Fight Aging! Newsletter, October 27th 2014

October 27th 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, 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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  • SENS Research Foundation 2014 Annual Report
  • The Near Horizon for Visions of Slowing Aging
  • Recent Research into Centenarians and their Biochemistry
  • The Prospects for a MicroRNA-Based Biomarker of Aging
  • Attractive Modern Websites for the Cryonics Providers
  • Latest Headlines from Fight Aging!
    • Towards Intestinal Tissue Engineering
    • Calico Undertaking Neural Plasticity Drug Research
    • NT3 and Regeneration from Noise-Induced Deafness
    • Using Olfactory Bulb Cells to Treat Spinal Injury
    • Physical Exercise is Protective of Brain Function, but Some of the Effects Decline in Old Age
    • Aging and Brain Rejuvenation as Systemic Events
    • Mitochondrial Mutations Contribute to Autoimmune Disease?
    • The Other Activities of Telomerase
    • Towards the Production of New Photoreceptor Cells In Situ
    • Screening for Stress Resistance Mutations in Mice


Following on from the recent Rejuvenation Research 2014 conference, the SENS Research Foundation staff have released their latest annual report. The Foundation is perhaps the only organization to presently focus entirely on advancing repair-based approaches to the development of treatments for aging: take the known root causes, the fundamental forms of damage that distinguish old tissues from young tissues, and build ways to fix them. Unlike other possible approaches to treating aging, there is a clear path forward, as all the forms of damage are identified and one or more potential strategies for developing effective forms of repair exists.

Unfortunately, the SENS approach to aging is still the disruptive, growing newcomer in the research community. The vast majority of longevity research efforts focus on altering the operation of metabolism in order to slow the pace of damage accumulation in aging. This is a part of the field in which there is no clear technical path forward, however. More than a billion dollars have been spent over the past decade with little to show for it but incrementally greater knowledge, and even if results were obtained in the decades ahead, they would be of little use to old people. There isn't much you can do with a way to slow aging if you are already so old and damaged as to be close to death. In time this present state of affairs will change, and SENS will take over the mainstream by virtue of producing better results and at a far lower cost.

This process of disruptive bootstrapping requires greater public support and greater funding than presently exists, however, which is why our help and our donations are so important. A great deal has already been achieved over the past decade as a small community of supporters and scientists took SENS from initial idea to ongoing research program that enjoys the support of many noted figures in the scientific community. Success is always just a starting point for the work of tomorrow, and much more lies ahead if we are to achieve the goal of an end to disease and frailty in aging. The times are changing:

SENS Research Foundation Annual Report 2014 (PDF)

The landscape of aging research is changing. At the Bethesda meeting of the NIH's Geroscience Interest Group it was clear that the walls between gerontological and disease research were beginning to come down. SENS Research Foundation was there. At the G8 Dementia Summit in London, Prime Minister David Cameron spoke of the UK government's vision of an aging society completely free from Alzheimer's. SENS Research Foundation was there.

This is a dialogue which reflects large, multinational efforts. It is a dialogue which goes beyond our own work at the Foundation, but in which we have played our part, affecting its direction at every opportunity. And now, 'big pharma' and nimble start-ups are beginning to change the public discourse, as they make statements about their intentions to address aging directly. This reimagining of what it means to age resonates with a growing global community of politicians, academics and industrialists.

The combined efforts of all these groups, together with regulatory and financial institutions, will be needed to end age-related disease. But it will also require an approach capable of delivering effective interventions against these diseases, interventions which cure rather than alleviate, which prevent rather than delay. That's why we do what we do: we are unique in our mission to ensure that these interventions - cures based on the damage-repair approach we call rejuvenation biotechnology - are developed. As part of that mission we are committed to ensuring that our voice and the voices of our wider community are heard in the arenas where they can effect real progress.

The present budget for the Foundation is modest for a research center or for an advocacy organization. At around $4 million for 2013 it is a tenth of the size of a major independent institution in the field such as the Buck Institute for Research on Aging. You might also compare it with the grants of a few million dollars apiece made by the Glenn Foundation for Medical Research over recent years to establish a network of aging research laboratories. In general aging research is the poor cousin in the broader field of medical research, and you'll see ten times these amounts floating around the cancer and stem cell research communities on a regular basis. That too is something that must change.

In 2012 SENS Research Foundation received a restricted grant from SENS Foundation EU, resulting from the settlement of the de Grey family trust. The total value of this grant, $13.1 million, was recorded as revenue in 2012 and added to our current assets as a pledge receivable. The terms of the grant allow SENS Research Foundation to use a specified amount of the total grant each year on research, education and outreach. In 2013 we used $2,381,952 of the grant in the furtherance of our mission. The generosity of our many supporters generated additional revenue of $1,721,904 in 2013.

The Foundation funds research programs in more than a dozen labs at the present time, and you'll find notes on all of them in the later pages of the report. You should of course read the whole thing:

SENS Research Foundation supports a global research effort. Our own scientists are based in our Mountain View, California facility and we fund researchers at field-leading institutions around the world. As we age, we accumulate decades of unrepaired damage to the cellular and molecular structures of our bodies. The types of damage are few in number - we count seven, currently - but cause a great many diseases of aging, including cancer, Alzheimer's and atherosclerosis. Rejuvenation biotechnologies target this underlying damage, restoring the normal functioning of our bodies' cells and essential biomolecules. As preventative interventions they halt the harmful accumulation of damage, stopping disease before it ever starts.

Cell Therapy for the Intestinal Tract, Wake Forest Institute for Regenerative Medicine

At WFIRM, SENS Research Foundation is funding a project to restore intestinal structure and function. The central goal is the development of a regenerative medicine approach to treating inflammatory bowel disease (IBD), an autoimmune disorder that devastates the cells lining the intestine. Though IBD is not a disease of old age, therapies that repopulate the cells of the gut are critical to the development of a new generation of cancer therapies, as these therapies are likely to depopulate the stem cell reserves of several tissues (and replace the missing cells with fresh, cancer-protected stem cells).

Clearance of Macrophage Oxysterols Driving Atherosclerosis, Rice University

The SENS Research Foundation-funded team at Rice University is working to tackle two intracellular aggregates driving age-related disease and dysfunction: macrophage oxysterols (the core lesion underlying heart disease, via foam cell formation) and lipofuscin (a potential factor in multiple degenerative aging processes).

Chemistry Toward Cleavage of Advanced Glycation Crosslinks, University of Cambridge, Yale University

Advanced glycation end-products (AGEs) are a class of compounds that accumulate in our tissues as part of the degenerative aging process. The Yale AGE team is working on new tools for the detection of AGEs and their precursors. The program will synthesize glucosepane, currently thought to be the single largest contributor to tissue AGE crosslinking, and the understudied crosslink pentosinane. The team will then to use these compounds to develop new antibodies and reagents to enable rejuvenation research. Ongoing experiments in collaboration with SENS Research Foundation's Cambridge research center are focused on developing antibodies against CML (a common reactive glycation product) and MGH. These efforts will be expanded once glucosepane constructs are prepared.

Investigating the Nature of Academia-Industry Interaction in the Translation of Gene Therapies, University of Oxford, Centre for the Advancement of Sustainable Medical Innovation

The recent clinical success of gene therapy has increased the visibility of the field, attracting interest from industry. It faces commercialization challenges which differ from conventional therapeutics due to complex manufacturing procedures, record-breaking price tags, and the potential for truly personalized approaches. The first stage of the project analyzes the features of researchers and research at the University of Oxford which have led to support from industry. Surveys of industry partners aim to identify how these features are perceived, and why they influence the allocation of industry funds. This project also examines the mechanisms by which collaborations form in preclinical research. The second stage of the project considers the critical role of academia-industry collaboration in the translation of these novel high-risk, high-cost technologies. This collaboration is critical in bringing these therapies to patients.

Optimizing the Quality and Effectiveness of Risk, University of Oxford, Centre for the
Advancement of Sustainable Medical Innovations

There is declining productivity in biomedical research and development in terms of new product approvals, in part due to an inherently risk averse regulatory pathway for novel healthcare innovations. This is despite major achievements and opportunities in novel technological platforms. The portfolio of risk:benefit methodologies have been applied inconsistently and often conflated with cost-effective analysis. This yields results that do not effectively inform clinical practice or strategies for biomedical innovation. This investigation aims to assess risk:benefit appraisal methodologies in the analysis of published randomized controlled trials for pre-licensure biomedical.

Targeting the Senescence-Associated Secretory Phenotype, Buck Institute for Research on Aging

Senescent cells also develop resistance to signals for apoptosis (cellular suicide) and secrete inflammatory signaling molecules and protein-degrading enzymes into their local environment. This last phenomenon is called the senescence-associated secretory phenotype (SASP). SASP is thought to play a role in the chronic inflammation that is widespread in aging tissues, which in turn promotes the progression and propagation of age-related frailty and the many diseases of aging. With SENS Research Foundation funding, the Buck Institute SASP project has been screening small molecules for their effects on fibroblasts (a kind of skin cell) that have been rendered senescent by ionizing radiation, with the aim of identifying agents that could either selectively kill senescent cells, or interrupt the SASP and prevent its harmful effects.

Maximally-Modifiable Mouse, Applied StemCell, Inc.

The goal of the Maximally Modifiable Mouse (MMM) project is to generate mouse models allowing easy genetic modification at any time point during the mouse's lifespan, thus hastening the process of testing potential interventions against age-related disease. The MMM project aims to generate a new line of transgenic mice with "docking sites" for a high-precision targeting system for gene insertion that are not typically found in mammals engineered into their genomes. The docking site will then be ready for the insertion of new therapeutic transgenes at any time during the mice's lifespan, allowing for the testing of candidate therapies.

Rejuvenation of the Systemic Environment, University of California, Berkeley

The experimental technique of heterochronic parabiosis, in which the circulation of an aged animal is joined to that of a young one, exposes the aged organism's tissues to a youthful systemic environment (and vice-versa). The UC Berkeley systemic environment team is exploring the influence of the systemic environment on aging processes using a novel computer-controlled technological platform and specialized hardware made from off-the-shelf and custom 3-D printed parts. This platform enables the group to easily and safely extract blood from small animals, process what they extract in any of several ways, and either return it to the original animal or exchange it with that of an oppositely-aged animal. Plasma contains the soluble signaling molecules of interest in parabiosis experiments, and the use of plasma instead of whole blood enables scientists to disentangle the effects of an old animal having access to the young animal's blood cells and organs from the effects of the factors found circulating in the systemic environment.

Clearance of RPE Aggregates Driving Macular Degeneration, SENS Research Foundation Research Center

Our cells contain vesicles called lysosomes that use enzymes to recycle cellular wastes. Some stubborn wastes, however, are beyond the lysosome's evolved capacity to break down. These products accumulate in the cell's main body or in the lysosome, and may even make their way outside the cell. In the eye, extracellular garbage called drusen gradually accumulates in a portion of the retina called the macula. Drusen accumulation is an indicator for age-related macular degeneration (ARMD), the leading cause of blindness in persons over the age of 65. The SRF-RC RPE aggregate team is working to identify enzymes capable of degrading recalcitrant wastes and restoring lysosomal activity in RPE cells, which could enable ongoing maintenance of macular photoreceptors and prevent the appearance of drusen and the development of ARMD.

Tissue-Engineered Thymus, Wake Forest Institute for Regenerative Medicine

The thymus engineering group at WFIRM is working to produce new thymus tissue with a rejuvenated ability to produce T-cells, helping to restore the immune system's youthful strength. The scientists are using the powerful "decellularized scaffold" approach. Researchers begin with a donor organ and strip it of its original cells, leaving a "scaffold" of extracellular matrix (ECM) onto which cells derived from the transplant recipient can be seeded.

Allotopic Expression of Mitochondrially-Encoded Proteins, SENS Research Foundation Research Center

The accumulation of cells harboring deletion-mutation-containing mitochondria is a significant consequence of aging, and is implicated in age-related disease. The SRF-RC mitochondrial mutations team is working to develop engineered mitochondrial genes that could be stored safely in the cell's nucleus and function as "backup copies" for cells whose mitochondria harbor deletion mutations. They are currently working to realize the potential of a new method for targeting these engineered nuclear-encoded genes to the mitochondria, and to optimize the precision of this targeting.

Diagnostic and Therapeutic Antibodies against Transthyretin Amyloids, University of Texas-Houston Medical School, Harvard University

A key driver of age-associated ill health is a form of molecular damage in which certain proteins in the body lose their native structure and bind together with one another, forming harmful aggregates. One less-known amyloid disease is senile systemic amyloidosis (SSA), a disorder caused by aggregation of a hormone-transporter protein called transthyretin (TTR). With SENS Research Foundation support, the UTHMS TTR amyloid team is working to develop engineered catalytic antibodies ("catabodies") targeting misfolded TTR as a rejuvenation biotechnology for prevention and treatment of TTR amyloidosis. These "catabodies" combine the specificity of conventional antibodies with the catalytic power of enzymes, giving a single catabody molecule the ability to permanently degrade large amounts of target amyloid.

Identification of the Genetic Basis of ALT, SENS Research Foundation Research Center

To survive, all cancers must develop a mechanism to re-lengthen their telomeres. Many cancers do this by hijacking the genes involved in regulation of the enzyme telomerase, which are only supposed to be expressed by certain specific cell types under very tight control. 10-15% of cancers, meanwhile, employ a telomerase-independent mechanism known as alternative lengthening of telomeres (ALT). The SRF-RC ALT group has has developed a fast, high-throughput assay method and will use the new, faster ALT assays to hunt for genes that might be involved in the ALT machinery, and screen libraries of drugs to identify new candidate treatments that would shut down ALT cancer cells.

Epimutations: Targets or Bystanders for Rejuvenation Biotechnology? Albert Einstein College of Medicine

Just as our genes can suffer mutations that damage the instructions cells use to make their encoded proteins, so too our cells can suffer damage to the "epigenetic" structures that help to regulate whether a particular gene is turned on or off in a particular kind of cell at a particular time. These epimutations therefore cause cells to turn the expression of particular genes on or off aberrantly. The Albert Einstein College of Medicine (AECOM) epimutations team is investigating the possibility that epimutations could be contributing to age-related disease. Numerous cells in a tissue could, in this scenario, be engaging in aberrant gene expression, leading over time to tissue dysfunction and eventual pathology.


The mainstream of the aging research community, or at least that fraction of it that is interested at all in increasing healthy longevity by intervening in the aging process, is almost entirely focused on the use of drugs to alter metabolism to slightly slow the onset of frailty and ill-health in later life. There isn't even much effort to find new drugs: candidates are largely existing drugs. Many of these researchers exclusively discuss compression of morbidity, the goal of extending healthy life without extending overall life span. There is still an aversion in many circles to any talk of extending overall human life spans, no matter how realistic the prospects, and the boundaries of the possible for these folk stops at slowing aging modestly. These are researchers who look ahead to another twenty years of research and development that looks exactly like the last fifty: a slow mining of the natural world in search of compounds that can be used as drugs to alter the operation of the human body to produce marginal benefits. No revolution, no great advances, just a continuation of the present trends.

This is an exceedingly narrow horizon, a box even. These researchers believe it will be challenging and expensive and slow to generate benefits, and if standard issue drug development after the 1970s model that is still with us today is all they plan to do, then that seems about right. Despite great advances in biotechnology, the research community is still only in the initial stages of of mapping the complexities of metabolism, epigenetics, and their changes with aging. There is little in the way of a clear path forward to actually slow aging in humans, and where there are potentially promising areas of study, such as calorie restriction, large amounts of funding and time have so far failed to produce meaningfully beneficial therapies based on calorie restriction mimetics.

This dismal situation is why we need a disruption of the entire field in favor of research approaches that might actually work to greatly extend healthy and overall human life, that have much more in the way of straightforward and defined research plans leading to therapies, and wherein the scientists involved are not afraid to stand up and state that the end of frailty and disease in aging, indeed the end of aging itself, is the goal. The present mainstream is not getting the job done: their primary focus is on gaining knowledge of metabolism and the fine details of aging, not of taking all that is known so far and building the best therapies possible.

The Strategies for Engineered Negligible Senescence (SENS) approach typifies the sort of reaction to the mainstream you'll find among more visionary researchers who see that much more can be done about aging in the near future. There are much better paths to a future of longer lives than the tired road of drug development. If all that happens over the next twenty years is more messing with metabolism in the vague hope that small and expensive benefits will be realized, than that will be a waste of a great opportunity. Enough is known to make real progress in treatments for aging today - the only thing missing is large-scale funding and widespread public support.

The open access paper quoted below provides a very clear and detailed look at the viewpoint of those who think that only marginal gains are possible, and that researchers shouldn't talk about or try to achieve extension of overall human life span. You should compare it with a reading of the introduction to the SENS research program. On the one hand a manifesto that has as an important strand of work digging through existing drugs in search of something, anything, that might do more good than harm. On the other, a call for taking the best of present knowledge to deliberately target the known root causes of aging with the aim of turning back the progression towards disability and disease. Night and day.

Translational Geroscience: Emphasizing function to achieve optimal longevity

Investigators working in fields related to the biology and biomedicine of aging ("Geroscientists") are among those at the forefront for creating solutions to the impending impact of global aging. Several strategies have been identified, the most well-known of which is the "compression of morbidity" paradigm advanced by Fries over 30 years ago. This approach is based on the idea that because most illness today is in the form of chronic diseases, if the onset of these disorders can be delayed to an older age, and the delay is greater than any associated increase in life expectancy, then illness, disability and their sequelae can be restricted to a shorter period at the end of life.

The key issue is how to best achieve compression of morbidity. Presently there is considerable support for the tactical approach of slowing the fundamental biological processes of aging, as opposed to treating (or even preventing) individual chronic diseases. Much of the momentum for this approach has been created by the tremendous advances made over the last 25 years in what is now the routine manipulation of lifespan in model systems such as Drosophila or C. elegans. The idea is that targeting specific 'upstream' pathways, originally identified in model systems, holds promise for delaying the age of onset of multiple age-associated comorbidities as a group, whereas delaying the clinical manifestation of a particular disease may simply result in some other age-related disorder "backfilling" the consequent reduction in risk. Slowing aging at the molecular and cellular levels would, theoretically, increase "healthspan", i.e., the period of life free from serious chronic diseases and disability, thus compressing morbidity and facilitating attainment of optimal longevity.

p>In the area of promising dietary and pharmacological strategies, the National Institute on Aging (NIA) Interventions Testing Program (ITP) has become a highly successful source of potential treatments to reduce age-associated pathologies and extend lifespan in mice. Moreover, independent laboratories working in basic aging biology recently have produced a remarkable number of potential targets and associated target-modulating treatments worthy of translational consideration. Overall, it seems likely that identification of candidate therapies from preclinical models will not be the major limitation for establishing effective interventions to slow the effects of aging and delay the onset of age-associated co-morbidities.

One of the main obstacles for translation of treatments to improve function with aging lies in the initial steps from assessments in animal models to testing for safety and efficacy in human subjects (phase I and II clinical trials). The process for bringing new prescription agents targeting aging to market has been described in detail by Kirkland, and the steps, time lines and costs involved are extensive. However, development of drugs for older patients with geriatric syndromes such as frailty, as well as clinical disorders that are antecedents of these syndromes, clearly is an important goal and area of interest for the pharmaceutical industry.

Complementary options to new proprietary prescription drug development also exist, and may represent, in some cases, a nearer-term source for new therapies with function-enhancing effects for older adults. For example, widely used FDA approved drugs with established safety and efficacy for treating age-associated clinical disorders such as cardio-metabolic diseases (e.g., metformin, statins, renin-angiotensin system inhibitors, recent generation beta-blockers) could undergo repurposing for treatment of at risk older adults or patients with aging syndromes. Although such agents could be prescribed presently for their off-label effects in cases in which the existing evidence supports likely efficacy, broad use of these drugs likely will require new trials with appropriate subject groups and clinical endpoints recognized by drug regulatory authorities.

On the one hand it is good that ever more of the research community and its supporters are waking up to the idea of treating aging and speaking in public on that topic, rather continue with the past course of patching its consequences in silence. On the other hand, the specific research and development strategies advocated by most factions are just not good at all. They will produce knowledge, certainly, but nothing in the way of treatments that might be expected to add even a decade to human life spans. We can and should do far better than this, and the way to do so is via SENS and other repair-based approaches to the damage of aging. Only repair can lead to a future of actual rejuvenation and the prospect of unlimited healthy life spans.


Some family lineages produce far more long-lived individuals than others with the same background: similar region, culture, wealth, and era. From that we can conclude that some natural genetic variations provide a greater chance of living longer in good health. The present high level view of genetics and aging is that outside of rare and catastrophic mutations, genetic variation has comparatively little influence on survival prior to old age: it's all about lifestyle choices, and to a first approximation those boil down to smoking, exercise, excess fat tissue, and how much you eat. After age 70 or so this changes, and genetic variation plays an ever larger role. Centenarians, those who reach age 100 or more, typically are less impacted by aging at any given age than their less fortunate peers. Aging is damage, they are less damaged, and their genetics has a role in this.

This is the logic that leads a great many researchers to investigate the biochemistry and genetics of centenarians and long-lived families in search of knowledge that can be turned to treatments to slow aging. This is little different to work on calorie restriction mimetics in terms of expected utility, however. It is hard work, a slow, expensive investigation of extremely complex systems that are at present poorly understood. The end result will not be any way to turn back aging, but at best to slow it. Genetic variations that show up more often in centenarians are not a guarantee of comparative longevity, they only swing the odds. There are many people with these genes, and very, very few of them live to be 100 or older. It's just that if you don't have that biochemistry the odds are even more terrible.

I don't want the future of aging research to be an expensive, slow scrabble for ways to slightly slow aging, or to make it slightly more possible to be burdened by a high load of cellular and molecular damage and yet remain alive. The future should be the targeted exploitation of what is known of the root causes of aging, so as to build repair and rejuvenation therapies that can maintain health and youth, and effectively cure age-related conditions in the old. That is the path to meaningful results in terms of more years lived in good health: repair the damage in the system you have, as this is a much more efficient approach in comparison to changing the system to slow its decay.

That doesn't mean that centenarian research is uninteresting, however. It is fascinating stuff. Just bear in mind that it most likely isn't a path to much of use other than greater knowledge of the fine details of the biology of aging. This is knowledge that we arguably have little need of in order to move a long way towards a cure for aging based on repair its known root causes.

Can Enhanced Autophagy be Associated with Human Longevity? Serum Levels of the Autophagy Biomarker Beclin-1 are Increased in Healthy Centenarians

Autophagy is a major clearance mechanism that degrades organelles and large protein aggregates to maintain cell survival and protein homeostasis. Although induction of autophagy can promote longevity in experimental models, the question as to whether increased basal levels of autophagy can be associated with human longevity remains open. In this pilot study, we investigated the association between serum concentrations of beclin-1, a key regulator of autophagy, and human exceptional longevity.

Serum beclin-1 was measured in three study groups: 79 healthy centenarians (39 males, aged 100-104 years); 178 non-diabetic patients who had experienced an acute myocardial infarction at a young age (101 males, 28-39 years); and 180 age- and sex-matched healthy young volunteers (103 males, 27-39 years). Healthy centenarians had significantly higher beclin-1 levels compared with both young patients with myocardial infarction and healthy controls, whereas no significant difference was observed between the two groups of young subjects. Our preliminary data suggest that elevated basal levels of autophagy as reflected by high serum beclin-1 levels may be a biomarker of healthy human exceptional longevity.

Disease variants in genomes of 44 centenarians

To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. We identified 130 coding variants that were annotated as "pathogenic" or "likely pathogenic" based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE ε4 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions.

Factors affecting the survival probability of becoming a centenarian for those aged 70, based on the human mortality database: income, health expenditure, telephone, and sanitation

The survival probability of becoming a centenarian (SPBC) is defined as an estimate of the production of centenarians by a population. The SPBC (70) is the survival probability of becoming a centenarian for those aged 70. Significant positive correlations were found between the SPBC (70), and the socioeconomic factors of gross national income (GNI), public expenditure on health as a percentage of gross domestic product (PEHGDP), fixed and mobile telephone subscribers (FMTS) as the standard of living, and improved sanitation facilities (ISF).


The development of accurate and cheap biomarkers of biological age is an important goal for the research community. The issue at hand is this: short of sitting back and waiting for years or decades, how should one test a supposed rejuvenation treatment? How to evaluate whether it works and how successful it is? If you have to wait and see, as is presently the case, then even mouse studies take years and cost millions of dollars apiece. If you could instead wait a month and take some blood samples, then suddenly a whole lot more research can be accomplished with that money.

Consider proposed SENS treatments that involve the clearance of age-related cross-link compounds such as glucosepane that harm tissue flexibility and integrity, for example. It is clearly the case that researchers will be able to tell how well they achieve that immediate goal, as they will measure cross-link levels in tissues beforehand and afterwards - a simple and straightforward test of effectiveness. Researchers can also assess secondary measures that are considered important in aging and known to correlate with the presence of cross-links, such as blood pressure, blood vessel elasticity, skin elasticity, and so forth. In theory these should all improve; if not, well that would be an unexpected setback. But if it works, and all these measures move back towards the values typical of a youthful individual, is that actually rejuvenation? Has this patient's biological age been reduced?

At the moment that question is impossible to answer without sitting back and waiting for decades. One group of researchers is well on the way to demonstrating the reliable use of specific patterns of changing DNA methylation as a measure of biological age, however, and so far their methodology seems like a promising candidate for a biomarker of aging. Where there is one such measure, we should expect there to be others. Everything in our biochemistry interacts with everything else, after all. Thus here researchers make the first steps towards the possibility of assembling a biomarker of aging from some combination of circulating microRNA levels. It is quite intriguing that their research demonstrates patterns that are characteristic of age, yet independent of health status in the case of their chosen group of patients:

Circulating MicroRNAs as Easy-to-Measure Aging Biomarkers in Older Breast Cancer Patients: Correlation with Chronological Age but Not with Fitness/Frailty Status

MicroRNA's (miRNAs) are short, non-coding and highly stable RNA's that are involved in post-transcriptional regulation of gene expression. They are known as fine-tuning mediators of a wide variety of normal physiological pathways, developmental processes and pathological conditions; it is thus plausible that they also play a role in cellular senescence and tissue/body aging.

Circulating miRNAs actually are attractive candidate biomarkers for clinical use, because of their easy accessibility and outstanding stability in serum/plasma. Here, we describe the potential use of microRNA signatures expressed in serum/plasma for the assessment of biological age in breast cancer patients. We compared a panel of 175 different microRNAs, known to be among the most relevant in serum/plasma, between older and young breast cancer patients and validated the findings of this initial exploratory screening in an independent breast cancer cohort. At least 5 circulating microRNAs emerged from this study that are worth to be further explored as potential aging biomarkers in larger cohorts of young versus old fit versus old frail individuals, both within and beyond a cancer background.

Plasma levels of miR-20a-3p, miR-30b-5p, miR106b, miR191 and miR-301a were confirmed to show significant age-related decreases. The remaining miRNAs included in the validation study (miR-21, miR-210, miR-320b, miR-378, miR-423-5p, let-7d, miR-140-5p, miR-200c, miR-374a, miR376a) all showed similar trends as observed in the exploratory screening but these differences did not reach statistical significance. Interestingly, the age-associated miRNAs did not show differential expression between fit/healthy and non-fit/frail subjects within the older breast cancer cohort of the validation study and thus merit further investigation as true aging markers that not merely reflect frailty.


Cryonics involves the low-temperature preservation of the recently deceased, and as an industry it has been around for some decades. Using modern techniques and if the preservation is accomplished with speed, this can result in a good preservation of the fine structure of the brain, and thus of the data that makes up the mind. There is a lot more to it than just the technology, however. Like all major medical procedures it requires considerable organization, legal, financial, and logistical, and much of the focus of a cryonics provider is on the work needed make such a one-time event, occurring on an unpredictable schedule and subject to the legal scrutiny of numerous government bodies, run as smoothly as possible.

A preserved individual has all the time in the world to wait on future advances in technology that will required for the task of restoring a preserved brain to new life in a new body. This isn't fantastical: it requires a mature molecular nanotechnology industry capable of producing and controlling complex medical nanorobot swarms, alongside the sort of control over cellular biology that we would expect to emerge later this century. A lot of serious scientific thought over the decades has gone into foreseeing exactly what would be needed for this task, and the only real issue is that this technology doesn't yet exist. People who are cryopreserved get to wait around for that to happen. People who go to the grave do not: they are lost and gone beyond all help, and it is a tragedy of staggering proportions that we live in a world in which cryonics is little thought of.

It was recently brought to my attention that the two cryonics providers in the US, the Cryonics Institute and the Alcor Life Extension Foundation, publish attractive modern business websites these days. In Alcor's case that is a recent update. If you want to find out more about cryonics, now is a good time:

We wanted to bring the appearance of up to date and make it more appealing. We also wanted to improve engagement with visitors. This revision is a major cosmetic facelift. We will follow up with significant changes to the content, designed to help visitors find the information most important to them. We have also added a chat function. In just the first couple of days, this is proving to be a valuable tool for engaging website visitors and answering their questions. Take a look!

This is a sign of the times perhaps: cryonics as an industry remains out of sight and out of mind for most people, but it nonetheless receives more positive attention these days than it has in the past. The people involved in running providers and research groups in the industry are ever looking to move beyond the non-profit and grassroots origins of the cryonics community over the past 40 years to become more professional and more businesslike. The underlying technologies, such as vitrification of tissues, will become used more broadly in medicine for long-term organ preservation and similar needs in the years ahead, and the transformation of the industry from community effort to ongoing businesses will speed up.

That said, this remains a niche market, albeit one that in a just world would be much larger. Service providers are a hybrid form of company, one third a membership society with aspects in common with life insurance businesses, another third the provision of medical services for members that has a lot in common with acute critical care and all of its complexities, and the remaining third a specialist long-term biomedical storage facility. That is a mix that doesn't occur in too many other places in the business community: some hospitals, perhaps, but few other places.


Monday, October 20, 2014

Researchers are making progress towards a methodology for growing intestinal tissues from a patient's cells. As is usually the case in this sort of work, the first results are not intended for use in therapies, but will instead provide raw materials that can help to speed further research:

Researchers have successfully transplanted "organoids" of functioning human intestinal tissue grown from pluripotent stem cells in a lab dish into mice. Through additional translational research the findings could eventually lead to bioengineering personalized human intestinal tissue to treat gastrointestinal diseases. "This provides a new way to study the many diseases and conditions that can cause intestinal failure, from genetic disorders appearing at birth to conditions that strike later in life, such as cancer and Crohn's disease. These studies also advance the longer-term goal of growing tissues that can replace damaged human intestine."

The scientists used induced pluripotent stem cells (iPSCs) - which can become any tissue type in the body - to generate the intestinal organoids. The team converted adult cells drawn from skin and blood samples into "blank" iPSCs, then placed the stem cells into a specific molecular cocktail so they would form intestinal organoids. The human organoids were then engrafted into the capsule of the kidney of a mouse, providing a necessary blood supply that allowed the organoid cells to grow into fully mature human intestinal tissue. The researchers noted that this step represents a major sign of progress for a line of regenerative medicine that scientists worldwide have been working for several years to develop.

Mice used in the study were genetically engineered so their immune systems would accept the introduction of human tissues. The grafting procedure required delicate surgery at a microscopic level, according to researchers. But once attached to a mouse's kidney, the study found that the cells grow and multiply on their own. Each mouse in the study produced significant amounts of fully functional, fully human intestine.

Monday, October 20, 2014

Probably indicative of the Calico Labs strategy for the foreseeable future, here is a piece of news from last month that I missed at the time. The initiative will be taking over funding of an established drug development program aimed at increasing neural plasticity, trying to find ways to spur the brain to generate more new neurons to compensate for damage. Like much of what goes on in modern medical research for age-related conditions, this is a compensatory approach, addressing proximate rather than root causes of degeneration. For many conditions, this may be useful and possibly even sufficient - Parkinson's disease, for example, affects a mechanical part of the brain that has little to do with the structure of the mind, and the cells there could in theory be replaced wholesale over and again as needed.

Generally, however, we want a research community that works to repair and prevent the root causes of aging, rather than one focused on trying to patch up late stage age-related damage after the fact, or worse, trying to alter the operation of metabolism to make it run slightly better when damaged. If the Calico Labs leadership intend to build an establishment rapidly over the next few years by adopting promising research programs, then the less optimal paths are largely what they'll be funding, however:

This week, UT Southwestern researchers published a new paper about the molecular target of P7C3 compounds, a class that has been shown to help in various animal models of neurodegeneration. UT Southwestern previously licensed the P7C3 compounds to Dallas-based 2M Companies. 2M and Calico have now entered into a new license agreement under which Calico will take responsibility for developing and commercializing the compounds resulting from the research program. Under the agreement, Calico will fund research laboratories in the Dallas area and elsewhere to support the program.

Death of nerve cells is the key mechanism in many devastating neurological diseases for which there are currently inadequate treatment options. [The UT Southwestern researchers] have collaborated since 2007 to find novel drugs that promote the growth of new nerve cells in the brain, a process known as "neurogenesis." The P7C3 compounds discovered by the team have previously been shown to be effective in animal models of age-related neurocognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and depression. New research [shows] that these drugs activate a cellular enzyme involved in energy metabolism, known as NAMPT (short for nicotinamide phosphoribosyltransferase), which is critical to the proper functioning and survival of cells. A separate [study] shows that the P7C3 compounds protect against brain dysfunction when given to rodents following traumatic injury.

Tuesday, October 21, 2014

Deafness due to noise exposure is apparently due in part to destruction of specific forms of synapses linking hair cells and nerve cells. Researchers are here manipulating cells in search of ways to boost the regrowth of these synapses:

NT3 is crucial to the body's ability to form and maintain connections between hair cells and nerve cells, the researchers demonstrate. This special type of connection, called a ribbon synapse, allows extra-rapid communication of signals that travel back and forth across tiny gaps between the two types of cells. "It has become apparent that hearing loss due to damaged ribbon synapses is a very common and challenging problem, whether it's due to noise or normal aging. We began this work 15 years ago to answer very basic questions about the inner ear, and now we have been able to restore hearing after partial deafening with noise, a common problem for people. It's very exciting."

After determining that inner ear supporting cells supply NT3, the team turned to a technique called conditional gene recombination to see what would happen if they boosted NT3 production by the supporting cells. The approach allows scientists to activate genes in specific cells, by giving a dose of a drug that triggers the cell to "read" extra copies of a gene that had been inserted into them. For this research, the scientists activated the extra NT3 genes only into the inner ear's supporting cells.

The genes didn't turn on until the scientists wanted them to - either before or after they exposed the mice to loud noises. The scientists turned on the NT3 genes by giving a dose of the drug tamoxifen, which triggered the supporting cells to make more of the protein. Before and after this step, they tested the mice's hearing using an approach called auditory brainstem response - the same test used on humans. The result: the mice with extra NT3 regained their hearing over a period of two weeks, and were able to hear much better than mice without the extra NT3 production.

Tuesday, October 21, 2014

Here is recent news of an approach to spinal injury that has produced benefits in one patient. It is worth tempering optimism until larger trials are attempted, however, as nerve regeneration has proven to be highly variable between individuals. The published paper on the results is open access, but very slow to load at the moment.

A paralysed man has been able to walk again after a pioneering therapy that involved transplanting cells from his nasal cavity into his spinal cord. Darek Fidyka, who was paralysed from the chest down in a knife attack in 2010, can now walk using a frame. The treatment used olfactory ensheathing cells (OECs) - specialist cells that form part of the sense of smell. OECs act as pathway cells that enable nerve fibres in the olfactory system to be continually renewed. In the first of two operations, surgeons removed one of the patient's olfactory bulbs and grew the cells in culture. Two weeks later they transplanted the OECs into the spinal cord, which had been cut through in the knife attack apart from a thin strip of scar tissue on the right.

They had just a drop of material to work with - about 500,000 cells. About 100 micro-injections of OECs were made above and below the injury. Four thin strips of nerve tissue were taken from the patient's ankle and placed across an 8mm (0.3in) gap on the left side of the cord. The scientists believe the OECs provided a pathway to enable fibres above and below the injury to reconnect, using the nerve grafts to bridge the gap in the cord.

Before the treatment, Mr Fidyka had been paralysed for nearly two years and had shown no sign of recovery despite many months of intensive physiotherapy. Mr Fidyka first noticed that the treatment had been successful after about three months, when his left thigh began putting on muscle. Six months after surgery, Mr Fidyka was able to take his first tentative steps along parallel bars, using leg braces and the support of a physiotherapist. Two years after the treatment, he can now walk outside the rehabilitation centre using a frame. He has also recovered some bladder and bowel sensation and sexual function.

Wednesday, October 22, 2014

There is plenty of evidence to link regular exercise with specific aspects of better health, such as measures of functionality in the brain and cardiovascular system. Here, however, researchers produce data to suggest that some of the protective effects of exercise decline in later old age. This may well be the case, but it is worth noting that this is a small study, and that other past studies have indicated that exercise at any age is beneficial:

Physical exercise in old age can improve brain perfusion as well as certain memory skills. This is the finding of [neuroscientists] who studied men and women aged between 60 and 77. In younger individuals regular training on a treadmill tended to improve cerebral blood flow and visual memory. However, trial participants who were older than 70 years of age tended to show no benefit of exercise. Thus, the study also indicates that the benefits of exercise may be limited by advancing age.

The 40 test volunteers were healthy for their age, sedentary when the study commenced and divided into two groups. About half of the study participants exercised regularly on a treadmill for 3 months. The other individuals merely performed muscle relaxation sessions. In 7 out of 9 members of the exercise group who were not more than 70 years old, the training improved physical fitness and also tended to increase perfusion in the hippocampus - an area of the brain which is important for memory function. The increased perfusion was accompanied by improved visual memory: at the end of the study, these individuals found it easier to memorize abstract images than at the beginning of the training program. These effects were largely absent in older volunteers who participated in the workout as well as in the members of the control group.

Physical exercise is known to have considerable health benefits: the effects on the body have been researched extensively, the effects on brain function less so. An increase in brain perfusion through physical exercise had previously only been demonstrated empirically in younger people. The new study shows that some ageing brains also retain this ability to adapt, even though it seems to decrease with advancing age. Furthermore, the results indicate that changes in memory performance resulting from physical exercise are closely linked to changes in brain perfusion.

Wednesday, October 22, 2014

It is always good to see more researchers talking openly about the prospects for treating aging, reversing dysfunction, and extending life. This review is open access, but the full paper is only available in PDF format at the moment:

Until recently, the aging process - the gradual detrimental effect of time on an organism that leads to death - was considered irreversible. However, research over the last 30 years has challenged this assumption, providing compelling evidence that the aging process can be affected by several factors, including the genetic composition of the organism, as well as the experiences the organism has with its environment. These findings indicate that aging is not a deterministic process, but is instead plastic, potentially availing itself to manipulation by means available to the fields of biology and medicine. The malleability of the aging process raises the exciting possibility that harnessing this plasticity may provide a means to slow or even reverse the aging process itself and rejuvenate physiological systems.

[This is] particularly evident in the loss of plasticity and cognitive abilities occurring in the aged central nervous system (CNS). However, it is becoming increasingly apparent that extrinsic systemic manipulations such as exercise, caloric restriction, and changing blood composition by heterochronic parabiosis or young plasma administration can partially counteract this age-related loss of plasticity in the aged brain. In this review we discuss the process of aging and rejuvenation as systemic events. We summarize genetic studies that demonstrate a surprising level of malleability in organismal lifespan, and highlight the potential for systemic manipulations to functionally reverse the effects of aging in the CNS.

Based on mounting evidence, we propose that rejuvenating effects of systemic manipulations are mediated in part by blood-borne 'pro-youthful' factors. Thus systemic manipulations promoting a younger blood composition provide effective strategies to rejuvenate the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged CNS as a means to rejuvenate regenerative, synaptic and cognitive functions late in life, with potential implications even for extending lifespan.

Thursday, October 23, 2014

Mitochondria, the cell's power plants, contain their own DNA. This is a legacy of their origin as symbiotic bacteria, but it makes them vulnerable to damage. Mitochondrial DNA is not as well protected and maintained in comparison to nuclear DNA, and it sits right next to an energetic biochemical process that generates plenty of potentially harmful reactive oxygen species. More serious mutational damage such as deletions are thought to contribute to aging by creating mitochondria that lack the proteins needed for proper function. Here, however, researchers speculate that other types of mutation that alter the produced proteins rather than block their production can contribute to the development of autoimmune disease:

Autoimmune disease is a critical health concern, whose etiology remains enigmatic. We hypothesized that immune responses to somatically mutated self proteins could have a role in the development of autoimmune disease. IFN-γ secretion by T cells stimulated with mitochondrial peptides encoded by published mitochondrial DNA was monitored to test the hypothesis. Human peripheral blood mononuclear cells (PBMCs) of healthy controls and autoimmune patients were assessed for their responses to the self peptides and mutated-self peptides differing from self by one amino acid.

None of the self peptides but some of the mutated-self peptides elicited an immune response in healthy controls. In some autoimmune patients, PBMCs responded not only to some of the mutated-self peptides, but also to some of the self peptides, suggesting that there is a breach of self-tolerance in these patients. Although PBMCs from healthy controls failed to respond to self peptides when stimulated with self, the mutated-self peptide could elicit a response to the self peptide upon re-stimulation in vitro, suggesting that priming with mutated-self peptides elicits a cross-reactive response with self. The data raise the possibility that DNA somatic mutations are one of the events that trigger and/or sustain T cell responses in autoimmune diseases.

Thursday, October 23, 2014

Telomerase extends telomeres, the protective ends of chromosomes. A portion is lost with each cell division, and this mechanism forms part of a clock regulating the replicative life span of ordinary cells. Stem cells maintain long telomeres and when active work to introduce into tissues a continual supply of new daughter cells with long telomeres. Average telomere length declines with illness or age most likely largely because of disturbances to this process of tissue maintenance: as the creation rate of new cells with long telomeres falls, the average telomere length in tissue will also fall.

Telomerase is vital to most cancers, in which individual cells maintain long lives and act more like unlimited stem cells than the ordinary cells they are descended from. A fair amount of modern research into telomeres and telomerase is conducted by the cancer research community. Ways to selectively block the activity of telomerase would be a potent cancer therapy.

One of the possible reasons why artificially increased levels of telomerase extends life in mice is that it improves stem cell function in this way. Extending telomeres is not the only function of telomerase, however. Evolution tends to produce systems in which components are promiscuously reused in many processes. For example, telomerase has been shown to improve mitochondrial function, and mitochondria are important in the aging process:

Telomerase activity is essential for human cancer cells in order to maintain telomeres and provide unlimited proliferation potential and cellular immortality. However, additional non-telomeric roles emerge for the telomerase protein TERT that can impact tumourigenesis and cancer cell properties. This review summarises our current knowledge of non-telomeric functions of telomerase in human cells, with a special emphasis on cancer cells.

Non-canonical functions of telomerase can be performed within the nucleus as well as in other cellular compartments. These telomere-independent activities of TERT influence various essential cellular processes, such as gene expression, signalling pathways, mitochondrial function as well as cell survival and stress resistance. Emerging data show the interaction of telomerase with intracellular signalling pathways such as NF-κB and WNT/β-catenin; thereby contributing to inflammation, epithelial to mesenchymal transition (EMT) and cancer invasiveness. All these different functions might contribute to tumourigenesis, and have serious consequences for cancer therapies due to increased resistance against damaging agents and prevention of cell death.

In addition, TERT has been detected in non-nuclear locations such as the cytoplasm and mitochondria. Within mitochondria TERT has been shown to decrease ROS generation, improve respiration, bind to mitochondrial DNA, increase mitochondrial membrane potential and interact with mitochondrial tRNAs. All these different non-telomere-related mechanisms might contribute towards the higher resistance of cancer cells against DNA damaging treatments and promote cellular survival. Understanding these different mechanisms and their complexity in cancer cells might help to design more effective cancer therapies in the future.

Friday, October 24, 2014

The evolution of cell therapies will most likely be towards treatments that alter cell type and behavior in place, drawing from the existing pool of cells and changing them to suit the needs of the patient. Given sufficient control over cell activities and cell state old cells might be repaired and entire organs could be regenerated through this approach. Present efforts in tissue engineering and transplants are a stepping stone to this more sophisticated future of regenerative medicine. Here is an early example of this trend underway:

Recent success in restoring visual function through photoreceptor replacement in mouse models of photoreceptor degeneration intensifies the need to generate or regenerate photoreceptor cells for the ultimate goal of using cell replacement therapy for blindness caused by photoreceptor degeneration. Current research on deriving new photoreceptors for replacement, as regenerative medicine in general, focuses on the use of embryonic stem cells and induced pluripotent stem (iPS) cells to generate transplantable cells. Nonetheless, naturally occurring regeneration, such as wound healing, involves awakening cells at or near a wound site to produce new cells needed to heal the wound.

Here we discuss the possibility of tweaking an ocular tissue, the retinal pigment epithelium (RPE), to produce photoreceptor cells in situ in the eye. Unlike the neural retina, the RPE in adult mammals maintains cell proliferation capability. Furthermore, progeny cells from RPE proliferation may differentiate into cells other than RPE. The combination of proliferation and plasticity opens a question of whether they could be channeled by a regulatory gene with pro-photoreceptor activity towards photoreceptor production. Studies using embryonic chick and transgenic mouse showed that indeed photoreceptor-like cells were produced in culture and in vivo in the eye using gene-directed reprogramming of RPE cells, supporting the feasibility of using the RPE as a convenient source of new photoreceptor cells for in situ retinal repair without involving cell transplantation.

Friday, October 24, 2014

The open access paper quoted below provides some insight into increasing sophistication of the work involved in identifying longevity-related genes and proteins in mammals. Many of these have been discovered over the past twenty years, leading to numerous ways to alter the operation of metabolism in order to slow aging and thus extend healthy life. This should probably be considered a part of the bigger picture of progress towards a better understanding of the fine details of biochemistry, however, and not a stepping stone to longer lives for you and I. Slowing aging by building a better metabolism is not a great strategy at this point in time in comparison to working on repair of damage. Researchers know much more about the damage that causes aging than they do about metabolism, so the choice is between easier and more promising lines of research versus much harder work that will produce far less useful results.

Unfortunately for us, since scientists are in the business of gaining knowledge rather than changing the world, most research is in fact directed towards the harder work that will do little to produce meaningful treatments for aging. That is why we need advocacy and grassroots fundraising programs and organizations aimed at changing the strategic direction of aging research.

Longevity is correlated with stress resistance in many animal models. However, previous efforts through the boosting of the antioxidant defense system did not extend life span, suggesting that longevity related stress resistance is mediated by other uncharacterized pathways. We have developed a high-throughput platform for screening and rapid identification of novel genetic mutants in the mouse that are stress resistant. Selection for resistance to stressors occurs in mutagenized mouse embryonic stem (ES) cells, which are carefully treated so as to maintain pluripotency for mouse production.

Initial characterization of these mutant ES cells revealed mutations in Pigl, Tiam1, and Rffl, among others. These genes are implicated in glycosylphosphatidylinositol biosynthesis, NADPH oxidase function, and inflammation. These mutants: (1) are resistant to two different oxidative stressors, paraquat and the omission of 2-mercaptoethanol, (2) have reduced levels of endogenous reactive oxygen species (ROS), (3) are capable of generating live mice, and (4) transmit the stress resistance phenotype to the mice. This strategy offers an efficient way to select for new mutants expressing a stress resistance phenotype, to rapidly identify the causative genes, and to develop mice for in vivo studies.


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