Fight Aging! Newsletter, December 7th 2015

December 7th 2015

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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  • The Aging Chart Resource
  • Investigating Gene Expression Changes in Nematode Aging
  • Interesting Comments by George Church
  • Evidence for Type 2 Diabetes to be Caused Specifically by Excess Fat in the Pancreas
  • Zero Gravity Orbital Habitation Causes Changes that are at Least Superficially Similar to Accelerated Aging
  • Latest Headlines from Fight Aging!
    • Cytomegalovirus Impairs the Immune Response to Exercise
    • An Example of Present Work on Improving Vitrification
    • MMP12 as a Mediator of Arterial Stiffening
    • It's Giving Tuesday Today: Donate to SENS Research!
    • An Update on Methuselah Foundation Funding of a C60 Cancer Study at Ichor Therapeutics
    • Decellularization Successfully Applied to Diaphragms in Rats
    • Senescent Cells, Inflammation, Telomere Length, and Mortality
    • Inhibition of bcat-1 Extends Life in Nematodes
    • An Update on the Development of Killfish as a Model Organism in Aging Research
    • SENS Research Fundraising on Giving Tuesday Went Well, and the Matching Fund Goal is Almost Reached


Here I'll point out the Aging Chart site, a new resource on aging and longevity research assembled by a group of largely Russian researchers. Over the past decade, the Russian-language side of the longevity science community, especially the folk associated with the Science for Life Extension Foundation, has produced all sorts of publicity and explanatory materials aimed at both laypeople and researchers. These range from glossy advocacy for development of effective treatment of aging to quite detailed visualizations of portions of the known molecular biology of aging and roadmaps for the future of rejuvenation research. The people involved here have always demonstrated a good sense of the need for advocacy and public support to bring lasting life to research efforts.

Collectively, the Russian aging research community has a vision that overlaps somewhat with that of the SENS Research Foundation in technical details, but is in general far more focused on tinkering with the operation of metabolism and epigenetic alterations than I would agree is the best path forward. In that it is perhaps closer to the Hallmarks of Aging opinions on how to classify the mechanisms of aging and thereby approach its treatment. You can see this at the detail level if you take a look at Alexey Moskalev's blog. You'll find a lot of the original Russian visualizations there, but sadly very few of them had been translated into English and made available until recently. Thanks to a closer collaboration between the English-language and Russian-language research communities in recent years, and a growing number of fluently bilingual researchers, more of these resources are becoming available to peruse in English.

Aging Chart

Aging Chart is a collection of community-curated pathways and knowledge related to aging. Aging Chart makes its debut stocked with 114 pathways, networks, and concept maps on all topics related to aging, from gene-centered pathways to those describing aging processes, age-related diseases, longevity factors, and anti-aging strategies. Contributions are openly encouraged. The pathway diagrams are interactive, with clickable nodes for user-led exploration that link to related pages and pathways for any particular element of interest.

Aging Chart: a community resource for rapid exploratory pathway analysis of age-related processes

As the world population is rapidly aging, the prevalence of aging-related diseases and the demand for expensive, long term health care is also rising. To offset the burden of this shift, scientific knowledge and innovation will become increasingly crucial, and anti-aging and disease prevention strategies will become national and international priorities. Aging research as a field will boom. Nevertheless, it faces several challenges, and the growth will need direction. One of the challenges is the current lack of a freely available, comprehensive collection of aging-related biological pathways and encyclopedia of aging knowledge. Biological pathways are one of the most powerful visualization tools in biology. They provide an intuitive, systems view of the interactions between the multitude of individual elements in any given process. They can be interactive for user-directed exploration and amenable to computational methods, and they are indispensable in making sense of large-scale data sets, where a multitude of individual changes may reflect a small number of more biologically important (and more statistically powerful) changes at the pathway level. Pathway collections are a key feature of many biological data repositories in the public domain.

The lack of an aging pathway collection until now may reflect the fledgling nature of the field but also stems in part from the sheer diversity of aging-related processes. Characterizing these is a monumental task. Aging itself is a complex process that occurs at all levels in all systems of the body, leads to a loss of function and triggers a number of diseases. There is ongoing debate as to whether aging is itself a treatable disease. As such, aging research involves a highly diverse community of researchers with various perspectives. If any single narrative of aging mechanisms is to be constructed, the community needs a platform where knowledge can be pieced together collaboratively into pathways, node by node, and ultimately into a unified theory. There have been many previous attempts at structuring aging data and knowledge on the web, but there is still a need for a rapid, intuitive, visual overview of aging processes, from environmental triggers down to molecular interactions. To our knowledge, no such resource yet exists. To fill this gap, we have developed Aging Chart, a wiki-based, community-curated biological pathway collection and encyclopedia of aging processes. Aging Chart will complement and add to the existing set of public aging-related data- and knowledge bases on the web.


Today I'll point out one representative example of the many ongoing research programs investigating the details of gene expression changes that occur with aging. Gene expression is the name given to the collection of processes that, step by step, act to manufacture proteins from their DNA blueprints, the genes. The pace of protein production changes in accordance with epigenetic modifications to DNA, and varying levels of proteins lead to alterations in cellular operation, which in turn feed back into further epigenetic modification processes. A living cell is a collection of countless feedback loops between its machinery, the pace of protein production, epigenetic decorations on DNA, and the surrounding environment. This cellular metabolism is enormously complex, and the ways in which it reacts to the changing environment and growing levels of cell and tissue damage over a lifetime are similarly complex. That damage, the root cause of degenerative aging, is the same for every individual, however, and so there are characteristic patterns to be found in epigenetic changes in aging.

Some research groups are presently gathering data on these patterns to try to build robust biomarkers of biological age, useful measures that might help speed up progress in longevity science by allowing fast validation or rejection of potential strategies, as well as an on-the-spot assessment of their estimated effect on life span. That remains a work in progress. Beyond this unified approach, I think we will also see a lot more in the way of ad-hoc measures of epigenetic changes adopted by single research groups or even for single studies. The paper quoted below is an example of the type; the researchers use measures of gene expression to support their particular interpretation of what a life-extending intervention is actually doing under the hood in the nematode worms used in the study. Beyond this, I should say, this is just another modest slowing of aging in a short-lived species, something that can now be achieved in scores of ways, and is of little relevance to human rejuvenation research. Drug interventions with large effects on longevity in short-lived species have very small or no effects in longer-lived species, and adjusting the operation of metabolism through drugs and the like is a dead end for meaningful human life extension. Next to nothing will come of it; the only viable path ahead towards radical healthy life extension of decades and more in the foreseeable future is that of damage repair, such as the SENS research programs.

That said, it doesn't make this research uninteresting; a great deal of the work that takes place in the aging research community, and which will do little for human longevity, is nonetheless both fascinating and enlightening. This research is an example of the way in which epigenetics is becoming a useful, necessary part of a wide range of research into aging, improving the output of the scientific community.

Scientists discover how to make youth last longer - in worms

Tests showed that a drug capable of prolonging life in nematodes by more than 30% worked by expanding only young adulthood, and had no effects on later life stages. The scientists made their discovery while testing a long list of compounds for any that might prolong the short lives of the short worms. When early hints suggested that the antidepressant mianserin extended their lifespan, the scientists set about testing it more thoroughly.

The group found that as normal, water-fed worms aged, their gene activity changed from being precisely coordinated to ever more disorganised. Genes that were involved in the same bodily function, and which usually worked together, began working against one another. The researchers call this loss of genetic orchestration "transcriptional drift" and after examining data from mice and from 32 brains of humans aged 26 to 106 found that the same process occurs in both. The scientists went on to develop a test that used genetic disorder as a measure of the age-related changes that happen from youth until old age. When they ran the test on worms fed on mianserin, they found that the drug suppressed transcriptional drift, but only when it was given early enough. "Based on their gene expression pattern, 10 day old worms looked seven days younger. What happens is the period of young adulthood is made longer, whilst all the rest that comes later stays the same. The life extension comes only from increasing the young period of life, and then when this period is over, the compound doesn't do anything any more."

Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality

We classified gene expression changes for groups of genes into two types. Type I changes describe whether the overall expression across an entire functional group/pathway increases or decreases i.e. whether the pathway is up or down regulated with age. Type II changes describe the relative changes in gene expression among genes within functional groups with respect to each other. We named the type II change transcriptional drift. As animals age, genes within functional groups change expression levels in opposing directions resulting in the disruption of the co-expression patterns seen in young adults.

In this study, we have analyzed the dynamics of aging C. elegans transcriptomes and how these dynamics are affected by mianserin treatment. In C. elegans, transcriptional drift continuously increases with age across the transcriptome, substantially altering stoichiometric balances observed in young animals. Longevity mechanisms induced by either pharmacologically blocking serotonergic signaling or by blocking insulin signaling by daf-2 RNAi attenuate transcriptional drift. Abolishing lifespan extension by these mechanisms by either blocking serotonergic signaling too late (mianserin, day 5) or by addition of daf-16 RNAi (daf-2) abolished the attenuation of transcriptional drift.

Using transcriptome-wide transcriptional drift values as a metric for age showed that mianserin treatment attenuated the age-associated increase of transcriptional drift, thereby preserving the characteristics of a much younger (~3 days-old) transcriptome up to chronological day 10. These results showed that mianserin caused a 7-8 days delay in age-associated transcriptional change and suggested that the physiological changes leading to a lifespan extension were already completed by day 10. Measuring mortality levels supported this conclusion. By day 12, the entire mortality curve was shifted parallel by 7-8 days showing that the physiological delay leading to a lifespan extension was already completed. Experiments in which animals were exposed to mianserin for limited periods of time confirmed that mianserin exposure for the first 5-10 days of adulthood was necessary and sufficient to fully extend lifespan. The most parsimonious explanation that accounts for all these results is that mianserin treatment slows degenerative processes specifically between day 1 and 10, extending the duration of the period of young adulthood thereby postponing the onset of major mortality around mid-life.


George Church is an important figure in the development of modern genomics and genetic engineering. Like a number of luminaries in the medical life sciences, in recent years he has become much more openly supportive of efforts to treat the causes of aging and extend healthy human life spans. You might recall the keynote he gave at the SENS6 rejuvenation research conference, and note that Church is a member of the SENS Research Foundation advisory board. With that context, I'll point you to recent remarks made to a journalist:

A Harvard professor says he can cure aging, but is that a good idea?

I mentioned to Church that CRISPR is the kind of work for which Nobels are awarded. He quickly responded that there are more important things in the balance than prizes. There are cures for human diseases, he said. Church thinks that one of the ailments he can cure is aging. When I met him early this year, in his laboratory at Harvard Medical School, where he is professor of genetics, he expressed confidence that in just five or six years he will be able to reverse the aging process in human beings.

"A scenario is, everyone takes gene therapy - not just curing rare diseases like cystic fibrosis, but diseases that everyone has, like aging," he said. He noted that mice die after 2.5 years but bowhead whales can live to be 180 or 200. "One of our biggest economic disasters right now is our aging population. If we eliminate retirement, then it buys us a couple of decades to straighten out the economies of the world. If all those gray hairs could go back to work and feel healthy and young, then we've averted one of the greatest economic disasters in history. Someone younger at heart should replace you, and that should be you. I'm willing to. I'm willing to become younger. I try to reinvent myself every few years anyway."

So on Tuesday, I asked him if he was still on track to reversing the aging process in the next five years or so. He said yes - and that it's already happening in mice in the laboratory. The best way to predict the future, he said, is to predict things that have already happened.

This is filtered through a layperson with mixed feelings about the whole business of trying to treat aging, so necessary context is lost. Church is big on the application of genetic tools to many present problems, no surprise given his background, and it is true that an entire class of solutions in medicine and other fields can be constructed atop robust, reliable gene therapy of the sort enabled by CRISPR. However, many types of genomic research into aging and longevity are presently taking place, and there are many types of intervention, existing and proposed, that can employ genetic engineering. Sadly, those gathering the greatest attention at the current time are also the least likely to produce meaningful results. Let me divide things up into a couple of categories:

Firstly, we have the search for longevity genes and the idea that we can use drugs, gene therapies, and other tools in the toolkit to adjust metabolism to look more like that of people with specific genetic or epigenetic traits that are linked to longer healthy lives. This covers a broad range of approaches, from calorie restriction and exercise mimetics to analysis of centenarian genomes in search of common factors. This is slow and expensive work, and so far has produced little more than knowledge. There is also the problem that in principle even complete success means tiny gains. What does it mean to have the full set of characteristic differences present in a centenarian's metabolism? It means you have perhaps a 1.5% chance of living to 100 rather than a 1% chance, to pull some numbers out of the air - the real numbers are along these lines. Identified genetic associations with longevity are a matter of a tiny increase in a tiny chance of survival, and if you get there you're still decrepit and age-damaged. The same goes for calorie restriction and exercise mimetics; even if completely recapturing the real thing, that gains a few years of additional life expectancy. You still age, you still die, and the schedule is much the same. This is not a goal worth spending billions and decades on, but it is nonetheless what most researchers are involved in.

Secondly we have classes of compensatory alteration to the genome, or equivalent therapies that change protein levels without changing genes. These are in principle capable of providing benefits that will have greater impact than any presently available option - such as calorie restriction - but they don't directly repair the damage that causes aging, and thus cannot on their own do more than delay the inevitable. In this category you'll find things such as follistatin or myostatin gene therapy to force greater maintenance of muscle mass, increased catalase production in mitochondria to slow their contribution to aging, attempts to mine regenerative and long-lived species for mechanisms that might be ported over to humans one day, and a range of gene and other therapies that spur old stem cells into action, overriding their response to cell and tissue damage, and restoring at least some of the tissue maintenance that falls off with age. The jury is still out on the degree to which these stem cell approaches raise the risk of cancer due to higher levels of damaged stem cell activity in damaged tissues, but so far it is less than expected. The bulk of researchers not involved in the first category above are working on something in the second, and this includes Church. I take his remarks quoted above to refer to the range of rodent studies from past years demonstrating a modest slowing of aging or partial restoration of some narrow set of measures relating to aging via gene therapies and the like.

Thirdly we have the role of gene therapies and genetics in repair therapies after the SENS model, addressing the causes of aging and thus in principle capable of producing indefinite healthy life spans if the repair is good enough and frequent enough. The SENS approach to mitochondrial DNA damage, currently in initial commercial development for inherited mitochondrial disease by Gensight, is a gene therapy, copying altered mitochondrial genes into the cell nucleus as a backup. Similarly forms of clearance of various forms of accumulated gunk - amyloid, lipofuscin, cross-links - that degrade cell and tissue function could well take the form of gene therapies to deliver additional tools needed for the job to cells, though it is more likely we'll see other forms of therapy at first. The SENS vision for preventing cancer may also be a gene therapy in its most complete form, acting to suppress the activity of all mechanisms capable of lengthening telomeres throughout the body. Here again, I suspect other less radical telomere extension blocking approaches will arise at first.

The point here is that genetic engineering and genomics covers a wide range of ground. A lot of it is pointless with respect to aging, at least from any perspective other than the scientific goal of full and complete knowledge of how the decay of the unmodified human machine progresses. Of the rest there are very definite classes of degree for the potential benefit that can be achieved. Not all approaches are the same, and in advance of trying them we can make reasonable predictions of the best possible benefit that could be achieved. We live in an age of rapid, radical progress in biotechnology. We should not be aiming low. I don't believe that slowing aging is good enough, and I don't believe that to be the best possible outcome achievable in the next few decades, were people to support the right lines of research. The weight of scientific evidence backing SENS rejuvenation approaches is compelling, and should be compelling enough to draw anyone away from tinkering with calorie restriction mimetic drugs or longevity-associated genes, lines of research with very limited best possible outcomes when it comes to translation to therapies for aging. Yet it is not, still, and this is why we continue to need advocacy and fundraising to advance the SENS cause, to produce more evidence, and persuade more support, and speed progress towards an end to aging.


Here I'll point out interesting research, suggesting that excess fat in the pancreas, and really nowhere else, is the cause of type 2 diabetes. Of course the only way to gain that pancreatic fat is the standard method of eating enough to put on a lot of excess visceral fat tissue and other fat tissue throughout the body, a path that shortens life expectancy, raises the risk of all of the common age-related conditions, and increases lifetime medical expenses. Visceral fat is metabolically active and causes increased chronic inflammation, among other issues, and inflammation contributes to the progression of degenerative aging. The important point to take away from this backdrop is that developing type 2 diabetes is a lifestyle choice, and so is the maintenance of the condition; even after pushing through metabolic syndrome into full-blown diabetes, a patient can choose to turn back by losing weight. It is frankly amazing that so few do, given the harms, pains, inconvenience, and cost of suffering this condition.

There are other types of diabetes that are not choices. Type 1 diabetes is an autoimmune condition that rarely emerges in later life. It is an unfortunate happenstance that, like all forms of autoimmunity, is still comparatively poorly understand. There is only a collection of theories regarding its origins rather than anything more concrete at this time. The immune system is enormously complex and incompletely mapped, as are its failure modes. Of late researchers have proposed a type 4 age-related diabetes produced by a different sort of immune system dysregulation, quite capable of arising in older people without excess fat tissue. Again this may well be happenstance, the result of a lifetime of cell and tissue damage producing disarray in complex bodily systems.

Returning to type 2 diabetes and this recent research, if the cause lies specifically in pancreatic fat, then this might go some way towards explaining the differing susceptibility across the population of people who have chosen to gain excess fat tissue. Some fraction becomes diabetic, the rest do not. If there is significant variation in the degree to which becoming overweight leads to fat in the pancreas, based on genetics or environmental factors such as level of physical activity for example, then that would be enough to produce the observed outcome.

Type 2 diabetes reversed by losing fat from pancreas

Type 2 diabetes is caused by fat accumulating in the pancreas - and that losing less than one gram of fat through weight loss reverses the diabetes, researchers have shown. In a trial, 18 people with Type 2 diabetes and 9 people who did not have diabetes were measured for weight, fat levels in the pancreas and insulin response before and after bariatric surgery. The patients with Type 2 diabetes had been diagnosed for an average of 6.9 years, and all for less than 15 years. The people with Type 2 diabetes were found to have increased levels of fat in the pancreas.

The participants in the study had all been selected to have gastric bypass surgery for obesity and were measured before the operation then again eight weeks later. After the operation, those with Type 2 diabetes were immediately taken off their medication. Both groups lost the same amount of weight, around 13% of their initial body weight. Critically, the pool of fat in the pancreas did not change in the non-diabetics but decreased to a normal level in those with Type 2 diabetes.

"For people with Type 2 diabetes, losing weight allows them to drain excess fat out of the pancreas and allows function to return to normal. So if you ask how much weight you need to lose to make your diabetes go away, the answer is one gram! But that gram needs to be fat from the pancreas. At present the only way we have to achieve this is by calorie restriction by any means - whether by diet or an operation."

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and associated with the simultaneous recovery of insulin secretory function. Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified.

Weight loss after surgery was similar, as was the change in fat mass. Pancreatic triacylglycerol did not change in NGT but decreased in the group with T2DM. First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT but normalized in T2DM. We conclude that the fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.


That old people will go into orbit to escape the rigors of gravity and thus live longer in their declining years was a staple of golden age and later science fiction. These works were written at a time in which our knowledge of human biochemistry - and the application of that knowledge to medicine - was crude in comparison to today. It is fascinating that we can say that for such a short span of years, a mere short lifetime past, but the differences between the medicine of the 1950s and the medicine of today are profound indeed. The writers of that time largely envisaged a future incorporating great gains in energy generation, and a consequent diaspora from Earth, while computation, medicine and the human condition remained much unchanged; older spacemen in the outer reaches struggling with heart disease in their fifties. Instead we found that expanding the generation, storage, transmission, and application of energy is very hard, and the largely unanticipated information revolution occurred instead. We lost the near future of cheap heavy lift to orbit and the solar system at our beck and call, but gained Moore's Law, biotechnology, nanotechnology, a pervasive internet, and medical progress that is in the early stages of conquering heart disease and may yet save us from all of degenerative aging.

As it turns out, retreating from the rigors of gravity may well have the opposite effect to that imagined by the authors of the last century. Among the alterations produced by orbital habitation in zero gravity are those that appear, at least superficially, much like accelerated aging of the cardiovascular system. The root causes have yet to be pinned down, since very few people are actually researching this topic, but since the onset of these symptoms is fairly rapid, I'd guess at the cause being more a matter of regulatory dysfunction than increased tissue damage, such as the presence of cross-links related to arterial stiffening in aging. Here I'll point out a few links to the work of one research group on this topic in recent years:

Waterloo to lead new experiment aboard International Space Station

The experiment will link changes in astronauts' hearts and blood vessels with specific molecules in the blood to determine why astronauts experience conditions that mimic aging-related problems and chronic diseases on earth. The findings will help identify important indicators for chronic disease and assist with the development of early interventions for people on earth. "We know that astronauts return from space with stiffer arteries and resistance to insulin, conditions affecting many adults as they age. For the first time, we will be able to track exactly how - and why - the body's blood vessels change, and use these findings to potentially improve quality of life and the burden of chronic disease."

"In space, astronauts' bodies show aging-like changes much faster than on Earth. The International Space Station provides a unique platform to study aging-related conditions providing insights that can be used to help understand some of the biggest health issues affecting society. Our research to date suggests that even though astronauts exercise every day, the actual physical demands of tasks of daily living are greatly reduced due to the lack of gravity. This lifestyle seems to cause changes in the vascular system and in the body's ability to regulate blood glucose that would normally take years to develop on earth."

U.Waterloo - Vascular Aging and Space Research Program

We study factors related to cardiovascular health with aging. One focus is on blood pressure regulation and its impact on brain blood flow to help us understand some of the factors that could contribute to falls in the elderly, especially those that occur on rising from bed. Another focus is on aging blood vessels. We have reported a strong link between peripheral arterial stiffness and a reduction in brain blood flow. Our space research program is very active. We recently completed the study Cardiovascular and Cerebrovascular Control on Return from the International Space Station (CCISS). We are currently collecting data for the project Cardiovascular Health Consequences of Long-Duration Space Flight (Vascular).

Cardiovascular Health Consequences of Long-Duration Space Flight (Vascular)

Cardiovascular Health Consequences of Long-Duration Space Flight (Vascular) investigates the impact of long-duration space flight on the blood vessels of astronauts. Space flight accelerates the aging process, and it is important to understand this process to develop specific countermeasures. Data is collected before, during, and after space flight to assess inflammation of the artery walls, changes in blood vessel properties, and cardiovascular fitness.

Spaceflight can cause stiffening of the arteries, affecting the body's ability to control blood pressure. This investigation assessed the blood vessels of astronauts and found decreased flexibility of the carotid artery during flight. Researchers found no relationship between the level of physical fitness and this decrease. The experiment also provided data on the mechanisms behind increased arterial stiffness from spaceflight. Further research is needed to establish effective ways to counter the cardiovascular consequences of spaceflight and ultimately help treat increased arterial stiffness from aging on Earth, which can cause high blood pressure and organ damage.

Impaired cerebrovascular autoregulation and reduced CO2 reactivity after long duration spaceflight

Long duration habitation on the International Space Station (ISS) is associated with chronic elevations in arterial blood pressure in the brain compared with normal upright posture on Earth and elevated inspired carbon dioxide. Although results from short-duration spaceflights suggested possibly improved cerebrovascular autoregulation, animal models provided evidence of structural and functional changes in cerebral vessels that might negatively impact autoregulation with longer periods in microgravity. Seven astronauts (1 woman) spent 147 ± 49 days on ISS. Preflight testing (30-60 days before launch) was compared with postflight testing on landing day or the morning 1 or 2 days after return to Earth. The results indicate that long duration missions on the ISS impaired dynamic cerebrovascular autoregulation and reduced cerebrovascular carbon dioxide reactivity.

Recent findings in cardiovascular physiology with space travel

The cardiovascular system undergoes major changes in stress with space flight primarily related to the elimination of the head-to-foot gravitational force. A major observation has been that the central venous pressure is not elevated early in space flight yet stroke volume is increased at least early in flight. Recent observations demonstrate that heart rate remains lower during the normal daily activities of space flight compared to Earth-based conditions. Structural and functional adaptations occur in the vascular system that could result in impaired response with demands of physical exertion and return to Earth. Cardiac muscle mass is reduced after flight and contractile function may be altered. Regular and specific countermeasures are essential to maintain cardiovascular health during long-duration space flight.


Monday, November 30, 2015

Here researchers provide evidence for one of the many detrimental consequences of cytomegalovirus (CMV) infection. CMV is a near ubiquitous persistent herpesvirus, present in the majority of the population by the time they reach old age. It is thought responsible for some fraction of the age-related disarray of the immune system, as it cannot be cleared and its presence over the years causes ever more memory cells to be uselessly specialized to track it, leaving ever less room for immune cells capable of taking action. One possible approach to this issue is to destroy the excess memory cells to free up space, possibly coupled with delivering new immune cells via cell therapy, but there is little work taking place on that front, as is true of most potential rejuvenation treatments.

The rapid redeployment of natural killer (NK) cells between the tissues and the peripheral circulation is an archetypal feature of the acute stress response. The response can be evoked using acute bouts of dynamic exercise and is often considered to be an accurate representation of an organism's ability to mount an effective immune response during fight-or-flight scenarios when tissue injury and infection are likely to occur. Acute exercise is associated with increased levels of stress hormones which interact with β-adrenergic receptors (β-AR) on the surface of lymphocytes. NK-cells express more β-AR than other lymphocytes and, as a result, they are the most responsive lymphocyte subset to exercise.

Cytomegalovirus (CMV) is a prevalent beta herpesvirus infecting 50-80% of the US population. We have shown that prior exposure to CMV profoundly impacts the redistribution of lymphocytes to an acute exercise bout. While those with CMV have an augmented redeployment of CD8+ T-cells and γδ T-cells, NK-cell mobilization is dramatically impaired. This blunted NK-cell response appears to be attributable to a CMV-induced accumulation of specific NK-cell subsets that have a lower expression of β2-AR and an impaired ability to produce cyclic AMP in response to in vitro stimulation with the β-agonist isoproterenol. Moreover, those with CMV fail to exhibit exercise-induced enhancements in NK-cell function, indicating that CMV may compromise NK-cell mediated immunosurveillance after an acute bout of strenuous exercise.

In addition to infection history, aging is known to have a profound impact on the cellular response to acute stress and exercise; however, studies investigating the effects of aging on NK-cell exercise responsiveness are lacking. While aging has been reported in some studies to have no effect on NK-cell mobilization with exercise, several of the phenotypic hallmarks of aging overlap with those associated with latent CMV infection in the young. Despite CMV prevalence increasing with age, previous studies have compared NK-cell responses between young and old exercisers without accounting for this confounding variable. We showed recently that CMV was associated with enhanced redeployment of CD8+ T-cells regardless of age, while, conversely, aging impairs the redeployment of γδ T-cells independently of CMV. However, no study to our knowledge has compared NK-cell responses to a single bout of exercise between different age groups while controlling for CMV status. Given that CMV prevalence increases with age and many of the effects of CMV mirror those attributable to aging, it is important to resolve the effects of age and CMV infection on the frequency and exercise responsiveness of distinct NK-cell subsets.

The aim of this study was to determine if latent CMV infection blunts the redeployment of NK-cells to a single exercise bout in older individuals as it does in the young and to delineate the effects of age and CMV on the redeployment of discrete NK-cell subsets. We show here that CMV has a potent blunting effect on exercise-induced NK-cell mobilization in both younger (23-39 yrs) and older (50-64 yrs) subjects with the greatest mobilization being seen in the CMV-negative older group.

Monday, November 30, 2015

Interest in developing means of reversible vitrification for tissue preservation has been growing outside the cryonics community in recent years. This is a good thing for cryonics as an industry, as a greater interest in reversible tissue preservation in the broader research community will lead to both technological improvements that can be used by cryonics providers and a greater acceptance of cryonics. Cryonics is a legitimate approach to medical intervention where there is no other option for the patient, but despite greater public support for cryonics from scientists, there remains considerable and unfounded hostility within some portions of the research community. Hopefully this will change in the years ahead with meaningful progress towards the broader use of vitrification:

Researchers have discovered a new approach to "vitrification," or ice-free cryopreservation, that could ultimately allow a much wider use of extreme cold to preserve tissues and even organs for later use. Cryopreservation has already found widespread use in simpler applications such as preserving semen, blood, embryos, plant seeds and some other biological applications. But it is often constrained by the crystallization that occurs when water freezes, which can damage or destroy tissues and cells. To address this, researchers have used various types of cryoprotectants that help reduce cell damage during the freezing process - among them is ethylene glycol, literally the same compound often used in automobile radiators to prevent freezing. A problem is that many of these cryoprotectants are toxic, and can damage or kill the very cells they are trying to protect from the forces of extreme cold.

In the new research, the engineers developed a mathematical model to simulate the freezing process in the presence of cryoprotectants, and identified a way to minimize damage. They found that if cells are initially exposed to a low concentration of cryoprotectant and time is allowed for the cells to swell, then the sample can be vitrified after rapidly adding a high concentration of cryoprotectants. The end result is much less overall toxicity. The research showed that healthy cell survival following vitrification rose from about 10 percent with a conventional approach to more than 80 percent with the new optimized procedure. "The biggest single problem and limiting factor in vitrification is cryoprotectant toxicity, and this helps to address that. The model should also help us identify less toxic cryoprotectants, and ultimately open the door to vitrification of more complex tissues and perhaps complete organs."

If that were possible, many more applications of vitrification could be feasible, especially as future progress is made in the rapidly advancing field of tissue regeneration, in which stem cells can be used to grow new tissues or even organs. Tissues could be made in small amounts and then stored until needed for transplantation. Organs being used for transplants could be routinely preserved until a precise immunological match was found for their use. Conceptually, a person could even grow a spare heart or liver from their own stem cells and preserve it through vitrification in case it was ever needed.

Tuesday, December 1, 2015

Loss of elasticity in blood vessels is an important aspect of aging, as it creates hypertension and cardiovascular remodeling that ultimately leads to heart disease and death, along the way increasing the damage done by blood vessel failure in the brain as well as raising the risk for many other age-related conditions. Arterial stiffening is thought to be caused by cross-links and calcification, alterations in the extracellular matrix that degrade its structural properties. It is worth assuming that nothing in biology ever has one cause or a simple set of contributing mechanisms, however. Researchers here provide evidence for increased levels of the enzyme matrix metalloproteinase-12 (MMP12) to be significantly involved in arterial stiffening, though the underlying root cause of that increase remains an open question:

Arterial stiffening is a hallmark of aging and risk factor for cardiovascular disease, yet its regulation is poorly understood. Here we use mouse modeling to show that MMP12, a potent elastase, is essential for acute and chronic arterial stiffening. MMP12 was induced in arterial smooth muscle cells (SMCs) after acute vascular injury. As determined by genome-wide analysis, the magnitude of its gene induction exceeded that of all other MMPs as well as those of the fibrillar collagens and lysyl oxidases, other common regulators of tissue stiffness. A preferential induction of SMC MMP12, without comparable effect on collagen abundance or structure, was also seen during chronic arterial stiffening with age.

In both settings, deletion of MMP12 reduced elastin degradation and blocked arterial stiffening as assessed by atomic force microscopy and immunostaining for stiffness-regulated molecular markers. Isolated MMP12-null SMCs sense extracellular stiffness normally, indicating that MMP12 causes arterial stiffening by remodeling the SMC microenvironment rather than affecting the mechanoresponsiveness of the cells themselves. In human aortic samples, MMP12 levels strongly correlate with markers of SMC stiffness. We conclude that MMP12 causes arterial stiffening in mice and suggest that it functions similarly in humans.

Tuesday, December 1, 2015

Giving Tuesday is a once a year charitable event to encourage donations, awareness, and advocacy for all causes - and today is the day. Donations made today to the SENS Research Foundation to help fund rejuvenation research programs aimed at effective treatment of the root causes of age-related disease will be matched three times over.

(And if SENS research isn't your cup of tea, then allow me to point out that the scientist behind DRACO anti-viral technology, capable of controlling near all viral infections including many that currently lack effective therapies, is presently raising funds for ongoing research and development at IndieGoGo. Regardless of views on the best way forward for aging research, I would hope we can all agree that the work to date on DRACO is very promising, the world will be a better place with fewer viral infections, and that helping this project is also a worthy cause).

The SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease, has joined #GivingTuesday, a global day of giving that harnesses the collective power of individuals, communities and organizations to encourage philanthropy and celebrate generosity worldwide. Every donation made to SRF up to the first 5,000 will be quadrupled, making these funds raised turn into 20,000.

SENS Research Foundation is aiming to reach a goal of 20,000 with the help of contributors who have pledged to match each donation up to the first 5,000. The Croeni Foundation, a philanthropic organization dedicated to giving, the environment and health, has pledged to match the first 5,000 raised. The foundation gave SRF an unrestricted 5,000 earlier this year, as well. Aubrey de Grey, CSO of SENS Research Foundation, has offered a matching challenge up to 5,000. And Fight Aging! will match every donation up to 125,000 through December 31, 2015.

"Today's cost for the treatment and care of chronic diseases of aging costs around 40,000 per second and will only continue to go up, as we spend more money per patient, while the number of patients is increasing. As a society, we need to change our ways and start treating age-related diseases more intelligently. The funds we raise on #GivingTuesday will help facilitate our efforts to do just that, as we work to continue learning how to prevent or reverse age-related diseases."

Wednesday, December 2, 2015

Carbon buckyballs, C60, have been a topic of interest to the longevity advocacy community since a study a few years ago claimed significant life extension in rats. I remain very skeptical: it was a small number of animals, carried out by people outside the aging research community, published in a journal that doesn't normally cover this topic, and the claimed effect was double that achieved by the mainstream community via other methods in rats. It just doesn't pass muster. Nonetheless, people are interested, and crowdfunded attempts to replicate the result are ongoing.

There is better, albeit still thin, support for C60 to be a beneficial adjuvant treatment or delivery method for chemotherapy in cancer therapies. Ichor Therapeutics has been looking to raise funds for some of their early stage work on this topic of late. The Methuselah Foundation stepped in to fund this research earlier in the year, and here is an update on this topic. This will no doubt be of interest to those who consider it worthwhile following up on claims of life extension via C60 in normal mice:

Ichor Therapeutics, Inc., is a pre-clinical biotechnology company that develops technologies to target age-related pathology. The company received 79,775 in grant funding from Methuselah Foundation in July, 2015, to develop a C60-based therapy for acute myeloid leukemia (AML). AML is a lethal blood cancer with only a 24% five-year survival rate. Ichor reports that short-term biodistribution studies have been completed, and long-term studies are ongoing. These studies track the accumulation and reduction of C60 in the blood and various organs over time, and are essential for establishing a safety profile during pre-clinical studies. The company has also initiated a large scale repeat of its pilot efficacy study, which led to a doubling of median lifespan in a mouse model of AML.

"We are eagerly awaiting the results of our efficacy study. Our current data supports the hypothesis that C60 may be a safe and effective therapeutic candidate for several age-related diseases, including cancer. Quality assurance is a critically important part of manufacturing, yet is often ignored in the context of research grade products. Methuselah Foundation supported early development of quality assurance measures in preparation for our studies. We were surprised to discover that when we evaluated multiple sources of C60, there were large disparities between what is reported by vendors, and what is actually contained within their products." While a promising therapeutic compound, C60 is not approved for use as a drug or supplement. Its manufacturing is currently unregulated.

"Methuselah and Ichor will be exploring appropriate solutions to the problem of unreliable formulations. Ichor is actively adopting cGLP and cGMP standards. Once in place, we can begin FDA compliant manufacturing and pre-clinical safety and toxicity testing. We think C60 could have immense potential to treat disease, but it is important to take a measured approach as we move towards the clinic. Any new compound should be rigorously investigated before human use, especially for safety." The company expects its studies to conclude by March, 2016, and intends to publish the results in an open access peer-reviewed journal.

Wednesday, December 2, 2015

Researchers continue to expand the application of decellarization to engineer more types of patient-matched tissues from more types of donor organ. Here is news of a proof of concept carried out in rats, in which a donor diaphragm is decellularized and transplanted successfully:

An international collaboration between scientists has resulted in the successful engineering of new diaphragm tissue in rats using a mixture of stem cells and a 3D scaffold. When transplanted, it has regrown with the same complex mechanical properties of diaphragm muscle. The diaphragm is a sheet of muscle that has to contract and relax constantly to allow breathing. It is also important in swallowing, and acts as a barrier between the chest cavity and the abdomen. The success of this study also offers hope for the possibility of regenerating heart tissue, which undergoes similar pressure as it contracts and relaxes with every beat. "So far, attempts to grow and transplant such new tissues have been conducted in the relatively simple organs of the bladder, windpipe and esophagus. The diaphragm, with its need for constant muscle contraction and relaxation puts complex demands on any 3D scaffold; until now, no one knew whether it would be possible to engineer. This bioengineered muscle tissue is a truly exciting step in our journey towards regenerating whole and complex organs. You can see the muscle contracting and doing its job as well as any naturally-grown tissue - there can be no argument that these replacements are truly regenerated."

In the current study, the researchers took diaphragm tissue from donor rats and removed all the living cells from it using a series of chemical treatments. This process removes anything that might cause an immune response in the recipient animals, while keeping all the connective tissue - or extracellular matrix - which gives tissues their structure and mechanical properties. When tested in vitro, these diaphragm scaffolds at first appeared to have lost their important rubber-like ability to be continually stretched and contracted for long periods of time. However, once seeded with bone marrow derived alloegenic stem cells and then transplanted into the animals, the diaphragm scaffolds began to function as well as undamaged organs. The method must now be tested on larger animals before it can be tried in humans, but the hope is that tissue-engineered repairs will be at least as effective as current surgical options.

Thursday, December 3, 2015

Here is an open access commentary on recent research into the damaged biochemistry of extremely old individuals, in which the authors pull together the strands of chronic inflammation, senescent cell accumulation, and erosion of telomere length, all associated with mortality and the progression of degenerative aging, though much more robustly for the first two in that short list:

Human aging is accompanied by a chronic low-grade inflammation, called "inflammaging", a phenomenon associated with frailty, morbidity, and mortality in elderly people. This condition is related to the accumulation of senescent cells in aged tissues through the senescence-associated secretory phenotype (SASP), which includes pro-inflammatory cytokines among its key constituents. A well-known trigger of cellular senescence, closely related to inflammaging, is telomere length shortening. However, while considerable evidence shows that circulating inflammatory markers are predictors of mortality in community-living elderly individuals, there are conflicting results on the role of telomere length.

It was recently demonstrated with a cross-sectional approach that telomere length, measured in the DNA extracted from whole blood of centenarian offspring, centenarians and (semi-)supercentenarians displays a superior maintenance compared to the one measured in community-living elderly subjects. Indeed, telomere length of centenarian offspring is maintained for more than 20 years at a length corresponding to 60 years of age in the general population. Interestingly, the authors observed that while long telomeres might be a prerequisite for exceptional lifespan in humans, they did not predict mortality. Conversely, they confirmed that a multibiomarker score of systemic inflammation, which included anti-cytomegalovirus IgG, IL-6, TNF-α and C-reactive protein levels, was associated with an increased risk of mortality, loss of cognitive function and physical function decline, in normal aging and at extreme old age (up to 110 years).

These data demonstrate that a multiple biomarker index may represent a more powerful predictor of mortality in older adults than a single inflammatory mediator, as also recently shown through a combined measure of interleukin 6 (IL-6) and soluble TNF receptor 1 (sTNFR1). Therefore, the development of reliable measures of inflammatory status is of great interest in clinical practice both as risk assessment tools of age-related chronic diseases, and to monitor clinical progression or as a powerful surrogate biomarker in the research of new anti-inflammatory therapeutics.

Hence, given that inflammation is a consolidated predictor of mortality, it is also important to investigate the sources of this phenomenon and their relative contribution. While it is known that cell senescence and inflammation can drive each other thus causing accelerated aging, these results suggest that blood telomere length might not reflect the phenomenon of accumulation of senescent cells in various tissues and organs. This could be particularly true if accumulating senescent cells will be confirmed as a major source of circulating inflammatory markers in aging. In this context, the development of strategies to remove senescent cells could represent an emerging tool for the suppression of chronic inflammation and to ameliorate human healthy lifespan.

Thursday, December 3, 2015

Another day, another method of slowing aging in a laboratory species. The diversity of techniques is increasing every year, and many slip by without comment, as there are simply too many now to remark on every one of them. This particular method has the look of working via hormesis - allowing an accumulation of molecules that cells react to as damage, and thus increase repair and maintenance activities, but which is not harmful enough in and of itself to outweigh the benefits of that increased cellular housekeeping.

One of the reasons for such a wealth of ways to slow aging in short-lived species is that there are countless possible methods by which researchers can provoke a hormetic response, and the same is true for the other underlying mechanisms that might work to modestly slow aging if manipulated. Everything in cellular biochemistry is connected, so a core mechanism of interest might be tweaked by altering any one of dozens of genes or levels of circulating proteins. Indeed, part of the challenge inherent in this situation is that it is very hard to determine the identity of the core mechanism when there are so many actions that produce benefits, and every change cascades throughout cellular biochemistry. Another thing to bear in mind while reading these sorts of research results is that all of the methods of slowing aging in short-lived animals for which we also have data in humans show that in our species the result on life span is small at best, even when the result on health is worth chasing, as is the case for calorie restriction and exercise:

Researchers used statistical models to establish an intersection of genes that were regulated in the same manner in the worms, fish and mice. This showed that the three organisms have only 30 genes in common that significantly influence the ageing process. By conducting experiments in which the mRNA of the corresponding genes were selectively blocked, the researchers pinpointed their effect on the ageing process in nematodes. With a dozen of these genes, blocking them extended the lifespan by at least five percent. One of these genes proved to be particularly influential: the bcat-1 gene. "When we blocked the effect of this gene, it significantly extended the mean lifespan of the nematode by up to 25 percent."

The researchers were also able to explain how this gene works: the bcat-1 gene carries the code for the enzyme of the same name, which degrades so-called branched-chain amino acids. Naturally occurring in food protein building blocks, these include the amino acids L-leucine, L-isoleucine and L-valine. When the researchers inhibited the gene activity of bcat-1, the branched-chain amino acids accumulated in the tissue, triggering a molecular signalling cascade that increased longevity in the nematodes. Moreover, the timespan during which the worms remained healthy was extended. As a measure of vitality, the researchers measured the accumulation of ageing pigments, the speed at which the creatures moved, and how often the nematodes successfully reproduced. All of these parameters improved when the scientists inhibited the activity of the bcat-1 gene.

The scientists also achieved a life-extending effect when they mixed the three branched-chain amino acids into the nematodes' food. However, the effect was generally less pronounced because the bcat-1 gene was still active, which meant that the amino acids continued to be degraded and their life-extending effects could not develop as effectively.

Friday, December 4, 2015

Researchers have in recent years made inroads into the infrastructure and knowledge needed to investigate the molecular biology of aging in killifish. The various species of killifish occupy a good compromise position between short length of life and the degree to which their biochemistry is relevant to human aging. As an added bonus, there is a fair degree of variation in life span between different killifish species, allowing for comparative investigations of their genetics and cellular biology. Short-lived animals mean faster studies, more research conducted for any given amount of funding, but the further removed from humans the species is, the more likely it is that the output of any given study provides no useful insight to direct the study of aging in mammals. As in all things, there are trade-offs involved.

A favourite of fish hobbyists since the 1970s, killifish are gaining popularity among scientists who study ageing, and dozens of labs now house them. Elderly killifish - a couple of months old - show hallmarks of ageing. Their bright scales fade and their cognition wavers; many develop tumours. Lifespan-altering experiments that take years in mice and decades in primates can be over in months in killifish, which are also more closely related to humans than are fruit flies, nematodes and other short-lived lab organisms popular in ageing research. "It turns out to be the shortest-lived vertebrate that can be raised in captivity."

The turquoise killifish genome contains several clues to its peculiar, fleeting life. Valenzano and his colleagues found that variations in genes involved in nutrient sensing, DNA repair and ageing have been selected for during its evolutionary history. Such genes might prove instructive for ageing in longer-lived animals. One such is IGF1R, which has been linked to extreme longevity in bowhead whales, naked mole-rats and Brandt's bat. Genes linked to IGF1R vary between an extremely short-lived killifish lab strain and a wild variety that can live for twice as long. A similar difference between short-lived and longer-lived strains was also seen in a gene that has been linked to dementia in humans. "Maybe these genes are central hubs for regulating survival. In some species they can accelerate ageing, and in some they can slow it down."

Genetic-engineering experiments - such as creating knock-out fish that lack particular genes - are needed to confirm whether the genes pinpointed in these studies truly influence ageing. These tests are already under way. Earlier this year a team used CRISPR-Cas9 genome editing in 'proof-of-principle' experiments to alter several ageing-related genes in killifish. "We are excited at trying to make it live longer." The team is also screening drugs in killifish to see if any lengthen its lifespan or slow tissue degeneration.

Friday, December 4, 2015

I'm pleased to note that more than 130 people donated a total of more than 27,000 to SENS rejuvenation research on Giving Tuesday. We are now just a few thousand short of hitting the 125,000 goal for this year's Fight Aging! SENS fundraiser. Thank you all for your support! With the additional 125,000 from the matching fund, together we'll soon have directed a total of 250,000 to speed progress towards regenerative therapies capable of repairing the cell and tissue damage that causes aging.

The SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease, received 27,317 on December 1, Giving Tuesday - more than double what the foundation raised on Giving Tuesday 2014. Funds received this year came from nine countries, including Australia, Canada, Czech Republic, Denmark, Norway and the United Kingdom, as well as the USA. In addition to the donations, SENS Research Foundation will receive two 5,000 challenge grants and a match for all the funds raised.

Giving Tuesday is a global day of giving that harnesses the collective power of individuals, communities and organizations to encourage philanthropy and celebrate generosity worldwide. The event is held annually on the Tuesday after Thanksgiving in the U.S. to kick-off the holiday giving season and inspire people to collaborate in improving their local communities and to give back in impactful ways to the charities and causes they support.

SENS Research Foundation's goal at the outset was 20,000 with the help of contributors who pledged to match donations up to the first 5,000. The Croeni Foundation, a philanthropic organization dedicated to giving, the environment and health, matched the first 5,000. The foundation gave SRF an unrestricted 5,000 earlier this year, as well. Aubrey de Grey, CSO of SENS Research Foundation, will also match 5,000, and Fight Aging! is matching donations up to 125,000 raised from October 1 to December 31, 2015. "We are thrilled to have exceeded our goal for this year's Giving Tuesday. We extend our sincere appreciation to all those who contributed funds including Jan Croeni and the Croeni Foundation, Aubrey de Grey, and Fight Aging! for their support. These funds will help us continue our research into the damage repair approach to the diseases and disabilities of aging."


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