Fight Aging! Newsletter, September 7th 2015

September 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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  • Officially Launches, Crowdfunding the Development of a Cure for Aging
  • October 1st is International Longevity Day: Events are Planned
  • Calorie Restriction: Good for Humans
  • An Illustrative Consideration of Mitochondrial Haplogroup Differences in Human Longevity
  • The Geroprotectors Database: Curated Lifespan Study Data
  • Latest Headlines from Fight Aging!
    • Regular Stem Cell Transplants Extend Life in Normal Rats
    • Rejuvenation Biotechnology 2015 Wraps Up on a High Note
    • Chimeric Antigen Receptor T-cells versus Solid Tumors
    • A Study Shows Older People are Now Smarter but Less Fit
    • Dietary Glycemia Correlates with Visual Health in Aging
    • Insight into the Machinations of Classifying Aging as a Disease
    • Autoimmunity as a Possible Side-Effect of Cancer Immunity
    • Raised Levels of FKBP1b Restore Calcium Regulation and Improve Cognitive Function in Aging Rats
    • The Mainstream View of Longevity Science: Drug Discovery to Slightly Slow Aging
    • CD47 as a Cancer Target May Rely on Dendritic Cells Rather than Macrophages


Philanthropy has an important role in funding medical research, and thus crowdfunding will have an equally important role in the years ahead: it is collaborative philanthropy, the diverse will of the public, organized and made real. The falling cost of early stage biotechnology research means that the suite of prototype technologies needed to arrest degenerative aging in mammals, preventing all age-related disease through periodic repair of the cell and tissue damage that causes aging, might be as little as a billion and ten years of work away from where we stand today. If we all get our act together.

Many hands make light work, and getting our act together is the point of This new non-profit crowdfunding initiative officially launched last week, showcasing a SENS mitochondrial research project that is a third of the way towards being funded as of today. is an outgrowth of the Life Extension Advocacy Foundation (LEAF), and the staff and volunteers seek to attract funding for the most important of early staging longevity research, speeding the advent of prototype rejuvenation therapies. This is certainly the time for it: today is still early in a great transformation in aging research, leaving behind the look but don't touch approaches and the palliative treatment of late stage symptoms without any hope of lasting cures. The near future is brightened by the promise of direct intervention in the underlying causes of aging and age-related disease, and thus the prospect of being able to cure not just age-related disease but the very process of aging itself.

The LEAF and president, Keith Comito, was kind enough to send me his thoughts on where this initiative comes from and where it is going. We're all of us on our own journeys through this space of development and potential in medicine; more traveling companions are always welcome:

My team and I created because we strongly believe that centralizing crowdfunding efforts in this field will help to create a powerful grassroots movement for the extension of healthy human lifespan. It can do this by not only building a focused community of passionate serial donors who can fund research directly, but also by providing an accessible gateway for the public at large to be introduced to the idea of life extension. can also be a powerful tool in positively shaping the dialogue surrounding life extending technologies going forward. The argument against life extension used to be that it was impossible and a waste of time, but now the critique is changing to one that takes on shades of income inequality: this technology might be possible, but it will be available only for the rich. can serve as a counter-force to this; giving the everyday person agency in the progression of this technology - democratizing relevant research and making the results open to the public.

In the near future we also plan to support with various forms of content, such as thought-provoking videos focused on engaging the broader public. Through this we can help reframe certain aspects of the ongoing conversation about transhumanist ideals such as life extension, which at times can be divisive, to a more positive one by genuinely inviting dialogue on the science and the societal issues relating to life extension, as well as providing a path for those who wish to become informed and involved. Personally I believe that many people can be reached on the issue if we speak with compassion and intelligence. Extending healthy life is not just for scientists or transhumanists - it is human; it is what we have always done since the very first poultices and medicines.

Realizing our work sits within a continuum of human development and thought both connects us to the past and empowers the drive to keep reaching for an even greater future. Ever since The Epic of Gilgamesh humanity has dreamed of this goal - it is exciting that right now we are in this unique moment of history where literally anyone can carry the torch forward, and help find the flower of rejuvenation Gilgamesh sought. You get the chance to be part of the first Hero's Journey, and that's pretty awesome. Call me optimistic, but I think we can inspire others to feel that excitement too.

Personally, I've always been interested in self-enhancement, and slowly that led me to seek out information on the concept of life extension. This eventually led me to Aubrey de Grey's book Ending Aging which made me aware that meaningful progress in this area was feasible in our lifetime. I reached out to him and we bounced some emails back and forth about creating a New York based organization to further this research. This started out as a discussion group that met once a month for about a year, the remnants of which coalesced into LEAF.

I believe a little reframing could go a long way towards reaching the everyman, instead of alienating him. As one example, I think "Do you want to live forever?" is the wrong question to ask, because of how cognitive biases affect the way we think of aging. Better to ask "Do you want to be alive tomorrow? And, do you expect the answer to that question to change tomorrow?" It is in essence the same question, but phrased in a way that mitigates the inherent cognitive bias. I think that if we can illustrate how combating aging is really about affording greater choice to everyone, we can reach more people than we think. Even if an individual doesn't want to live longer or be free from terrible age-related diseases, the odds are that someone they know, someone they love, would like the freedom to have that choice - I believe most people could be convinced that giving their loved ones that choice is a good thing.


October 1st is the UN International Day of Older Persons, but our community would like it to also be Longevity Day, a time to remind the world that research into human rejuvenation is practical, that near-future therapies are plausible, and that all of this will move much faster with greater funding and support. This year, as last, grassroots advocates will hold events around the globe, many of which are coordinated through the International Longevity Alliance and related groups.

October 1st is also the launch date for this year's Fight Aging! matching fundraiser in support of the rejuvenation biotechnology programs coordinated by the SENS Research Foundation. This is a chance for all of us to do our part to help speed things along; the progress you see today in SENS technologies relevant to treating aging as a medical condition came about as the result of similar fundraising in past years. The matching fund for 2015 weighs in 125,000, and we'll be seeking to raise that much again, matching every donation with the same amount from the fund. This is a stretch goal for our community, and all offers of assistance in preparation and fundraising are greatly appreciated.

If you are interested in holding an event this year to mark Longevity Day, then contact the International Longevity Alliance: there is a month left in which to organize, and the Alliance has plenty of helpful materials and references. With regards to the Fight Aging! fundraiser, there are message posters that we'd love to see more widely distributed. Pass them around, show them off, or - even better - improve on them and share the results.

International Longevity Day - October 1, 2015

There has been emerging a tradition by longevity researchers and activists around the world to organize events dedicated to promotion of longevity research on or around October 1 - the UN International Day of Older Persons. This day is sometimes referred to in some parts of the longevity activists community as the "International Longevity Day". As this is the official UN Day of Older Persons, this provides the longevity research activists a perfect opportunity, perhaps even a perfect excuse, to emphasize the importance of aging and longevity research for the development of effective health care for the elderly, in the wide public as well as among decision makers.

Let us maintain and strengthen this tradition! Let us plan and organize a mutually reinforcing network of events worldwide. If you plan to organize an event for that day - either live meetings or on-line publications and promotions - please let us know. Together we can create an activism wave of strong impact.

The critical importance and the critical need to promote biological research of aging derives from the realization that tackling the degenerative processes and negative biological effects of human aging, at once and in an interrelated manner, can provide the best foundations to find holistic and effective ways for intervention and prevention against age-related ill health. Such an approach has been supported by scientific proofs of concept, involving the increase in healthy lifespan in animal models and the emerging technological capabilities to intervene into fundamental aging processes.

The focus on intervention into degenerative aging processes can provide solutions to a number of non-communicable, age-related diseases (such as cancer, heart disease, type 2 diabetes and neurodegenerative diseases), insofar as such diseases are strongly determined by degenerative aging processes (such as chronic inflammation, cross-linkage of macromolecules, somatic mutations, loss of stem cell populations, and others). This approach is likely to decrease susceptibility of the elderly also to communicable, infectious diseases due to improvements in immunity. The innovative, applied results of such research and development will lead to sustainable, economically viable solutions for a large array of age-related medical and social challenges, that may be globally applicable. Furthermore, such research and development should be supported on ethical grounds, to provide equal health care chances for the elderly as for the young.

Therefore it is the societal duty, especially of the professionals in biology, medicine, health care, economy and socio-political organizations, to strongly recommend greater investments, incentives and institutional support for the research and development dealing with the understanding of mechanisms associated with the human biological aging process and translating these insights into safe, affordable and universally available applied technologies and treatments. October 1 - the International Day of Older Persons - provides the researchers and advocates an opportunity to raise these points and make these demands.

The Critical Need to Promote Research of Aging Around the World

Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.

The Tasks of Longevity Promotion: Science, Ethics and Public Policy - Potential presentation topics on longevity research

The task of healthy life extension, or healthy longevity extension, dictates a broad variety of questions and tasks, relating to science and technology, individual and communal ethics, and finally public policy, especially health and research policy. Despite the wide variety, the related questions may be classified into 3 groups.

The first group of questions concerns the feasibility of the accomplishment of life extension. Is it theoretically and technologically possible? What are our grounds for optimism? What are the means to ensure that the life extension will be healthy life extension?

The second group concerns the desirability of the accomplishment of life extension for the individual and the society, provided it will become some day possible through scientific intervention. How will then life extension affect the perception of personhood? How will it affect the availability of resources for the population?

Yet, the third and final group can be termed normative. What actions should we take? Assuming that life extension is scientifically possible and socially desirable, and that its implications are either demonstrably positive or, in case of a negative forecast, they are amenable - what practical implications should these determinations have for public policy, in particular health policy and research policy, in a democratic society? Should we pursue the goal of life extension? If yes, then how? How can we make it an individual and social priority?

Given the rapid population aging and the increasing incidence and burden of age-related diseases, on the pessimistic side, and the rapid development of medical technologies, on the optimistic side, these become vital questions of social responsibility.


Results from the most recent two year CALERIE trial of human calorie restriction were published earlier this year, but the associated publicity materials have only just now made it to the presses.

Calorie restriction, or to be more precise calorie restriction with hopefully optimal but at least adequate nutrition, is the practice of reducing calorie intake while maintaining a suitable level of micronutrients in the diet. Reducing recommended dietary intake by about 25% is a common target, as was the case in this study. That would mean somewhere around 1500 calories per day for the mythical completely average individual. It is just about impossible to achieve this goal without structuring a very healthy diet that is comparatively low in processed sugars and the like, which is an added bonus. When you are settled into a healthy calorie restricted diet, hunger is nowhere near the bugbear that people like to make it out to be, while the short term benefits are fairly obvious and arrive quickly, including lowered chronic inflammation, reduced visceral fat tissue, lower blood pressure, less sleep needed, and so forth.

The short term benefits of a calorie restricted metabolism to health have been established and measured extensively over the past few decades. The evidence shows they are altered in much the same way in people as in mice. Unlike mice, however, people do not live 40% longer when calorie restricted - we would have noticed by now. There have been religious orders across the course of history where this would have been the case, and in our time many members of the Calorie Restriction Society have been practicing calorie restriction with optimal nutrition for somewhat longer than the CALERIE program has existed. There is a good evolutionary explanation for the difference in the calorie restriction response when comparing short-lived and long-lived species: famines are seasonal, and a season is a large fraction of a mouse lifespan but a small fraction of a human life span. Thus only the mouse evolves a relatively large plasticity of life span in response to food scarcity.

But from a mechanistic point of view - how exactly does this all work under the hood, what are cells and tissues actually doing to extend life - there is still a long way to go if you are looking for the complete explanation. The challenge here is that near every measure and aspect of cellular biochemistry changes in response to nutrient availability. Aging is slowed, but why, exactly? Which of the scores of likely candidates are contributing, and to what degree? Picking apart cause and effect has been the subject of decades of ever-expanding research so far, and looks set to take decades more yet. It is a fair wager to suggest that we will likely see the first crude rejuvenation therapies based on repair of cellular damage before the emergence of a comprehensive accounting of the calorie restriction response and its effects on aging.

Don't let that stop you from giving it a try, however. Like exercise, calorie restriction is backed by the gold standard of scientific evidence when it comes to things you can do today that are expected to have a noticeable positive effect on your present and future health. The interesting take in the commentary here, from a perspective of having read the paper a few months back, is that researchers expected to see more in the way of benefits than they did. That might be explained by the lesser degree of calorie restriction obtained versus that aimed for, which itself was smaller than that of some animal studies:

NIH study finds calorie restriction lowers some risk factors for age-related diseases

Results from a two-year clinical trial show calorie restriction in normal-weight and moderately overweight people failed to have some metabolic effects found in laboratory animal studies. However, researchers found calorie restriction modified risk factors for age-related diseases and influenced indicators associated with longer life span, such as blood pressure, cholesterol, and insulin resistance. "The study found that this calorie restriction intervention did not produce significant effects on the pre-specified primary metabolic endpoints, but it did modify several risk factors for age-related diseases. It is encouraging to find positive effects when we test interventions that might affect diseases and declines associated with advancing age. However, we need to learn much more about the health consequences of this type of intervention in healthy people before considering dietary recommendations. In the meantime, we do know that exercise and maintaining a healthy weight and diet can contribute to healthy aging."

CALERIE was a two-year randomized controlled trial in 218 young and middle-aged healthy normal-weight and moderately overweight men and women to measure these outcomes in a CR group, compared with a control group who maintained their regular diets. The calorie restriction participants were given weight targets of 15.5 percent weight loss in the first year, followed by weight stability over the second year. This target was the weight loss expected to be achieved by reducing calorie intake by 25 percent below one's regular intake at the start of the study. The calorie restriction group lost an average of 10 percent of their body weight in the first year, and maintained this weight over the second year. Though weight loss fell short of the target, it is the largest sustained weight loss reported in any dietary trial in non-obese people. The participants achieved substantially less calorie restriction (12 percent) than the trial's 25-percent goal, but maintained calorie restriction over the entire two-year period. The control group's weight and calorie intake were stable over the period.

The study was designed to test the effects of calorie restriction on resting metabolic rate (after adjusting for weight loss) and body temperature, which are diminished in many laboratory animal studies and have been proposed to contribute to its effects on longevity. The study found a temporary effect on resting metabolic rate, which was not significant at the end of the study, and no effect on body temperature. Although the expected metabolic effects were not found, calorie restriction significantly lowered several predictors of cardiovascular disease compared to the control group, decreasing average blood pressure by 4 percent and total cholesterol by 6 percent. Levels of HDL ("good") cholesterol were increased. Calorie restriction caused a 47-percent reduction in levels of C-reactive protein, an inflammatory factor linked to cardiovascular disease. It also markedly decreased insulin resistance, which is an indicator of diabetes risk. T3, a marker of thyroid hormone activity, decreased in the calorie restriction group by more than 20 percent, while remaining within the normal range. This is of interest since some studies suggest that lower thyroid activity may be associated with longer life span.

A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity

To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. We conclude that sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.


In the open access paper quoted here, researchers suggest that variations in the MOTS-c peptide encoded in mitochondrial DNA may have some effect on life expectancy in at least some human populations. The present landscape of statistical data for human gene variants and longevity points to a complex array of many, many individually tiny contributions to longevity, these contributions interacting with one another so that the patterns and relationships are very different in different populations. The correlations found in one study of genetics and longevity are very rarely replicated in others. Only a few gene variants are reliably associated with longevity in multiple human study populations, and their effects are dwarfed by the contribution of exercise and calorie intake to long-term health.

To a first approximation we all age in the same way, for the same underlying reasons, which is to say the accumulation of unrepaired damage produced as a side-effect of the normal operation of cellular metabolism. Effective treatments for aging will be mass-produced, repairing exactly the same forms of damage in every patient in exactly the same way. That is the path to real results in healthy life extension, not trying to find genetic alterations that might slightly, trivially slow down the damage, or slightly, trivially change the response to damage, and thus slightly, trivially alter the odds of living in suffering and pain for an extra year or two. Deciphering the enormously complex relationship between genes and aging is a worthy goal for the scientific community, but it isn't the path to useful therapies for degenerative aging.

If you were looking for genetic variants associated with longevity, however, then there are far worse places to start than mitochondrial DNA. Unlike nuclear DNA, there are only a handful of different mitochondrial genomes, haplogroups defined by accumulated mutations that spread throughout populations in the generations since the recent common ancestor, Mitochondrial Eve. Each haplogroup is carried by an enormous human population, and many existing sets of epidemiological data include haplogroup identification. This makes obtaining data and running statistical analyses a much easier prospect than is the case for the alternatives, and is one of the reasons why there are numerous studies on whether or not some mitochondrial haplogroups are modestly better than others, linked to small statistical advantages in health or longevity.

The research linked below is a good example of this sort of thing, and gives some insight into the types of investigation underway at the border between relentless genetic information gathering on the one hand and the struggle to understand the details of the progression of degenerative aging on the other. It is a rich mix of data analysis, modeling, inference, collaboration, and genetics:

The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?

The number of people aged ≥60 years is expected to almost triple by 2050, with the 'oldest old' group (older than 85 years) being the most rapidly expanding segment in Western societies. Among long-lived individuals, those who reach exceptional longevity (EL, i.e., centenarians (≥100 years) and supercentenarians (SCs, ≥110 years)) are arguably the paradigm of successful aging. Several genetic factors might contribute to EL, as suggested by the differences found in the frequency distribution of several genetic variants among centenarians compared with their ethnic-matched referents of younger ages. Factors related to inflammation, metabolism or nutrition, among others, can also influence the likelihood of reaching EL. Japan has clearly the longest life expectancy in the world, as well as the highest number of SCs, as we recently reviewed. Thus, Japanese long-lived people represent an interesting model to study the biology of EL, and to gain insight into the nature vs. nurture debate.

Mitochondrial DNA (mtDNA) can influence EL. Human mtDNA contains 13 genes that codify proteins involved in mitochondrial oxidative phosphorylation (OXPHOS), as well as 2 rRNA and 22 tRNA genes that are necessary for protein synthesis within mitochondria. Mitochondria are one of the most important players to understand the aging process at the cellular level as they are both the main source and target of oxidative damage. Mitochondrial dysfunction is in fact a main hallmark of aging, which is partly caused by accumulation of mtDNA damage as we age. Thus, because mtDNA haplotypes or haplogroups (i.e., characteristic clusters of tightly linked mtDNA polymorphisms that form continent-specific genotypes) might influence individual susceptibility to mtDNA damage, they could also influence EL in a continent- or ethnic-specific manner.

For instance, the association between mtDNA and EL is controversial in Spanish people, with researchers reporting no association between mtDNA haplogroups and EL but others find that the Caucasian haplogroup J (which would be associated with lower mtDNA damage) might confer a higher chance to attain high longevity (85+ years) compared with other haplogroups in Northern Spaniards. On the other hand, although mtDNA haplogroups D4b2b, D4a, and D5 are not associated with type 2 diabetes, they are linked with EL in Japanese population. We also showed that the mtDNA m.1382A>C polymorphism, which is specific for the ancestor haplogroup D4b2, is associated with EL in the Japanese population.

Mitochondrial-derived peptides (MDP) are encoded by functional short open reading frames in the mtDNA. These include humanin, a 24-amino acid peptide encoded in the 16S rRNA region with strong cytoprotective actions and the recently discovered mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), which is a 16-amino acid peptide that regulates insulin sensitivity and metabolic homeostasis. We have recently suggested that MOTS-c might also be involved in the aging process.

The aforementioned m.1382A>C polymorphism is located in the MOTS-c encoding mtDNA, a short open reading frame in the 12S rRNA region. The m.1382A>C variation causes a Lys14Gln replacement in the MOTS-c peptide equivalent to nucleotide position 1382 of the mtDNA; this is likely to have functional consequences, as the physicochemical difference between the original and the altered amino acid residues is relatively high, with a Grantham value of 53, that is, above the average value (=50) that differentiates radical from conservative single amino acid replacements. This amino acid replacement is also predicted to have a functional effect with the PROVEAN (PROtein Variation Effect ANalyzer) tool, that is, yielding a score of −4.000, below the specifically predicted cutoff score (=−2.5) above which the variant would be 'neutral'. The m.1382A>C polymorphism is specific for the Northeast Asian population and may be among the putative biological mechanisms explaining the high longevity of Japanese people. Further, MOTS-c is an important 'mitokine', with this term referring to mitochondrial-derived signals that impact other cells in an endocrine-like manner.


The Geroprotectors online database was recently announced, a curated reference of lifespan data studies carried out in recent years. It isn't surprising to see João de Magalhães on the list of those involved, given his past focus on producing online databases relevant to aging research: GenAge, AnAge, LongevityMap, the Digital Aging Atlas, LibAge, and so on. The Geroprotectors database is in line with those efforts, being an attempt to make interesting data more accessible to that faction of the research community interested in intervening in the aging process.

I should say that this reference work follows the mainstream of aging research in being entirely focused on pharmacology, the expensive process of finding drugs and supplements to slightly slow down the aging process by adjusting the operation of metabolism. That's fair enough when looking at the last few decades of life span studies; approaches other than calorie restriction, exercise, and drug discovery to alter the operation of metabolism haven't yet progressed to the point of producing more than a sparse handful of animal studies. In particular the SENS approach of periodic damage repair is still largely at earlier stages of research prior to expensive, long-running animal studies, with a few exceptions such as senescent cell clearance and mitochondrial repair technologies that are entering clinical trials, but not for aging.

The point to be made here is that the future of treating aging is not pharmacology in the traditional sense of mining the natural world for compounds that happen to do more good than harm in any one specific situation. There will certainly be a lot of work done there through sheer inertia, but in the fullness of time it will be abandoned as a path towards therapies because it will be proven ineffective in comparison to SENS and related approaches, which look much more like gene therapies, cell therapies, repair of specific molecular breakages, and so on. It is self-evident that in any complex system of machinery we should expect periodic repair of damage to be more effective than slowing down damage accumulation without repair, and that is without taking into account that adjusting metabolism into new safe configurations is harder and more expensive than repairing known forms of damage to maintain the known healthy configuration of metabolism.

That doesn't stop Geroprotectors from being a very interesting set of data, of course. It is important to recognize that scientific knowledge always has value, and there is certainly far too little investment in it in our modern societies, but it isn't necessarily the case that any particular field or approach is capable of laying the foundations for effective therapies. It we were all already ageless that wouldn't matter, but we are not; the clock is ticking, and so there is merit in talking about which strategies are likely to be more or less effective in the treatment of aging.


The risk for many chronic diseases increases as we age. These diseases include cardiovascular and metabolic syndrome-related problems such as type II diabetes, atherosclerosis, hypertension, myocardial infarction and stroke, as well as cancer and neurodegenerative diseases. Studies show that some agents which extend the lifespan in animal models may also be effective in humans. Geroscience, which aims to conserve the healthy state of the body, may therefore become a key concept in biomedicine in the near future, as chemicals become available which slow ageing and prevent or delay the onset of age-related diseases.

A "geroprotector" is any intervention that aims to increase longevity, or that reduces, delays or impedes the onset of age-related pathologies by hampering aging-related processes, repairing damage or modulating stress resistance. The database comprises more than 250 life-extension experiments in 11 wild-type model organisms (including M. musculus and C. elegans, among others). We gathered data about more than 200 chemicals promoting longevity, including compounds approved for human use. This database integrates information about lifespan-increasing experiments and related compounds, suppression of aging mechanisms, activation of longevity mechanisms and age-related diseases obtained from research papers and databases. For descriptions of compounds and their effects on model organisms, we have used many sources with information about chemical and biological information. All substances have descriptions including data on their toxicity, clinical use, clinical trials (actual data), biological and pharmacological activities, interactions and so on. a new, structured and curated database of current therapeutic interventions in aging and age-related disease

As the level of interest in aging research increases, there is a growing number of geroprotectors, or therapeutic interventions that aim to extend the healthy lifespan and repair or reduce aging-related damage in model organisms and, eventually, in humans. There is a clear need for a manually-curated database of geroprotectors to compile and index their effects on aging and age-related diseases and link these effects to relevant studies and multiple biochemical and drug databases.

Here, we introduce the first such resource, Geroprotectors. Geroprotectors is a public, rapidly explorable database that catalogs over 250 experiments involving over 200 known or candidate geroprotectors that extend lifespan in model organisms. Each compound has a comprehensive profile complete with biochemistry, mechanisms, and lifespan effects in various model organisms, along with information ranging from chemical structure, side effects, and toxicity to FDA drug status. These are presented in a visually intuitive, efficient framework fit for casual browsing or in-depth research alike. Data are linked to the source studies or databases, providing quick and convenient access to original data. The Geroprotectors database facilitates cross-study, cross-organism, and cross-discipline analysis and saves countless hours of inefficient literature and web searching.


Monday, August 31, 2015

Researchers here demonstrate extended life spans in rats as a result of life-long regular transplantation of stem cells. The specific mechanisms are unknown, but the researchers suggest that the proximate causes involve altered levels of various signal molecules leading to better operation and maintenance of native cells and tissues. Given that one study can't measure everything of interest, this should probably be taken as a preliminary set of suppositions, though reasonable given what is known of stem cell therapies at this point. Following on from this work it is definitely the case that more life span studies should take place for stem cell treatments.

Aging brings about the progressive decline in cognitive function and physical activity, along with losses of stem cell population and function. Although transplantation of muscle-derived stem/progenitor cells extended the health span and life span of progeria mice, such effects in normal animals were not confirmed.

Human amniotic membrane-derived mesenchymal stem cells (AMMSCs) or adipose tissue-derived mesenchymal stem cells (ADMSCs) were intravenously transplanted to 10-month-old male F344 rats once a month throughout their lives. Transplantation of AMMSCs and ADMSCs improved cognitive and physical functions of naturally aging rats, extending life span by 23.4% and 31.3%, respectively. The stem cell therapy increased the concentration of acetylcholine and recovered neurotrophic factors in the brain and muscles, leading to restoration of microtubule-associated protein 2, cholinergic and dopaminergic nervous systems, microvessels, muscle mass, and antioxidative capacity.

The results indicate that repeated transplantation of AMMSCs and ADMSCs elongate both health span and life span, which could be a starting point for antiaging or rejuvenation effects of allogeneic or autologous stem cells with minimum immune rejection.

Monday, August 31, 2015

An official release from the SENS Research Foundation on the recent Rejuvenation Biotechnology 2015 conference:

The Rejuvenation Biotechnology conference brings together experts from research, academia, industry, policy, finance and regulatory fields to share ideas - and the latest research and developments - on diseases that are impacting the aging population on a global scale, such as Alzheimer's disease, cancer, and cardiovascular disease. The Rejuvenation Biotechnology Conference creates a forum for thought leaders from multiple disease communities to consider the wider potential of novel strategies for early intervention, while evaluating the feasibility of preventive and combinatorial medicine applications to treat all aging-related diseases.

"For the second year in a row, the Rejuvenation Biotechnology Conference achieved its mission of bringing together a global community to transform the treatment of age-related diseases. With the explosive growth this past year in research into the underlying causes of the diseases of aging, we have an even greater opportunity to continue to accelerate the construction of the Rejuvenation Biotechnology industry. SENS Research Foundation will continue to grow our outreach efforts through conferences and general advocacy, because we believe that a world free of age-related disease is possible."

The theme for this year's Rejuvenation Biotechnology Conference was "Bringing Together a Global Community to Transform the Treatment of Age-Related Diseases". Tracks included "Age-Related Diseases," "Therapeutic Approaches," and "Translation to Treatment," the latter of which included investigation into economics, investment, industry, regulatory issues, and the impact of digitization on healthcare. The conference featured over 50 leading speakers from industry, academia, government, and the financial community. Highlights included keynoters Chas Bountra, SGC Oxford Chief Scientist, Professor of Translational Medicine, Nuffield Department of Clinical Medicine, and Associate Member, Department of Pharmacology, University of Oxford, who spoke on "Transforming the Discovery of New Medicines," and Frances Colón, Acting Science and Technology Adviser to the Secretary of State of the United States, who spoke on "Science and Technology for Diplomacy." Among the additional speakers were representatives of leading biotech firms including Sanofi, Sartorius Stedim, Fate Therapeutics, Biolatris, Sangamo BioSciences Inc., and Asterias Biotherapeutics, Inc. as well as CIRM, Stanford University, Scripps Institute and the Harvard Stem Cell Institute and other leading universities.

Tuesday, September 1, 2015

The future of cancer research is targeting, meaning the ability to destroy cancer cells efficiently and with few to no side-effects on normal tissues. Chimeric antigen receptor (CAR) T-cells are a step forward in this regard, and have proven to be an effective treatment for leukemia in trials. Researchers are now attempting to adapt their use to other types of cancer. In this example, the T-cells are engineered to make them more discriminating when targeted at solid tumors:

Many solid cancers have high levels of certain proteins such as ErbB2 and EGFR, which make them suitable targets for anticancer therapies. However, such proteins are also present at low levels in normal cells. Because of this, CAR T cells that are developed to target one of these proteins on tumor cells also recognize and attack normal cells that have the protein, causing severe toxicity.

To develop CAR T cells that can distinguish between cancer and normal cells, researchers first constructed a panel of CARs with the single chain variable fragments (scFv) - the part of the CAR T cell that recognizes the tumor target - using sequences from mutated 4D5 antibodies that had varying affinities to ErbB2, a protein present at high levels in some solid tumors, including breast cancer. Next, they incorporated different scFvs into the CAR backbone or "construct," such that they resulted in a range of CAR T cells - from those that had high affinity to ErbB2 to those that had low affinity to ErbB2. The newly engineered CAR T cells varied in their affinity to ErbB2 by three orders of magnitude. The researchers then conducted a series of experiments to test the functionality of the affinity-tuned CAR T cells and found that high-affinity CAR T cells did not discriminate tumor cells from normal cells and attacked all of them, whereas low-affinity CAR T cells were sensitive to tumor cells that had high levels of ErbB2 and not to normal cells that had low levels of the protein.

Next, they tested the engineered CAR T cells in mice that bore human cells with high levels of ErbB2 on one side of their bodies and human cells with normal levels of ErbB2 on the other side of their bodies. Here again, low-affinity CAR T cells selectively eliminated cells that had high levels of ErbB2 but had no effect on cells that had normal levels of the protein. In order to prove that this technology can be extended to other solid tumor targets, the researchers developed low-affinity CAR T cells targeting EGFR, a protein present in high levels in some lung and colon cancers, among others, and preliminary preclinical results showed that these CAR T cells were able to discriminate between cancer cells and normal cells.

Tuesday, September 1, 2015

Trends in technology and increasing wealth improve health due to greater access to better forms of medicine, but also tend to produce a fatter, less fit older population, a consequence of the broadening range of attractive and affordable transportation devices and calories. Gains from medicine compete in many people with the losses due to diminished personal fitness. This is very noticeable in countries like South Korea where the transition from poverty to wealth was rapid, taking place over just a handful of decades. Here researchers show similar trends in European populations:

People over age 50 are scoring increasingly better on tests of cognitive function, according to a new study. At the same time, however, the study showed that average physical health of the older population has declined. The study relied on representative survey data from Germany which measured cognitive processing speed, physical fitness, and mental health in 2006 and again in 2012. It found that cognitive test scores increased significantly within the 6-year period (for men and women and at all ages from 50 to 90 years), while physical functioning and mental health declined, especially for low-educated men aged 50-64. The survey data was representative of the non-institutionalized German population, mentally and physically able to participate in the tests.

Previous studies have found elderly people to be in increasingly good health - "younger" in many ways than previous generations at the same chronological age - with physical and cognitive measures all showing improvement over time. The new study is the first to show divergent trends over time between cognitive and physical function. "We think that these divergent results can be explained by changing lifestyles. Life has become cognitively more demanding, with increasing use of communication and information technology also by older people, and people working longer in intellectually demanding jobs. At the same time, we are seeing a decline in physical activity and rising levels of obesity."

A second study found similar results suggesting that older people have become smarter also in England. "On average, test scores of people aged 50+ today correspond to test scores from people 4-8 years younger and tested 6 years earlier." The studies both provide confirmation of the "Flynn effect" - a trend in rising performance in standard IQ tests from generation to generation. The studies show that changes in education levels in the population can explain part, but not all of the effect. "We show for the first time that although compositional changes of the older population in terms of education partly explain the Flynn effect, the increasing use of modern technology such as computers and mobile phones in the first decade of the 2000s also contributes considerably to its explanation."

Wednesday, September 2, 2015

Researchers here note a correlation between glycemic index, a measure of the impact of carbohydrate content of food on blood glucose, and risk of suffering age-related blindness. Given the comparatively large influence of calorie intake over all aspects of health and metabolism, and the composition of the typical modern diet, I think one has to consider the usual suspects of total overall calories consumed, visceral fat, and chronic inflammation before moving on to look at things like the contribution of diet to cross-links in the eye or lipofuscin formation in the retina.

Extending healthful life is a millennia-old dream and objective. During the intervening centuries a multitude of concoctions and remedies have been offered, usually with few substantiated results. During the last century it was demonstrated that limiting caloric intake is associated with extended life in many mammals, albeit results remain to be clarified in humans. A myriad of modeling studies have revealed signaling pathways that are associated with life extension and the last two decades have seen an interest in the types of dietary carbohydrates that might confer health advantage, and possibly longevity.

Loss of vision due to age-related cataracts or age-related macular degeneration is widely prevalent, affecting about 85% and 15% of the elderly respectively. With centenarians among the fastest growing segments of societies, and with loss of vision a very costly personal and societal burden, there is keen interest in extending vision - that is, delaying age-related macular degeneration and cataract - or diminishing risk for these debilities. Using extensive epidemiologic and nutritional information from the Nurses' Health Study and Age-Related Eye Disease Study (AREDS) we determined that measures of total carbohydrate, and even more so, glycemic index (GI), are associated with visual health. We also modeled this relationship in mice in order to elucidate etiologic relationships between dietary glycemia, visual health, and genetics.

Wednesday, September 2, 2015

The open access paper quoted here provides some insight into present attempts to change the regulatory classification of aging in the lab and the clinic: the prospect for meaningful progress in the science is real, but regulation is holding things back, which is why so many articles have appeared of late on whether or not aging is a disease.

The bureaucracy of what is and is not officially a disease is baroque and slow-moving, a many-faceted entity with areas of different importance depending on whether clinical medicine or research or translation or funding is being considered. There is considerable interest at the present time in doing something about that fact that aging is generally not accepted to be a treatable medical condition in most parts of the system that matter, which is to say those relating to the flow of money into early stage and translational research. That flow of money is tiny at this time; there is very little support for developing any of the clear paths towards treating aging as a medical condition, and this has a lot to do with regulatory barriers. If it is illegal to treat aging, none of the big for-profit concerns are going to go all in on building potential therapies, for example.

Aging is a complex continuous multifactorial process leading to loss of function and crystalizing into the many age-related diseases. Here, we explore the arguments for classifying aging as a disease in the context of the upcoming World Health Organization's (WHO)'s 11th International Statistical Classification of Diseases and Related Health Problems (ICD-11), expected to be finalized in 2018. We hypothesize that classifying aging as a disease will result in new approaches and business models for addressing aging as a treatable condition, which will lead to both economic and healthcare benefits for all stakeholders. Classification of aging as a disease may lead to more efficient allocation of resources by enabling funding bodies and other stakeholders to use quality-adjusted life years (QALYs) and healthy-years equivalent (HYE) as metrics when evaluating both research and clinical programs. We propose forming a Task Force to interface the WHO in order to develop a multidisciplinary framework for classifying aging as a disease

The recognition of a condition or a chronic process as a disease is an important milestone for the pharmaceutical industry, academic community, healthcare and insurance companies, policy makers,and individual, as the presence of a condition in disease nomenclature and classification greatly impacts the way it is treated, researched and reimbursed. However, achieving a satisfactory definition of disease is challenging, primarily due to the vague definitions of the state of health and disease.

Despite the growing abundance of biomarkers of aging, classifying aging as a disease will be challenging due to the absence of the "ideal norm." Despite significant effort from the academic and industry communities, sarcopenia is still not classified as a disease despite clear clinical and molecular representation and similarity with premature musculoskeletal aging and myotonic disorders. One approach to address this challenge is to assume an "ideal" disease-free physiological state at a certain age, for example, 25 years of age, and develop a set of interventions to keep the patients as close to that state as possible. Considering the WHO definition of health, it may be possible to agree on the optimal set of biomarkers that would be characteristic to the "state of complete physical, mental and social well-being, not merely the absence of infirmity" and agree on the physiological threshold after which the net totality of deviation of these biomarkers from norm can be considered a disease.

Thursday, September 3, 2015

It has long been hypothesized that there is a link between autoimmune conditions and the immune response to cancer, and this article covers some of the high points. Autoimmune conditions are a set of complicated failure modes in a very complex system, in which the immune system attacks the patient's own tissues. They are perhaps the least well understood diseases, and this is reflected in the poor state of treatments for autoimmunity: no cures, and the best that can be done for patients is to dampen the overall immune response. Any path forward that grants additional insight into the early development of autoimmunity is welcome.

Generations of in-depth research into human anatomy, histology, and basic physiology have largely explained the physical manifestations of diseases affecting nearly every organ of the body. Yet there remains an entire class of illnesses that present systemically, do not respect the boundaries of organ systems, and wreak havoc on quality of life and longevity. And we still have little idea of what starts the vicious cascade in the first place. This category of maladies is called autoimmune disease, and it is our fundamental lack of knowledge about these disorders that so greatly hinders our ability to prevent, diagnose, and treat them.

There is much we know, or think we know, about the risk factors and manifestations of autoimmune disease, and we even have some diagnostic tests for antibodies that often closely correlate with specific subtypes of disease. However, the fundamental biological mystery remains: What initiates the formation of antibodies that react with the body's own proteins and result in the destructive processes that define autoimmune disease? Have we simply failed to detect an infectious or environmental exposure that initiates the inflammatory cascade? Is there a benefit accrued via autoantibodies that serves an important biological purpose and helps to explain their existence?

While many theories have been and continue to be posited in answer to these etiological questions, a particularly interesting hypothesis first proposed in the 1960s has been reborn and, if it holds true, could have tremendous implications for the fields of rheumatology, oncology, immunology, neurology, endocrinology, and many others: autoimmune disease may represent collateral damage from the body's fight against developing cancers. Scientists have long recognized that patients with certain autoimmune diseases are at increased risk of cancer, but only recently has a possible mechanism been identified. Research involving patients with concurrent cancer and scleroderma revealed somatically mutated genes in the patients' tumors that initiated cellular immunity and cross-reactive humoral immune responses, producing antibodies that reacted to the cancer and are known to play an important role in scleroderma itself. The finding implies that the autoimmune disease may arise as an unintended consequence of the body's own immune response to a developing cancer, which in certain patients will never become clinically evident.

Thursday, September 3, 2015

Researchers here argue that failing calcium regulation provides a meaningful contribution to neurodegeneration, and demonstrate improvement in old rats via altered levels of a protein involved in calcium metabolism. As is the case for most research, this identifies only one step of cause and consequence in longer chain of events. We should expect, given the necessary time and resources, for researchers to be able to trace back age-related changes to fundamental forms of cell and tissue damage that occur as a side-effect of the normal operation of cellular metabolism. That is a long road, however, and given that we already have a catalog of those fundamental forms of damage, it would be faster to start by repairing them to see what happens. That approach is still a minority concern in the research community, sadly.

Building on scientific evidence implicating disturbed calcium regulation in brain aging accumulated through the past 30 years, a research team has found a connection between unhealthy brain aging and a protein responsible for regulating calcium at the molecular level, called FKBP1b. Excess calcium in brain cells appears responsible for important aspects of unhealthy brain aging, and may also increase susceptibility to diseases such as Alzheimer's, ALS, Parkinson's and vascular dementia. Until now, the precise molecular cause of the disturbed calcium regulation in brain aging has remained unknown to scientists. After learning about the FKBP1b protein's recently uncovered role in the heart, researchers wondered whether FKBP1b in the hippocampus region declines with brain aging. They then found evidence of reduced FKBP1b gene expression with aging in the hippocampus. This discovery prompted the researchers to test whether boosting FKBP1b in the hippocampus region could reverse or prevent brain aging linked to memory loss.

The team used an advanced gene therapy approach to inject harmless virus particles, which created additional copies of the FKBP1b protein, into the hippocampus of aging rats. The memory abilities of three groups of rats were tested two months after the injections. One group of young rats received a control injection, one group of aged rats received a control injection and one aged group received an injection of the FKBP1b-producing virus particles. The aged group with raised levels of FKBP1b showed restored calcium regulation and dramatically improved cognitive function, allowing them to perform the memory task as well as or better than the young rats. In addition, the researchers have repeated and extended the results in a subsequent study being prepared for publication.

The research provides evidence the manifestations of brain aging can be reversed, and cognition and memory function restored, by altering levels of FKBP1b. This finding is also significant for Alzheimer's patients as the researchers found a decline in the FKBP1b protein in the hippocampus of people who had early-stage Alzheimer's. The research has implications for preventing brain aging associated with the progression of Alzheimer's, and opens the door for pharmaceutical development aimed at sustaining levels of FKBP1b and keeping calcium in check.

Friday, September 4, 2015

As the paper linked here illustrates, pharmacology remains the main focus for that part of the research community interested in intervening in the aging process. Those involved understand that this progress is very slow and very expensive while any near-future drug therapies will be marginal and come with potentially hazardous side-effects: this is a matter of trying to safely adjusting the enormously complex and still poorly understood operation of metabolism to limp along a little better when damaged by aging, or slightly slow down the pace of damage accumulation. The future that I predict is that this approach to research will continue to swallow enormous sums of money and generate nothing of any real value in terms of treatments for aging, and that this state of affairs will last until periodic damage repair approaches like SENS consistently demonstrate far better and far cheaper results in animal studies and clinical trials. There is a great deal of cultural and regulatory inertia driving the relentless focus on old-style pharmacology in medicine, regardless of its actual fit for any given situation.

Aging can be defined as the progressive decline in tissue and organismal function and the ability to respond to stress that occurs in association with homeostatic failure and the accumulation of molecular damage. Aging is the biggest risk factor for human disease and results in a wide range of aging pathologies. Although we do not completely understand the underlying molecular basis that drives the aging process, we have gained exceptional insights into the plasticity of life span and healthspan from the use of model organisms such as the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Single-gene mutations in key cellular pathways that regulate environmental sensing, and the response to stress, have been identified that prolong life span across evolution from yeast to mammals. These genetic manipulations also correlate with a delay in the onset of tissue and organismal dysfunction.

While the molecular genetics of aging will remain a prosperous and attractive area of research in biogerontology, we are moving towards an era defined by the search for therapeutic drugs that promote healthy aging. Translational biogerontology will require incorporation of both therapeutic and pharmacological concepts. The use of model organisms will remain central to the quest for drug discovery, but as we uncover molecular processes regulated by repurposed drugs and polypharmacy, studies of pharmacodynamics and pharmacokinetics, drug-drug interactions, drug toxicity, and therapeutic index will slowly become more prevalent in aging research. As we move from genetics to pharmacology and therapeutics, studies will not only require demonstration of life span extension and an underlying molecular mechanism, but also the translational relevance for human health and disease prevention.

Friday, September 4, 2015

CD47 is a marker for cancer cells in a broad range of cancers, and thus targeting it offers the prospect of a cancer treatment that can be applied to many more patients than is usually the case. A number of research groups are working on refining this basic idea into practical treatments, or improving first attempts, as is the case here:

By changing the mouse model they use to study how the immune system responds to cancer, a team of researchers hopes to shift the focus for one emerging form of cancer immunotherapy back to the standard approach - relying on antigen-presenting dendritic cells - and away from the current upstart, macrophages. Although macrophages, like dendritic cells, also take up antigens, they are more likely to degrade them than present them to T cells. The recent emphasis on macrophages stems, in part, from promising, but problematic, efforts to develop an effective macrophage-driven T cell-mediated immunotherapy.

Researchers report that using a monoclonal antibody called anti-CD47, which blocks the "don't-eat-me" signal on malignant cells, to treat mice with an intact immune system provides a much more lifelike way to study and develop an immune-based cancer therapy. "Tumor rejection requires both innate and adaptive immune responses against tumor cells. We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer."

The shift of focus from one set of scavengers, dendritic cells, to another, macrophages, was initiated by ground-breaking studies demonstrating that many aging cells, and most cancer cells, display a protein called CD47 on the cell surface. The presence of CD47 protects these cells; it instructs circulating macrophages not to devour them. But as cells age or evolve, many slowly lose their protective CD47 and the macrophage system can confront them. The investigators found that when they used antibodies against CD47 to negate this "don't-eat-me" signal, macrophages were able to chew up many of these cancer cells.

Researchers now point out that these initial studies relied on human tumors transplanted into mice. The mice also had significant immune defects. They argue that a more appropriate model, transplanting tumors from mice into genetically identical hosts with fully intact immune systems, would be more informative and clinically relevant. When they used such mice to test their approach, they found that the bulk of therapeutic effect from CD47 blockade relied not on macrophages but on dendritic cells. These triggered the secretion of interferons, an immune system activator, and the priming of CD8+ T cells. They note that anti-CD47-mediated tumor rejection "requires both innate and adaptive immune responses."


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