Fight Aging! Newsletter, December 28th 2015

December 28th 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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  • One Week Left for the 50,000 Foster Foundation SENS Research Matching Fund - Nearly Half Way to the Target
  • Exercise Differences Do Not Produce Longevity Differences in Identical Twins
  • Recent Research into Longevity-Associated Human Genes
  • Major Mouse Testing Program Launches
  • Yet More Evidence for Long-Term CMV Infection to Increase Disease and Mortality in Old Age
  • Latest Headlines from Fight Aging!
    • The Economic Promise of Delayed Aging
    • Lower Epigenetic Measures of Age Observed in the Children of Long-Lived Individuals
    • Enhancing Proteasomal Activity in the Brain as an Approach to Treating Neurodegenerative Diseases
    • Progress in Tooth Tissue Engineering
    • The Muscles of Old, Still Active Athletes are as Aged as Those of Non-Athletes
    • A Small Step Towards Determining the Relevance of Nuclear DNA Damage to Normal Aging
    • Petitioning the German Government to Fund Longevity Science
    • Investigating the Decline of Nrf2 in Aging
    • Circadian Clock Mechanisms are Required for Longevity via Calorie Restriction?
    • Calorie Restriction Benefits in Rats Do Not Scale As Expected

This has been a great year for SENS rejuvenation research, both in progress in the lab and in fundraising from the growing community of supporters. The work needed to build the first therapies capable of repairing the root causes of aging, and thereby preventing and turning back age-related disease and disability, is moving forward. New allies are arriving, and more attention by industry, public, press is being given to this critical area of medical research. The year ends a little under a week from now, and there is still more than 25,000 left in the final matching fund put up a week ago by the Foster Foundation. All charitable donations made to the SENS Research Foundation before the end of 2015 will be matched from this fund - so it isn't too late to make a difference this year.

We are pleased to announce that the Foster Foundation, a longtime supporter of SENS Research Foundation, has offered us a final year end challenge. They will match up to 50,000 raised from December 14th to 31st. Formerly the Rose and Winslow Foster Family Foundation, the Foundation has provided over 150,000 in donations to SRF this year. We thank them for their amazing support of our mission. Help us secure this challenge grant by donating today and helping enable SRF's critical work to end age-related disease.

Earlier this year, the SENS Research Foundation crowdfunded more than 45,000 for mitochondrial DNA repair research via This year also saw progress in the for-profit world towards the first practical single-gene implementation of this same technology for the treatment of inherited mitochondrial disease, an important part of building a robust clinical technology platform to prevent the contribution of mitochondrial DNA damage to degenerative aging. Our 2015 Fight Aging! matching fundraiser, held in collaboration with the SENS Research Foundation, was also a success and raised 250,000 for research into the effective treatment of aging over the last few months.

Going on for 600 people donated to this year's SENS fundraisers, or at least to those where I can count the totals. The more attention we can create, the more discussion, the more modest donations made in the same spirit as people donate to cancer research, the better off we will all be. It is the hum and chatter and spirited donations from the grassroots that draw the attention of high net worth philanthropists and conservative traditional funding sources. The only way to see six and seven figure checks in the mail is to first have thousands of people cheering you on. Those with deep pockets rarely lead the crowd: they put their support to organizations with backing. Early stage research in the life science is very cheap these days - that 45,000 for mitochondrial repair research will enable six months of highly productive work at the cutting edge by people who know more about the particular approach taken by the SENS Research Foundation than near anyone else in the world. Our donations are not of token value, and enable real and meaningful progress. Nonetheless, in the long term the greater value we provide to the future of humanity is to shine a light, to be a beacon pointing out the worth of SENS research - and the value of the treatment of aging as a goal - to those who can fund causes with millions and more.

This is an important, transformative time in the shift from the old approach to age-related disease towards the new approach of medicine to treat aging itself. The avalanche is starting, and what we do today will shape the direction and pace of progress for years to come. So back the causes you believe in.


An interesting open access paper on exercise in identical and non-identical twin pairs was recently published, the data suggesting that long-term differences in physical activity between identical twins don't result in any significant difference in longevity, even though other differences in health outcomes are observed. We might draw parallels between this and similar results observed in a mouse study from a few years back, in which the exercising mice had better health but no increase in maximum life span. The researchers here theorize that the well-known epidemiological association between exercise and increased life expectancy is perhaps as much a matter of genetics as of choice.

For any observed statistical relationship in humans there are always questions of causation. This is especially true in the web of associations related to aging and mortality in population data, in which life expectancy, wealth, social status, intelligence, education, exercise, diet, and culture all have ties to one another. That we pay great attention to these relationships is a function of having no good way to treat aging, I've long thought: we care about trivial differences in life expectancy of a few years here and a few years there because this is all that is in our power to change right now, and that will continue until the development of rejuvenation therapies. Life expectancy and exercise are linked robustly in many data sets, and even more so now that accelerometers are so cheap and ubiquitous that even large studies can use them to obtain actual rather than self-reported data on physical activity. There are studies to demonstrate longer life expectancy in athletes, longer life expectancy in those who exercise modestly versus those who are sedentary, and so forth. What are these studies measuring, however? For example, what if people who are more robust and would live longer regardless of exercise tend to exercise more? Or perhaps exercise levels are a good proxy for lower levels of visceral fat tissue and consequent chronic inflammation - themselves linked to greater risk of age-related disease and mortality.

The results of this study definitely muddy the waters in the search for causation and mechanism in exercise and mortality reduction, providing evidence to support a state of considerable complexity in the relationship between exercise, genetics, and outcomes in health. Nothing in biology is ever as simple as we'd like it to be, so this should perhaps be expected. Regardless he data presented below should be added to the many past studies on exercise and mortality, and its weight balanced accordingly - never take any single set of data and interpretations as gospel in science. This doesn't change the consensus, which is that you should exercise, and that you are expected to obtain benefits by doing so. It does add subtlety to the picture, however.

Lifespan - genetic background and physical activity

Animal studies have already shown that a strong link exists between genetic background and physical activity level. The purpose of our study was to investigate the associations between genetic background, physical activity level, and lifespan. We studied also both identical and non-identical same sex twin pairs of which one was physically active and his/hers co-twin was inactive. We looked for the association between physical activity level and lifespan by following the mortality of the twins for 23 years.

High physical activity level was associated with longer lifespan when looking at non-identical twins that differ for their genetic background. However, in identical twins, that share the same genetic background, in pairwise analyses comparing physically active members of a twin pair with their inactive co-twin, there was no difference in lifespan. Our results are consistent with previous findings, that animals that have high aerobic capacity are physically more active compared to animals with low aerobic capacity. The findings in human twins were in agreement with this: discordance in physical activity level was clearly more common among non-identical twins than in identical twins showing an effect of genetic background on physical activity level.

Vigorous physical activity in adulthood did not increase lifespan in human twins, even though physical activity is well-known to have various positive effects on health, physical fitness, and physical function. Based on our findings, we propose that genetic factors might partly explain the frequently observed associations between high physical activity level and later reduced mortality in humans. Our finding covers vigorous physical activity started at adulthood, hence physical activity started during childhood may have different effects. Thus, it will be critical to determine whether physical activity has a positive effect on lifespan when commenced early in life.

Physical activity in adulthood: genes and mortality

Observational studies report a strong inverse relationship between leisure-time physical activity and all-cause mortality. Despite suggestive evidence from population-based associations, scientists have not been able to show a beneficial effect of physical activity on the risk of death in controlled intervention studies among individuals who have been healthy at baseline. On the other hand, high cardiorespiratory fitness is known to be a strong predictor of reduced mortality, even more robust than physical activity level itself. Here, in both animals and/or human twins, we show that the same genetic factors influence physical activity levels, cardiorespiratory fitness, and risk of death. Based on both our animal and human findings, we propose that genetic pleiotropy might partly explain the frequently observed associations between high baseline physical activity and later reduced mortality in humans.

The prospective Finnish Twin Cohort includes all same-sex twin pairs born in Finland before 1958. Physical activity was measured with a structured questionnaire. We used persistence and changes in vigorous physical activity during the years 1975, 1981, and 1990 as baseline predictors of mortality. Altogether, 11,325 twin individuals (4190 complete twin pairs) answered the required physical activity questions for all three baseline time points. Of the 4190 same-sex twin pairs, we identified 179 persistently discordant for participation in vigorous physical activity.

Taken together, our results are consistent with previous data on rodents and humans, which indicated that genetic predisposition plays a significant role in exercise participation. These results are also consistent with our previous suggestion that genetic pleiotropy may partly explain the associations observed between high physical activity and mortality in our past epidemiological studies, which called for high quality intervention studies to analyse the true effects of physical activity on morbidity and mortality among initially healthy individuals. Our results also support the notion that inherited aerobic capacity is a predictor of longevity, but further study in both animals and humans is required to determine whether this is true for the portion of aerobic capacity enhanced by vigorous physical activity. Our findings are also consistent with previous studies that show positive effects of physical activity on glucose metabolism in rodents and human twins. However, vigorous physical activity does not improve longevity in twins or rodents, particularly when commenced in maturity. It is to note that randomized controlled trials show that vigorous physical activity has other health benefits.


Today I'll point out a couple of recent publications on the topic of longevity-associated genetic variants in humans. The research community devotes a lot of effort to the identification and confirmation of human genetic variants associated with greater longevity. The cost of obtaining genetic data continues to fall rapidly, and a few years from now will become small in comparison to the other costs of running a study. Ever more researchers are joining in as genetic studies fall within their budgets. In the world of pure scientific endeavor, the quest for knowledge, this is all good. There are few realms as large as that of genetics and cellular biochemistry, and the floodgates of data are opening as never before. Decades of work lie ahead to map even a sizable fraction of the intersection of aging and cellular metabolism at the detail level of molecular biology. In the long term, this is all useful: no data goes to waste, and whatever sort of comprehensive molecular nanotechnology that comes after medicine as we understand it today will require the complete map of human biochemistry as a starting point. That is a long way away, however.

From a practical point of view, in the context of producing ways to treat aging soon enough to matter, establishing the reasons why some people tend to live somewhat longer than others is a sideshow, however. It has little to no relevance to meaningfully extending the healthy human life span for everyone. For one, it is clear from work to date that (a) there are many, many contributing factors to the relationship between genetics and aging, (b) any single factor has a tiny, sometimes almost indistinguishable statistical effect on mortality, and (c) the vast majority of those factors are different for every study population. You can fill a book with the associations found to date and never replicated, while there are only a few genetic variants that hold up in multiple studies, such as APOE. Secondly, given drugs or other therapies that accurately alter genes and protein levels in a human to mimic those of a centenarian, what does that get you? A very small boost to your chances of living more years in a state of advanced aging and increasing frailty. The vast majority of those with the same genetic variants as long-lived study populations die on much the same schedule as the rest of us. If the research community is going to invest time and effort on treatments for aging, then they should at least be treatments with a large expectation value in terms of mortality reduction and healthy life extension.

These studies are representative of the range of work presently taking place: initial identification of possible associations with longevity; confirmation studies discarding the majority of associations found elsewhere; and studies outlining ways to improve the process of identifying genetic associations with longevity.

Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

Longevity is a complex phenotype, and few genetic variants that affect lifespan have been identified. However, aging and disease are closely related, and a great deal is known about the genetic basis of disease risk. Here, we show using genome-wide association studies (GWAS) of longevity and disease that there is an overlap between loci involved in longevity and loci involved in several diseases, such as Alzheimer's disease and coronary artery disease. We then develop a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from 14 large studies of disease and disease-related traits in order to narrow the search for SNPs associated with longevity. Using iGWAS, we found eight SNPs that are significant in our discovery cohorts, and we were able to validate four of these in replication studies of long-lived subjects. Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits. Beyond the study of human longevity, iGWAS can be applied to boost statistical power in any GWAS of a target phenotype by using larger GWAS of genetically-related conditions.

In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40). With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated included APOE/TOMM40 (associated with Alzheimer's disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease).

Association study of polymorphisms in FOXO3, AKT1 and IGF-2R genes with human longevity in a Han Chinese population

FOXO3, AKT1 and IGF-2R are critical members of the insulin/IGF-1 signaling pathway. Previous studies showed that polymorphisms (SNPs) in FOXO3, AKT1 and IGF-2R were associated with human longevity in Caucasian population. However, the association of these SNPs in different ethnic groups is often inconsistent. Here, we investigated the association of genetic variants in three genes with human longevity in Han Chinese population. Twelve SNPs from FOXO3, AKT1 and IGF-2R were selected and genotyped in 1202 long-lived individuals (nonagenarians and centenarians) and younger individuals. Rs9486902 of FOXO3 was found to be associated with human longevity in both genders combined in this study. The other eleven SNPs were not significantly associated with human longevity in Han Chinese population.

Serum BPIFB4 levels classify health status in long-living individuals

People that reach extreme ages (Long-Living Individuals, LLIs) are object of intense investigation for increase/decrease of genetic variant frequencies, genetic methylation levels, protein abundance in serum and tissues. The aim of these studies is the discovery of the mechanisms behind LLIs extreme longevity and the identification of markers of well-being. Our recent multi-step genetic analysis of Italian (the screening set), and US and German LLIs (replication sets) and relative control populations, identified a variant in BPIFB4, down-regulated during aging and high in CD34+ of LLIs, and the codified protein (LAV-BPIFB4) to be a powerful boost for endothelial vasorelaxation and revascularization, two functions lost during aging and cause of human frailty.


The news for today is that the Major Mouse Testing Program has launched. This is an initiative set up by advocates and researchers associated with the non-profit International Longevity Alliance, and is intended to speed up testing and replication of promising potential treatments for aging in mice - though of course there are considerable differences by scientific faction as to just what is considered a promising potential treatment. The Major Mouse folk will be crowdfunding their efforts, building on the growing experience in the community in raising funds for research this way in recent years.

Within the SENS portfolio of repair biotechnologies there are actually few options presently at the point of viable interventions that are both low cost and worth trying: senescent cell clearance has a number of potential approaches, mitochondrial DNA repair is getting close, though not on the cost front due to the reagents needed, there have been demonstrations of improved lysosomal function in old animals leading to functional rejuvenation of tissues, and so on. We can argue about which portions of the very broad field of stem cell medicine might be considered rejuvenation biotechnology at this point. Even in this comparatively small present portfolio of practical options there is far too little work taking place in mice, however. There should be dozens of studies running for senescent cell clearance alone given the potential it shows. This is just considering SENS, however. For people who are more interested in the mainstream approach of trying drugs to slow aging, such as the development of calorie restriction mimetics, autophagy enhancers, and the like, for all that this is likely an expensive way to produce marginal benefits, there is an enormous array of things to test that are not being tested.

A lot of compounds and drugs have been tested in mice (and other laboratory species) in the past few decades. Most of these results have to be thrown out, especially those showing modest extension of lifespan, as few of those studies controlled adequately for inadvertent calorie restriction or were otherwise robust enough to pass muster. Calorie restriction has a large effect on aging and lifespan in short-lived animals, larger than almost any other intervention tested to date: if a compound makes animals nauseous, they will eat less and live longer, but there are many other ways to accidentally create incorrect data. The National Institute on Aging runs the Interventions Testing Program (ITP), which conducts very robust life span studies in mice. The most important output of this program, to my mind, is that it has demonstrated that most currently available interventions have tiny positive effects at best. Hopefully it has served to convince more people that developing drugs to alter metabolism with the aim of slowing aging is a road to nowhere, and that a different approach - i.e. SENS-like therapies that repair the damage that causes aging - is needed.

The Major Mouse Testing Program exists because the ITP is slow, and very few groups outside the ITP are doing anything of this nature. The ITP staff test only a few options in any given year, and adventurous tests such as "let's combine everything shown to extend life so far and see what happens," or "let's try something related to SENS" are never going to be on the agenda at the NIA, or at least not for the foreseeable future. The Major Mouse folk are not so constrained, however.

Major Mouse Testing Program

We live in exciting times - for the first time in human history extending healthy human lifespan is rapidly becoming a realistic prospect. Scientific breakthroughs in research mean we could soon be living healthy, active lives for much longer than people do now. Some drugs tested have been found to increase mouse lifespan such as Metformin and Rapamycin for example and are considered for human testing. Many more substances have never been tested and we do not know if they might extend healthy lifespan. More studies are needed before we can move onto human tests - and ultimately medicines that people can use. What happens next depends on how much more quality research is being done by scientists - and that research needs funding. We are launching an ambitious international project, called the Major Mouse Testing Programme (MMTP) via a crowdfunding campaign to support this important work.

Right now very few high impact studies investigating lifespan are initiated each year - and with around one in ten promising substances tested so far found to actually make mice live longer, this is painfully slow progress. We are working to redress this situation and with an international team of dedicated lead researchers, three high quality laboratories and a dedicated team, we are hoping to make a real contribution to the field of regenerative medicine. The Major Mouse Testing Programme is a project that aims to speed up the pace of progress up by rapidly testing longevity interventions - meaning research which would have taken 100 years at today's rate can be done in five. It is also plausible that some interventions, when combined could have a synergy where the effects are greater than the individual compounds, this has certainly been the case for senescent cell clearance with Dasatinib and Quercetin. It is likely there are more synergies to be discovered and this is where the MMTP plans to push forward, not only testing single interventions but also combinations to seek out these powerful combinations.

We have opted to test with mice partly due to the costs involved and mouse studies are also considerably easier to organize and are the usual starting point prior to moving into higher animals such as rabbits, dogs and ultimately humans. Organisations such as the FDA for example also usually require substantial animal data prior to approving any clinical trials involving people so this is another reason for choosing to begin here. The initial phase of the project has a limited number of substances to be tested, but importantly it will demonstrate that the team is able to conduct the large scale intervention studies testing more complicated and expensive interventions demand. As part of the current project we are planning to test at least two substances. One which is known to increase mouse lifespan (Rapamycin) to show that the labs can generate the same consistently high quality data. This will serve as our positive control group to ensure all three labs are operating to the same rigorous high standards and are producing the same data.

You can see the first set of interventions the team plans to test in their research portfolio, along with explanations as to why these drugs have been chosen. You'll see that the senolytic drug combination to clear senescence cells reported earlier this year is on the list. Running a replication study there is a useful thing to do, I'd say, given that the original researchers don't seem all that interested in following up on their work with a life span study.


A few weeks ago I pointed out recent study data from a German population on cytomegalovirus (CMV) and its role in immune aging. Today I'll note a companion study of a different population of older people that focuses more on the relationship between CMV and mortality. It is the story you might expect if you've been reading on this topic for any great length of time, as testing positive for CMV infection is here found to be associated with a significantly greater rate of age-related disease and mortality. Cytomegalovirus (CMV) is a pervasive herpesvirus that, like its peers, cannot be effectively cleared from the body by the immune system. Unlike its peers CMV has no obvious and immediate effect on health for anyone with a normally functioning immune system. You probably have it already, you never noticed your initial infection, and the overwhelming majority of people test positive for CMV infection by the time they are old. A growing body of evidence implicates long-term CMV infection in the development of immunosenescence, the processes that result in declining effectiveness and growing dysfunction of the immune system in aging.

The immune system is one of the more intricate cellular systems in the body, and it is far from fully understood at the detail level. Most of the ways in which it can fall into persistent dysfunction, as is the case in autoimmune disease and aging, are similarly at best currently understood only in outline. Yet the immune system is very important in the progression of degenerative aging. It has numerous roles that go beyond defending against invading pathogens, such as the elimination of potentially cancerous or senescent cells, both of which can be a source of harm. Further, a dysfunctional, aged immune system generates ever greater levels of chronic inflammation, and this inflammation contributes to the development of all of the common, ultimately fatal age-related conditions.

The immune system in adults has a very slow rate of generation of new immune cells, and this and other factors give it many of the characteristics of a system that is limited by space. Present thinking on CMV is that its constant presence causes the immune system to devote ever more of this limited space to cells that are specialized for CMV and useless for everything else. Further, constant immune activity, such as when battling pathogens like CMV that cannot be cleared, tends to force more immune cells into an exhausted, senescent state - this is a well studied phenomenon for HIV and AIDS, for example. This is no doubt an incomplete sketch of a complicated and nuanced collection of destructive processes, but what can be done about it? A way to clear CMV won't fix the damage done to date, and infection doesn't appear to do any harm beyond this slow immune destruction, so targeting CMV is probably not the best of approaches - more of a nice to have for the long term. Delivering lots of new immune cells on a regular basis to circumvent natural limits, such as via cell therapies or rejuvenation of the thymus will be more effective for the elderly. The other side of the coin is targeted destruction of CMV-specialized and useless immune cells, which should spur replacement with unspecialized and useful cells. As the paper quoted below demonstrates, something effective must be done:

CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

Human cytomegalovirus (CMV) is a ubiquitous herpes virus and shares a high prevalence in developed countries. A growing body of evidence suggests an important role of CMV during aging. Seropositivity for CMV is one of the parameters in the immune risk profile (IRP), associated with increased mortality in longitudinal studies in octo- and nonagenarians. While the IRP was present in only 20% of the 85-year-olds, CMV seropositivity is present in approximately 80-90% of octogenarians. CD8 T-cell responses in CMV-seropositive elderly are characterized by an accumulation of dysfunctional T cells with short telomeres and low proliferation potential, often considered as replicative senescent. Clinically, CMV has been linked to an increased incidence of coronary heart disease (CHD) in a number of studies. It has been proposed that CMV-driven cardiovascular mortality might be the main cause for the observed increase in mortality in CMV-seropositive people over the age of 65 years.

The goal of our study was to evaluate whether in octogenarians CMV seropositivity and T-cell senescence are independent predictors of all-cause and especially cardiovascular and CHD-mediated mortality. we prospectively analyzed peripheral blood samples from 751 octogenarians (38% males) from the Newcastle 85+ study for their power to predict survival during a 65-month follow-up (47.3% survival rate). CMV-seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%) compared to CMV-seronegative participants together with lower CD4/CD8 ratio and higher frequencies of senescent-like CD4 memory cells and senescent-like CD8 memory cells. CMV seropositivity was also associated with increased six-year cardiovascular mortality (hazard ratio 1.75) or death from myocardial infarction and stroke (hazard ratio 1.89). Analysis revealed that low percentages of senescent-like CD4 T cells and near-senescent CD8 T cells reduced the risk of cardiovascular death. We conclude that CMV seropositivity is linked to a higher incidence of CHD in octogenarians and that senescence in both the CD4 and CD8 T-cell compartments is a predictor of overall cardiovascular mortality as well as death from myocardial infarction and stroke.


Monday, December 21, 2015

As a companion to the recently published book Aging: The Longevity Dividend, you might take a look at this paper on the economics of even marginal success in slowing aging. The gains examined are very small in the grand scheme of things, a few additional years of health via some form of drug-based therapy to adjust the operation of cellular metabolism, such as calorie restriction mimetics, or other approaches such as enhancing autophagy. Drugs based on recapturing the well-studied calorie restriction response have been promised for years, but have yet to arrive in any meaningful way, despite a large research investment in time and money.

Biomedicine has made enormous progress in the last half century in treating common diseases. However, we are becoming victims of our own success. Causes of death strongly associated with biological aging, such as heart disease, cancer, Alzheimer's disease, and stroke, cluster within individuals as they grow older. These conditions increase frailty and limit the benefits of continued, disease-specific improvements.

Here, we show that a "delayed-aging" scenario, modeled on the biological benefits observed in the most promising animal models, could solve this problem of competing risks. The economic value of delayed aging is estimated to be 7.1 trillion over 50 years. Total government costs, including Social Security, rise substantially with delayed aging - mainly caused by longevity increases - but we show that these can be offset by modest policy changes. Expanded biomedical research to delay aging appears to be a highly efficient way to forestall disease and extend healthy life.

7.1 trillion over 50 years is ~140 billion a year, which is about half of the present yearly direct costs of chronic disease in the US. The opportunity costs of aging and disease, in the form of people unable to work and support themselves, are much higher. Delayed aging is not solved aging, of course. If we want an end to aging, and an end to the costs of age-related disease, then rejuvenation research should be the primary approach, meaning efforts to repair the causes of aging rather than only trying to slowing them down. It isn't any harder to achieve this goal, so why aim for the worse outcome?

Monday, December 21, 2015

Researchers here demonstrate that a biomarker of aging presently under development shows a lower measure of age in the children of long-lived individuals. A number of research groups are involved in trying to create a standard measure of biological age based on patterns of DNA methylation, a type of epigenetic modification that regulates the production of specific proteins from their genetic blueprints. Cells react to circumstances, and one of those circumstances is the accumulation of molecular damage that causes aging. These forms of damage are the same in all of us, and so we should expect to find patterns in the epigenetic changes that accompany aging: some are individual, a matter of circumstances and environment, but others are shared and reflect the level of age-related cell and tissue damage suffered over the years.

Ageing researchers and the general public have long been intrigued by centenarians. We find it useful to further distinguish centenarians from semi-supercentenarians (i.e. subjects that reach the age of 105 years, 105+) and supercentenarians (subjects that reach the age of 110 years, 110+) because subjects in these latter categories are extremely rare. As of January 1, 2015, in the 60,795,612 living individuals in Italy, 100+ are 19,095, 105+ are 872, and 110+, which constitute an even smaller subgroup, are 27, according to the data base from the Italian National Institute of Statistics. On the whole, 105+ and 110+ subjects have to be considered very rare cohorts of particular interest for the study of both the ageing phenotype and the healthy ageing determinants. This means that 105+ and 110+ are most informative for ageing research, even if it is not yet known whether 105+ reach the last decades of their life according to a molecular trajectory which progresses at a normal rate of change or whether the attainment of this remarkable age results from a slower molecular ageing rate.

Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as "epigenetic clock". We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6), 63 semi-supercentenarians' offspring (mean age: 71.8), and 47 age-matched controls (mean age: 69.8). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference of 5.1 years) and that centenarians are younger (8.6 years) than expected based on their chronological age. Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing.

Tuesday, December 22, 2015

Researchers here demonstrate some of the benefits of enhanced cellular housekeeping in mice, the latest work on a general class of therapies to slow the progression of aging based on producing a state of more diligent cellular maintenance. Maintenance processes of interest include the various systems of autophagy responsible for recycling damaged cellular components, as well as the activities of proteasomes responsible for breaking down damaged or otherwise undesirable proteins. These processes are known to be more active in many of the interventions that extend life and slow aging in animals. Despite interest in this approach there has been little concrete progress beyond the laboratory over the past decade; the research here is similar to a number of past animal studies that have gone little further.

A study of mice shows how proteasomes, a cell's waste disposal system, may break down during Alzheimer's disease, creating a cycle in which increased levels of damaged proteins become toxic, clog proteasomes, and kill neurons. The study suggests that enhancing proteasome activity with drugs during the early stages of Alzheimer's may prevent dementia and reduce damage to the brain.

The proteasome is a hollow, cylindrical structure which chews up defective proteins into smaller, pieces that can be recycled into new proteins needed by a cell. To understand how neurodegenerative disorders affect proteasomes, researchers focused on tau, a structural protein that accumulates into clumps called tangles in the brain cells of patients with Alzheimer's disease and several other neurodegenerative disorders known as tauopathies. Using a genetically engineered mouse model of tauopathy, as well as looking at cells in a dish, the scientists discovered that as levels of abnormal tau increased, the proteasome activity slowed down.

Treating the mice at the early stages of tauopathy with the drug rolipram increased proteasome activity, decreased tau accumulations and prevented memory problems. They found that the drug worked exclusively during the early stages degeneration, which began around four months of age. It helped four-month old tauopathy mice remember the location of hidden swimming platforms as well as control mice, and better than tauopathy mice that received placebos. Treating mice at later stages of the disease was not effective. "These results show, for the first time, that you can activate the proteasome in the brain using a drug and effectively slow down the disease, or prevent it from taking a hold."

Rolipram was initially developed as an antidepressant but is not used clinically due to its side effects. It increases the levels of cyclic AMP, a compound that triggers many reactions inside brain cells. Rolipram works by blocking cyclic AMP phosphodiesterase four (PDE4), an enzyme that degrades cyclic AMP. The scientists found that cyclic AMP levels are critical for controlling proteasome activity. Treating brain slices from tauopathy mice with rolipram, or a version of cyclic AMP that PDE4 cannot degrade, reduced the accumulation of tau and sped proteasome activity.

Tuesday, December 22, 2015

Here is a demonstration of splitting tissue engineered teeth early in their development process so as to multiply the number of teeth produced. Researchers have for years now been able to grow functional teeth from cells in rodents, either by implanting suitable cells into the jaw, or more recently growing entire teeth outside the body. Work on refining the techniques involved continues apace, and one might well ask what is taking so long in moving these advances to human medicine. Dentistry is usually one of the more rapid areas of progress in clinical medicine, and it is getting on for near a decade now since the first demonstrations of teeth grown from cells in mice:

Researchers have found a way to - literally - multiply teeth. In mice, they were able to extract teeth germs, groups of cells formed early in life that later develop into teeth, split them into two, and then implant the teeth into the mice's jaws, where they developed into two fully functional teeth. Teeth are a major target of regenerative medicine. Approximately 10 percent of people are born with some missing teeth, and in addition, virtually all people lose some teeth to either accidents or disease as they age. Remedies such as implants and bridges are available, but they do not restore the full functionality of the teeth. Growing new teeth would be beneficial, but unfortunately humans only develop a limited number of teeth germs, the rudimentary cell groups from which teeth grow.

"We wondered about whether we might be able to make more teeth from a single germ." To demonstrate that it might be feasible, the group focused on the fact that teeth development takes place through a wavelike pattern of gene expression involving Lef1, an activator, and Ectodin, an inhibitor. To manipulate the process, they removed teeth germs from mice and grew them in culture. At an appropriate point in the development process, which turned out from their experiments to be 14.5 days, they nearly sliced the germs into two with nylon thread, leaving just a small portion attached, and continued to culture them. The hope was that signaling centers - which control the wave of molecules that regulate the development of the tooth - would arise in each part, and indeed this turned out to be true. The ligated germs developed naturally into two teeth, which the team transplanted into holes drilled into the jaws of the mice.

The teeth ended up being fully functional, allowing the mice to chew and feel stimulus, though they were only half the size of normal teeth, with half the number of crowns - a result that could be expected given that the researchers were using already developed germs. Significantly, they were able to manipulate the teeth using orthodontic methods, equivalent to braces, and the bone properly remodeled to accommodate the movement of the teeth.

Wednesday, December 23, 2015

The oldest of active athletes retain greater muscle power than the average older person, though there is always the question of cause and effect: to what degree is this a consequence of the choice to continue as an athlete, accompanied by all that exercise, versus being a situation in which an individual can only continue to be an athlete because he or she happens to be more resilient. As this study demonstrates, the resistance to age-related loss of overall muscle power in these individuals is not due to suffering a lower level of the shared fundamental degeneration of capabilities in muscle fibers:

Elite runners do not experience the muscle weakening associated with aging as non-athletes do. Movement and strength come from the muscle fibers that make up a muscle group contracting and generating tension. Muscle weakening happens when the fibers contract slower and with less force. Muscle fiber samples were taken from the quadriceps of older elite runners and non-athlete adults in the same age range. "These are individuals in their 80s and 90s who actively compete in the world masters track and field championships. In the study, we had seven world champions, and everyone placed in the top four of their respective events."

The fibers' contraction speed and force were compared to fibers from 23-year-old non-athlete adults. Muscle fibers from older non-athletes contracted considerably slower and weaker than fibers from young non-athletes. To the researchers' surprise, the muscle fibers of masters athletes contracted at a speed and force similar to those of older non-athlete adults, not the young adults. Success in high-performance sports in old age does not appear to be due to maintained contraction capability of the fibers. This study suggests that aging is associated with decreased muscle quality regardless of physical activity status. However, other studies have shown that muscle fibers can be arranged in a variety of ways to optimize strength, speed and power of the whole muscle, so there are many structural ways to compensate for the reduced performance at the fiber level to maintain performance at the whole muscle level.

Wednesday, December 23, 2015

Researchers recently reported the development of a system to generate a form of damage to nuclear DNA in a sizable number of discrete locations in a controlled, isolated way, and use it to test a limited hypotheses regarding the contribution of DNA damage to age-related epigenetic changes. This is a small step forward towards determining whether or not nuclear DNA damage is a meaningful cause of aging. This damage occurs constantly and randomly, most of it repaired, but the few mutations that slip through accumulate in tissues across a lifespan. You have more of this damage if you are old, and this is one of the reasons that cancer is an age-related disease: the more mutations, the more likely it is that the right combination to spark a cancer occurs. But beyond cancer, is this random nuclear DNA damage, different in every cell, a significant cause of aging over the present human life span? The consensus is yes, and the thinking is that these mutations cause enough dysregulation of cellular activities to be harmful, but this consensus is disputed.

What is needed is a way to either create or repair random nuclear DNA damage in isolation of other cellular processes. There are plenty of interventions to slow aging in laboratory animals that happen to slow the rate at which nuclear DNA damage occurs, but these interventions also alter vast swathes of the operating details of cellular metabolism. There is no way to pin down the relevance of nuclear DNA damage on its own in that situation. The methodology reported in the open access paper linked here is a small step towards the sort of biotechnology needed to reproduce random nuclear DNA damage in much the same way as it occurs naturally, and thus run a study on whether or not it is a cause of aging. There is still a way to go towards that end result, however:

The accumulation of DNA damage is a conserved hallmark of cancer and aging. Of all DNA lesions, DNA double-strand breaks (DSBs) are arguably the most harmful. Defects in DSB repair can result in cell cycle arrest, apoptosis or genomic aberrations and have been linked to both disease progression and a premature onset of aging phenotypes. Consistent with the latter, DSB induction was found to be sufficient to promote a subset of age-related pathologies in mice. In addition to the often detrimental effects of mutations and chromosomal abnormalities, DSBs cause significant changes in the chromatin environment both at and beyond the break site, raising the intriguing possibility that DSB repair contributes to (persistent) epigenetic defects that may eventually alter cell function. It is of note that epigenetic dysfunction in a small subset of cells may be sufficient to affect entire tissues, and possibly organismal aging.

The distinction between cell-intrinsic and systemic consequences of DSB induction is, thus, critical to advance our understanding of the role of DSBs in age-associated functional decline. However, despite numerous cell-based reporter systems for DSB induction, there is a scarcity of tools to follow the consequences of DSBs for cell and tissue function in higher organisms. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at ∼140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo. Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction.

Thursday, December 24, 2015

The German parliament has a formal petition system that does actually seem to result in dialog with politicians, unlike the comparable setup in the US that is for show and little else. This is one of many examples showing why single issue political parties are more of a viable approach to advocacy in European countries, and why you see more of that type of initiative in Europe. The German parliament started using an internet version of their petition system some years ago, and here is an example of the longevity science advocates of the German Party for Health Research supporting a petition to increase funding for research aimed at the treatment of aging. They are looking to obtain 50,000 signatures from German citizens to get to the point of consideration:

The German Party for Health Research is supporting the petition, directed to the German parliament (Bundestag), for more research against age-related diseases. Please help to reach the quorum of 50,000 signatures. If you are a German or live in Germany, sign the petition and spread the link. Only if enough people hear about the petition, the quorum can be reached. If you can, also try to inform the media. You can also donate to the German Party for Health Research, with reference "petition" - we would have more options to promote the petition (e.g., via Facebook ads). The petition translated into English is follows:

The German Parliament should decide that additional 2% of the federal budget is invested into research against age-related diseases such as cancer, cardiovascular diseases, Alzheimer's and type 2 diabetes. Age-related diseases cause most of the suffering in Germany and worldwide and contribute considerably to health costs. Using today's biotechnologies we have now the opportunity to develop therapies against all age-related diseases. The fact that even big companies such as Google already invest large amounts of money into the development of such therapies reveals that this isn't just an utopian endeavor anymore.

Damage and waste products are caused by normal metabolism inside and outside of cells, which accumulate during the lifespan and give rise to age-related diseases as soon as a certain amount is reached. By repairing the damage and getting rid of the waste products at a molecular and cellular level, it will in future be possible to cure and prevent age-related diseases. The more research in this area is done, the greater the chance that such therapies are developed sooner. The additional money should be used to establish new research institutes and educate more scientists in relevant areas. This implies the expansion of concerned faculties at the universities. Not only would the development of these therapies be a humanitarian act, but Germany would also greatly benefit economically in the long term. Since most people will eventually be hit by age-related diseases, each individual would benefit. To finance it, one can subtract 2% from every other budget area, for example.

Thursday, December 24, 2015

Nrf2 regulates a range of proteins associated with cellular repair and stress resistance, and is considered a longevity-assurance gene. There is more of it and its activities in some long-lived species, and also as a result of some of the interventions known to modestly slow aging in laboratory species. Levels of Nrf2 decline significantly with aging, however, and the balance of evidence suggests that we'd be modestly better off if that didn't happen. Researchers are slowly tracing back down the chain of cause and consequence to better understand the proximate causes of this loss:

Nrf2 is both a monitor and a messenger. It's constantly on the lookout for problems with cells that may be caused by the many metabolic insults of life - oxidative stress, toxins, pollutants, and other metabolic dysfunction. When it finds a problem, Nrf2 essentially goes back to the cellular nucleus and rings the alarm bell, where it can "turn on" up to 200 genes that are responsible for cell repair, detoxification of carcinogens, protein and lipid metabolism, antioxidant protection and other actions. "At least one important part of what we call aging appears to be a breakdown in genetic communication, in which a regulator of stress resistance declines with age. As people age and their metabolic problems increase, the levels of this regulator, Nrf2, should be increasing, but in fact they are declining."

Nrf2 is so important that it's found in many life forms, not just humans, and it's constantly manufactured by cells throughout the body. About half of it is used up every 20 minutes as it performs its life-protective functions. Metabolic insults routinely increase with age, and if things were working properly, the amount of Nrf2 that goes back into the nucleus should also increase to help deal with those insults. Instead, the level of nuclear Nrf2 declines. "The levels of Nrf2, and the functions associated with it, are routinely about 30-40 percent lower in older laboratory animals. We've been able to show for the first time what we believe is the cause."

The reason for this decline is increasing levels of a microRNA called miRNA-146a. MicroRNAs were once thought to be "junk DNA" because researchers could see them but they had no apparent biological role. They are now understood to be anything but junk - they help play a major role in genetic signaling, controlling what genes are expressed, or turned on and off to perform their function. In humans, miRNA-146a can turn on the inflammation processes that, in something like a wound, help prevent infection and begin the healing process. But with aging, this study now shows that miRNA-146a expression doesn't shut down properly, and it can significantly reduce the levels of Nrf2. This can cause part of the chronic, low-grade inflammation that is associated with the degenerative diseases that now kill most people in the developed world, including heart disease, cancer, diabetes and neurological disease. "The action of miRNA-146a in older people appears to turn from a good to a bad influence. It may be causing our detoxification processes to decline just when we need them the most."

Friday, December 25, 2015

Researchers have recently suggested that the practice of calorie restriction requires elements of the circadian clock to be present and functional in order to extend life, implying that adjustment of these mechanisms is a part of the way in which calorie restriction works to slow aging. There has been an increased interest in the circadian clock in aging research of late, a system of regulation that governs changes in cellular metabolism and tissue function over the course of a day. Elements of the clock become dysregulated with advancing age, though as for most of the catalog of known age-related changes in cellular behavior it is unclear as to where this failure sits in the grand chain of cause and consequence in aging. This chain spans the processes that lead from fundamental molecular damage through complex and poorly understood interactions all the way to the end stage of age-related disease and death. Is disarray of the circadian clock closer to the damage end, and thus produces many detrimental consequences in and of itself, or is it closer to being a final consequence, with little further damage done as a result? In this context research of the sort linked here is interesting:

Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock - transcriptional factor BMAL1 - results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR.

The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on an ad libitum (AL) diet but failed to increase life span of Bmal1-/- mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CR vs. AL by 50-70% in WT mice at several daily time points tested, while in Bmal1-/- the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, while Bmal1-/- induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression of Bmal1 (by 150%) and its downstream target genes Periods (by 470% for Per1 and by 130% for Per2).

We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.

Friday, December 25, 2015

Over the last twenty years researchers have undertaken a great many rodent studies of calorie restriction, also known as dietary restriction, and its ability to improve health, slow aging, and extend longevity. As this paper goes to show there is much left to learn, however. In particular, the relationships between degrees of calorie restriction, enhanced longevity, and benefits to particular narrow aspects of health are complex. One of the unexpected outcomes here is that mild calorie restriction has a very similar outcome in terms of life expectancy as that of more rigorous calorie restriction - at least in one particular commonly used laboratory rat lineage. That qualification is necessary, as results have varied over a selection of various lineages.

Given that short-lived species such as mice and rats have far more plastic life spans than long-lived species such as humans, the long-term characteristics of the calorie restriction response when it comes to aging and disease are likely to be quite different for us in many of the important details. Certainly it doesn't extend human life by up to 40% as it does in mice, as that outcome would have been noticed centuries ago at the very least. This is the case even though many of the short-term measures of changing metabolism in response to calorie restriction are similar for all mammals, and it has been shown to result in notable health benefits for human practitioners.

Dietary restriction (DR) has become the gold standard to which manipulations that increase life span and appear to retard aging are compared. DR has been shown to increase life span and reduce or delay the increase in age-related pathologies and the decline in most physiological functions in numerous genotypes of laboratory rodents. DR increases the life span of a wide variety of other organisms. These data have led to the view that the effect of DR on longevity and aging is universal, a view that was reinforced in 2009 with the first data showing that DR significantly decreased the incidence of age-related deaths and delayed the onset of age-related pathologies in rhesus monkeys. The universality of the effect of DR on longevity was called into question in 2010 when researchers reported the effect of DR on approximately 40 different recombinant inbred lines of male and female mice. Surprisingly, approximately one-third of the mice showed a decrease in life span on the DR diet; one-third showed no effect of DR on life span; and only one-third showed the expected increase in life span.

One possible explanation for the recent contradictory data on DR is that the level of DR required to increase life span is genotype dependent, and because the previous studies used only one, relatively high, level of DR, which might have had a negative effect (instead, lower levels of DR might increase life span). The standard DR diet that is usually used in DR rodent studies one in which rodents are fed 60% of the diet consumed by animals fed ad libitum (AL) (i.e., 40% DR). This is the level of restriction used by the National Institute on Aging (NIA) for their aged rodent colonies, which have been available to investigators studying aging. It is generally believed that the increase in life span is directly related to the level of DR, that is, increasing the level of restriction leads to a greater increase in life span up to a certain point (e.g., around 60% DR) where further restriction is harmful. However, there are only limited data to support this view.

The purpose of this study was to determine whether a modest level of DR (10% DR) could increase the life span of male F344 rats and compare its effects on life span and pathology to the effects of 40% DR. We found that 10% DR significantly increased mean life span, and surprisingly, the increase in mean life span obtained by 10% DR was similar to that observed with 40% DR. However, we observed differences in the effects of 10% and 40% DR on the incidence of fatal neoplasia; 40% DR resulted in a significant reduction in fatal neoplastic diseases, especially leukemia, which was the most common neoplastic disease in the rats.


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