, and on animal studies structured in order to prove that benefits derive from exercise.

Physical activity (PA) is known to improve health and decrease the risk of developing cardiovascular disease (CVD) in a variety of populations. However, less is known regarding the influence of habitual or daily PA in preventing cardiovascular events among older adults. In particular, data are lacking regarding the influence of daily PA on cardiovascular risk among older adults with mobility limitations that restrict the ability to engage in PA.

Although associations between the quantity of PA and cardiovascular risk factors have been reported in older adults, few have made these connections using objective measurements of PA. To date, most studies have relied on self-reported measures of PA, which commonly misclassify the volume and/or intensity of PA. Although PA has been shown to have an inverse relationship with cardiovascular risk factors and morbidity, it is unknown whether participation in activity reduces cardiovascular incidence in populations of older adults displaying habitually low levels of PA. Prospective studies to date have largely focused on increasing exercise participation, although formal exercise interventions have been insufficient in reducing the incidence of cardiac events in this population. However, few studies have utilized objective measurements using accelerometry to evaluate cardiovascular risk in older adults.

Our previous study found that every 25 to 30 minutes per day spent being sedentary - defined by less than 100 accelerometry counts per minute - was associated with a 1% higher predicted risk of myocardial infarction (MI) or coronary-related death. Conversely, daily time spent in activities registering 100 to 499 counts per minute was associated with lower predicted hard coronary heart disease risk. Every 30 to 35 minutes of inactivity in this range was also associated with a 1-mg/dL lower circulating high-density lipoprotein cholesterol concentration. Somewhat surprisingly, however, the mean intensity of daily activities was not associated with predicted cardiovascular risk in this population.

The cross-sectional nature of the prior study prevented the ability to draw causal inferences and provided only a projection of cardiovascular risk. Therefore, the overarching objective of the present study is to expand on these prior findings using longitudinal assessment of accelerometry-based PA patterns and the observation of cardiovascular events among this population. The primary finding of this study is that objective measurement of PA via accelerometry was significantly associated with incidence of cardiovascular events among older adults with limited mobility. The 1,590 study participants had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data at baseline. At baseline, every 30 minutes spent performing activities ≥500 counts per minute were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day and duration of activity ≥500 counts per minute were significantly associated with lower cardiovascular event rates.

The SENS Research Foundation Comments on Calico's Research into Apparent Rejuvenation in Oocytes

The normally secretive California Life Company, or Calico, recently shared some of their investigations into the rejuvenation that takes place in the earliest stages of the reproductive process - parents are old and children are young, so a form of rejuvenation must happen at some point, or reproductive cells must be exceptionally well protected from aging. The Calico team showed that in nematodes and frogs, egg cells, or oocytes, undergo a burst of cellular housekeeping when they are used, clearing out damaged proteins. It is thought that something similar happens in mammalian early embryonic development, a process that also seems to be triggered in part by induced pluripotency. Is this all useful and relevant to efforts to produce rejuvenation therapies? Here is a lengthy commentary from the SENS Research Foundation, whose founder has been one of a number of researchers very critical of Calico Labs in the past:

Some readers got the impression that this study had uncovered a special molecular mechanism that allows these nematodes' oocytes uniquely to stay "young," even as the body as a whole grew old. This impression may have been reinforced by a quote from one researcher, contrasting the aging of the human body with the (seeming) "immortality" of the germline (the "line" of sperm and egg genes that actually passes from generation to generation): "You take humans - they age two, three or four decades, and then they have a baby that's brand new."

Taken together, some readers came away with the suggestion that the fact that babies are born young implies the ability of oocytes to "sweep themselves clean" of their adult parents' lifetime burden of deformed proteins, and excitedly hoped that the tricks that oocytes use to execute this feat could somehow be engineered into aging cells elsewhere in the body to keep our muscle and brain cells young. Unfortunately, no such tricks emerged from this study, nor are they likely to. This study adds substantial insight to a body of work on nematode (and later frog) oocyte biology sparked by a discovery made by French scientists in 2010 and prior work in yeast and in mouse embryos. However, there is nothing here that can be exploited for developing anti-aging therapies.

The real finding of the paper is better captured by its own title than the newspaper headlines: "A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage." The key word in there is not "immortal," but "renewal" - renewal of "proteostasis," the somewhat equivocal concept of the young cell's dynamic maintenance of stably low levels of damaged proteins. As it turns out, the "renewal" in question is a reactivation of the normal "proteostatic" activity of the lysosome - the cell's recycling center, where old and damaged proteins are broken down into raw materials that can then be reused to build new proteins.

While oocytes are held in storage, they adopt a metabolically dormant state to conserve energy and reduce the production of metabolic wastes. This much is just as true in mammals as it is in the roundworms and frogs studied in this new report. What the new study uncovered is a particular energy-conservation strategy these animals' oocytes use. No special rejuvenative power is involved in this process: other cells clean up these same wastes routinely, as a matter of day-to-day housekeeping, instead of letting them build up until it's absolutely necessary to get rid of them.

Despite the lengths to which the body goes to maintain only viable, "young" eggs, oocytes do still manage to degenerate with age, which is part of the reason why older parents are less fertile. The silver lining in all of this bad news: because the nature of the degenerative aging process in the reproductive system is not different from the aging of the rest of the body at the cellular and molecular level, the "damage-repair" heuristic of rejuvenation biotechnology can be applied to rejuvenate the aging reproductive system just as it can to the rejuvenation of the rest of our bodies.

We're not going to solve the degenerative aging process by borrowing any special tricks from the oocyte. The oocyte doesn't really have any tricks for us to profitably exploit - and more importantly, no cell in the body is naturally able to remove or repair many of the kinds of damage that accumulate in aging bodies and ultimately lead to age-related disease, debility, and death. The oocyte has no way to clear beta-amyloid from aging brains, or TTR amyloid from aging hearts - nor to cleave AGE crosslinks from aging arteries, as they are subject to none of this damage. It has no internal means to replace cells that are lost to aging damage, and is no more able to degrade the truly stubborn intracellular aggregates that accumulate in aging cells than any other cell type. For that, we need a new class of medicines that can do what we can't do on our own: remove, repair, replace, or render harmless the cellular and molecular damage of aging in our tissues. It is when we develop rejuvenation biotechnologies and deploy them comprehensively that we will finally be able to effectively "turn back time" for aging bodies as a whole.

Pineapple Fund Donates 1 Million in Bitcoins to the SENS Research Foundation

The Pineapple Fund is one of the more sensible responses to sudden wealth that I've seen in my time, a charitable giving initiative set up by someone who finds themselves a multi-millionaire as a result of the enormous rise in the valuation of blockchain initiatives over the past couple of years. We might hope that this will inspire other newly wealthy long-term holders of cryptocurrencies to take similar steps to support the change they want to see in the world.

Today's good news is that the anonymous principal of the Pineapple Fund has chosen to donate 1 million in bitcoins to the SENS Research Foundation, one of the larger donations to SENS rejuvenation research made over the years. Thank you to all involved! This will make a large difference over the next few years, allowing the SENS Research Foundation scientists and their allies to unblock more of the lines of research that lead to a comprehensive toolkit of therapies to control the causes of aging. As that work spins out into the broader research community, we will see a blossoming of treatments that can reverse age-related disease and greatly reduce the suffering of old age.

The breaking news today is that the SENS Research Foundation has managed to secure the sum of 1 million in bitcoins from the Pineapple Fund. The Pineapple Fund is a charitable initiative run by a very generous person who wishes to remain anonymous and has a large number of bitcoins to donate to charities. The suggestion was made on Reddit to the founder of the Pineapple Fund to donate some bitcoins to SENS and they agreed. Thanks to the work of a number of people in the community, Dr. Aubrey de Grey was alerted and he promptly arrived to talk to the amazingly generous person behind the Pineapple Fund.

"Sometime around the early days of bitcoin, I saw the promise of decentralized money and decided to mine/buy/trade some magical internet tokens. The expectation shattering returns of bitcoin over many years has lead to an amount far more than I can spend. What do you do when you have more money than you can ever possibly spend? Donating most of it to charity is what I'm doing."

So who is the mysterious caped crusader behind this awesome initiative? We do not know who you are but we know why you do what you do and we think it is fantastic! There is only so much money a person can spend and giving the rest away to help charities in need is one of the greatest things a person can do. From everyone working in the field of rejuvenation biotechnology and the community who support a future free from age-related diseases, thank you!

Cellular Senescence and Stem Cell Decline in Age-Related Cardiac Hypertrophy Caused by Hypertension

Cellular senescence is one of the causes of aging; senescent cells accumulate in tissues, and their inflammatory and other disruptive signaling causes considerable harm. With the newfound and rapidly spreading interest in senescent cells in the research community over the past few years, a lot of efforts are now underway to better understand how cellular senescence fits into the existing knowledge of the biochemistry of age-related conditions. Since senescent cells are a cause of chronic inflammation, and since inflammation and oxidative stress go hand in hand, near any condition in which inflammation or oxidative stress feature prominently is a good candidate for reexamination.

Recently, evidence has emerged for senescent cells to be involved in the growth and weakening of heart muscle that follows the age-related increases in blood pressure known as hypertension. Hypertension occurs because stiffening of blood vessels and dysfunction in the muscle of blood vessel walls breaks the intricate feedback system that controls blood pressure. The consequences include damage to delicate tissues, such as those of the brain and kidney, as small vessel rupture at an accelerated rate, and the aforementioned restructuring of heart muscle. The heart becomes larger and weaker. But why? The paper here looks at oxidative stress and senescent cells on heart stem cells that occurs in rats engineered to develop hypertension.

In human hearts there is 0.5 to 1% of myocyte turnover annually, envisaging the role of cardiac stem cells (CSCs) in the maintenance of cardiac tissue homeostasis. CSCs differentiate and replace the lost myocytes; and in the event of myocardial injury, stem cells contribute towards tissue repair. The involvement of stem cells in cardiac failure associated with age and disease has been speculated. However, the temporal variation in the density and efficiency of cardiac stem cells and the effect of disease on the stem cell characteristics has not been systematically analyzed.

Cardiac hypertrophy is recognized as an independent risk factor for cardiac failure. Efficient management of hypertensive heart disease requires identification of factors that can possibly mediate the transition from hypertrophy to heart failure. Decline in the proportion of healthy cardiac stem cells (CSCs) can affect tissue regeneration. In pathological conditions, apart from natural aging, an adverse microenvironment can lead to decrease in efficiency of CSCs. This study was designed with the objective of examining the age associated variation in stem cell attributes of Spontaneously hypertensive rats (SHR) in comparison with normotensive Wistar rats. Spontaneously hypertensive rat was used as the experimental model since the cardiac remodeling resembles the clinical course of hypertensive heart disease.

DNA damage and the proportion of senescent CSCs increased with age both in SHR and Wistar rats. Age associated increase was observed in the oxidative stress of stem cells, possibly mediated by the enhanced oxidative stress in the microenvironment. The changes were more pronounced in SHR, and as early as six months of age, there was significant decrease in efficiency of CSCs of SHR compared to Wistar. The density of healthy CSCs determined as a fraction of the differentiated cells was remarkably low in 18-month-old SHR. Age associated decrease in functionally efficient CSCs was therefore accelerated in SHR.

The expression of senescence-associated markers p21 and p16ink4a and the proportion of SA-β-gal positive cells increased with age. The proportion of senescent cells was significantly higher in SHR compared to age matched Wistar rat. Senescence and death of CSCs with increasing age in wild type mice has been implicated in impairment of growth and turnover of cells in the heart. Senescent stem cells affect their microenvironment by decreasing regenerative potential of the entire stem cell pool, while also affecting neighboring myocytes and vasculature. This study for the first time reports the increased expression of p16ink4a and p21 in CSCs with age and its preponderance in SHR. The difference between SHR and Wistar was apparent as early as 6 months of age, which is the compensatory phase of hypertrophy.

In conclusion, age associated decrease in efficiency of stem cells can be responsible for the degenerative cardiac changes in physiological aging. Aging of CSCs can affect migration and proliferation and promote apoptosis. Accelerated aging in stem cells isolated from hearts of SHR is possibly mediated by an adverse microenvironment. Decrease in the healthy stem cell pool can affect efficient tissue repair and precipitate the transition from compensated hypertrophy to cardiac failure. Enhanced oxidative stress in the microenvironment can be a predominant factor contributing to stem cell aging. The salient findings of accelerated decline in cardiac stem cell efficiency in SHR provide insight for further studies to examine whether reduction of cardiac oxidative stress can restore stem cell function and prevent progressive cardiac remodeling.


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