Fight Aging! Newsletter, December 18th 2017

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.

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.

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.

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.

"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."

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.

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.

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.

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.

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 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.

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 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.

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.

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.

The breaking news today is that the SENS Research Foundation has managed to secure a donation 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!

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.