Fight Aging! Newsletter, August 24th 2015

August 24th 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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  • "A History of Life-Extensionism in the Twentieth Century" is Now Freely Available Online
  • Considering the Measurement of Frailty
  • Methodology Matters Greatly in Regenerative Therapies
  • Initial Coverage of Rejuvenation Biotechnology 2015
  • RIP3 Knockout Reduces Inflammation and Mortality in Mouse Model of Atherosclerosis
  • Latest Headlines from Fight Aging!
    • The Moral Imperative for Bioethics: Get Out of the Way
    • Healthy Longevity and the Imperative of Human Progress
    • Invertebrates in the Study of Aging
    • Considering the Influence of Post-Reproductive Lifespan
    • Launched: Crowdfunding the Cure for Aging
    • Crowdfund the Mitochondrial Repair Project at
    • A Small Step Towards Inducing Salamander-Like Regeneration in Human Tissues
    • Senescent Cell Presence in Skin Correlates with Skin Aging
    • An Active Life Correlates with Better Health and Lower Mortality in Old Age
    • Investigating the INDY Longevity Gene in Nematodes


I'm pleased to note that the book A History of Life Extensionism in the Twentieth Century is now freely available online, a step that everyone who publishes should undertake. After the initial wave of sales is done there is simply no reason to leave a book locked up: everyone who wants to pay to read it already has, and everyone who wants to read it for free will simply download a copy whether or not formally permitted to do so. Both author and audience are far better served by making it easier to read published works.

In this case, A History of Life Extensionism in the Twentieth Century was published last year as the culmination of several years of research and writing on the topic by author Ilia Stambler. His book covers many past contributions to the culture of medicine and views on longevity, influences that lead us to where we stand today, but are perhaps too easily overlooked by those of us focused on the near future. It is a fascinating read. Beyond this work Stambler is active in a number of longevity advocacy movements; you might recall his contributions to the position papers published following last year's International Conference on Aging and Disease, for example.

One of the more interesting things one sees from the references explored in A History of Life Extensionism in the Twentieth Century is just how strikingly similar the proposals and debates on extended longevity were a century or more ago. Many of the commentaries that dealt with motivations for the defeat of age-related disease could be republished today largely unchanged and still fit right in. The important difference between then and now is that we are today able to make meaningful progress towards the goal of rejuvenation treatments: we can create detailed plans built on solid science such as the SENS research programs, knowing that building them has a high expectation of producing large benefits to human health and longevity. This is a new age of biotechnology, but it never hurts to look back at the bigger picture of how we came to be where we are now.

A History of Life-Extensionism In The Twentieth Century

This work explores the history of life-extensionism in the 20th century. The term life-extensionism is meant to describe an ideological system professing that radical life extension (far beyond the present life expectancy) is desirable on ethical grounds and is possible to achieve through conscious scientific efforts. This work examines major lines of life-extensionist thought, in chronological order, over the course of the 20th century, while focusing on central seminal works representative of each trend and period, by such authors as Elie Metchnikoff, Bernard Shaw, Alexis Carrel, Alexander Bogomolets and others. Their works are considered in their social and intellectual context, as parts of a larger contemporary social and ideological discourse, associated with major political upheavals and social and economic patterns.

This work pursues three major aims. The first is to attempt to identify and trace throughout the century several generic biomedical methods whose development or applications were associated with radical hopes for life-extension. Beyond mere hopefulness, this work argues, the desire to radically prolong human life often constituted a formidable, though hardly ever acknowledged, motivation for biomedical research and discovery. It will be shown that novel fields of biomedical science often had their origin in far-reaching pursuits of radical life extension. The dynamic dichotomy between reductionist and holistic methods will be emphasized.

The second goal is to investigate the ideological and socio-economic backgrounds of the proponents of radical life extension, in order to determine how ideology and economic conditions motivated the life-extensionists and how it affected the science they pursued. For that purpose, the biographies and key writings of several prominent longevity advocates are studied. Their specific ideological premises (attitudes toward religion and progress, pessimism or optimism regarding human perfectibility, and ethical imperatives) as well as their socioeconomic conditions (the ability to conduct and disseminate research in a specific social or economic milieu) are examined in an attempt to find out what conditions have encouraged or discouraged life-extensionist thought. This research argues for the inherent adjustability of life-extensionism, as a particular form of scientific enterprise, to particular prevalent state ideologies.

The third, more general, aim is to collect a broad register of life-extensionist works, and, based on that register, to establish common traits and goals definitive of life-extensionism, such as valuation of life and constancy, despite all the diversity of methods and ideologies professed. This work will contribute to the understanding of extreme expectations associated with biomedical progress that have been scarcely investigated by biomedical history.


What is frailty, the state of being physically frail? As is the case for the related - but not identical - state of being old we know it if we see it, but a single rigorous and commonly agreed upon measurable definition of frailty remains elusive. Not for lack of trying, of course; there are numerous published and proposed scales of measurement, and debate over their utility. The paper referenced here argues for a better language and categorization of frailty in aging, pointing out that that the present clinical applications of scientific knowledge are not what they might be, while new approaches are at this point just as likely to muddy the waters as clear things up.

The treatment of aging and its many degenerative conditions by the medical profession has a foot in two worlds. There is the established world of observation, simple measures of function used for decades, the judgement calls of medical professionals based on sparse data, the acceptance that there is little that can be done but assess the downward spiral. Within this world there is still as much reluctance to measure aging in common practice, as there is a movement towards better use of existing tools to pin down aging and be more rigorous. That old way of doing things now coexists with increasingly sophisticated by quite narrow applications of modern biotechnology that accurately measure aspects of, and to some degree treat, specific age-related dysfunctions. Despite representing sizable steps forward these new technologies have yet to give rise to a biomarker for biological age - a rigorous measure of damage and dsyfunction - despite some promising ongoing lines of research such as analysis of DNA methylation patterns. Such a biomarker would produce unambiguous results based on the state of cellular biochemistry rather than the present commonly used measures such as grip strength, recollection, or walking ability.

The practice of medicine is constantly in transition in this age of rapid progress in biotechnology. Papers such as the work referenced here are one manifestation of the tensions and necessary organization involved in the departure of old, established practice taking place concurrently with the advent of unfinished works-in-progress that will one day become the future standard of care.

Frailty: a tale of two concepts

Frailty in older adults is most often defined as a late-life vulnerability to adverse health outcomes. Although frailty consensus work has focused on physical frailty, a theoretically based construct built around a core group of activity-based and strength-based measurements, the frailty index (FI), has emerged as a useful strategy to measure risk for mortality and other adverse health outcomes in older adults. The FI utilizes simple counts of up to 71 co-morbidities, laboratory measures, and social and functional declines (termed deficits) to construct a score. Proponents of this approach have noted that the component measures are interchangeable, the approach can be applied in bedbound or ambulatory populations, and fewer variables can successfully predict mortality than originally proposed.

In the present study, the authors develop an aging-related biological index that utilizes 40 biological measures found to be age-associated in the Newcastle 85+ study. This index contains measures ranging from telomere length to induced cytokine production from isolated lymphocytes to the components of a complete blood count. Although prior studies of older adults have developed indices focused on clinical laboratory measurements, the authors are to be commended for working toward the development of an index that attempts to assess biological age and associated risk through biological measurements. Their findings regarding the complementarity of clinical and biological measures for predicting mortality risk are potentially important: One can imagine, for example, the identification of older adults who "look" healthy but may benefit from interventions to address significant latent risk factors.

The approach is pragmatic in that measures can be for the most part interchanged with other measures without substantial change in the predictive ability of the tools. There are likely a large number of age-related aggregated biological precursors that drive frailty and late-life decline, and the systemic effects as measured by risk to adverse outcomes can in part be detected through an index approach. Hence the approach can be used to predict outcomes, and the combination of FI and a biomarker-based frailty index (FI-B) seems to hold considerable promise to this end. The approach also likely allows the tracking of vulnerability in a reasonable way.

Despite this flexibility in measurement and substantial predictive ability of a high index score, notable obstacles remain if this approach is to be further developed as a true biological aging index or measure of systemic effects. For example, it is not clear that systemic effects are being measured unless index components are selected and validated vis a vis a system. Moreover, including a preponderance of age-associated clinical measures may result in an assessment of chronic disease states rather than aging per se. The FI-B construction, and the authors' characterization of frailty as "a state of increased risk, compared with others of the same age," suggests that any marker conferring risk of mortality (or possibly other adverse geriatric outcomes) contributes usefully to frailty measurement. We, and others who consider frailty as a specific physiological state with a definable phenotypic presentation, would disagree.

The specificity embedded within the phenotype approach offers benefits if the goal is to elucidate mechanisms and physiological etiology. To approach such a goal scientifically, theories describing plausible processes by which frailty arises, and how they are linked to one another, are needed. Indices (psychometrically: as opposed to "scales") fail to provide this. Moreover, the more heterogeneously a large collection of variables arises, the higher the risk of masking a key driver that can be targeted by specific interventions. In sum, various conceptualizations of frailty have complementary strengths; however, if etiology is to be elucidated and targeted interventions are to be pursued, we believe the field would benefit from more strongly distinguishing disparate concepts which currently share the single label of "frailty."


You can't just throw stem cells or signal proteins to change the behavior of existing cells at injured tissue and expect reliably good results. A great deal of craft and sophistication goes into even the first generation stem cell transplant treatments, and the need for this complexity is demonstrated by the variability of outcomes seen in stem cell trials. The results are all over the map even for treatments that use the same types of cell to spur regeneration the same types of tissues. There are all sorts of factors at work: how the cells are cultured, how they are supported after being delivered into tissues, what signals are provided along with the cells, whether or not the cells are further engineered before being introduced into the patient, and so forth. The same is true for therapies that do not involve cell transplants, but instead deliver signal molecules to attempt to spur native cells to do the work of healing.

The research results linked below well illustrate this point, as the scientists demonstrate a selection of methods and combinations of methods for heart regeneration in rats. There are large differences in the outcomes, both in the degree of regeneration of healthy tissue (good) and in the generation of scar tissue rather than healthy tissue (bad). The results demonstrate that small changes in technique that alter the timing of the introduction of supporting molecules can have large effects on cell behavior and the bottom line of healing.

In practice this means that it is hard to write off any one particular approach to signal therapies and cell therapies in regenerative medicine as a dead end just because the results to date have been less than promising. It may be that all that is needed is one more adjustment to the delivery method, or the biomaterials, or the signals and factors delivered with the cells. Unfortunately finding the flecks of gold amidst all of the sand is a slow and painful process, even with the large-scale funding presently pouring into this field. There is an enormous space of possible approaches to try, growing rapidly as fundamental research delivers new information on relevant cellular mechanisms, but very few of them are of any real use. The difference in quality between a mediocre and a good approach is large, so settling for mediocre results in return for evading a large amount of work is not a viable trade-off. On that note, I think that you'll find the stained cross-sectional images of regenerated heart tissue from the publicity materials to be particularly interesting:

Repairing The Heart With A Protein-Hydrogel Combo

Even if a person survives a heart attack, the lack of blood flow damages tissue, which often leads to heart failure. Now researchers have developed a new approach to therapy that combines two experimental techniques for reviving heart tissue after a heart attack. One approach is to inject a scaffolding material to reinforce the weakened muscle wall. Another is to inject stem cells or growth factors to help repair the damaged tissue. The researchers devised a special trick to deliver a growth protein trapped within a hydrogel. The gel protects the protein, keeps it at the heart attack site, and supports the damaged walls of the heart right after a heart attack. They used a tissue-signaling protein called Sonic hedgehog that is known to protect cardiac cells and help them grow by inducing the formation of blood vessels.

The researchers mixed it with negatively charged heparin, which is a widely used anticoagulant, and a polycation, which attaches to the oppositely charged heparin molecules to form micrometer-sized liquid droplets. Next, they combined the droplets with a polyethylene glycol gel. The gel targets the signaling protein to damaged tissue because it degrades in the presence of an inflammatory enzyme secreted after a heart attack.

To test the new strategy, the researchers induced heart attacks in rats, and divided the animals into four groups. One group got an injection of the new combination material at the site of the heart attack, while the others got injections of only the protein-containing droplets, only the hydrogel, or saline. After two and four weeks, echocardiograms showed that hearts treated with the combination therapy pumped more blood per beat. The team also examined cross sections of hearts removed four weeks after treatment. Rats treated with the hydrogel-protein combination had at least 25% less scar tissue than those in the other groups.

Coacervate Delivery of Growth Factors Combined with a Degradable Hydrogel Preserves Heart Function after Myocardial Infarction

Numerous technologies have been evaluated for alleviating or reversing the damage caused by cardiac ischemia. These technologies fall into two general categories: bioactive therapies and structural "bulking" therapies. The former aims to provide the resources and signals necessary for tissue preservation and regeneration, and several therapeutic approaches including stem cells, growth factors, and gene therapy have been evaluated in U.S. controlled clinical trials. On the other hand, the primary aim of structural therapies is to reinforce the damaged heart wall and thereby alleviate wall stress to prevent wall thinning and ventricular dilation. Clinical trials have been initiated to evaluate intramyocardial injections of alginate and cell-seeded collagen. However, no biological or structural therapy has shown enough promise to receive USFDA approval for treatment of MI. Therefore, new approaches need to be developed and those that combine both bioactive and structural components are particularly appealing

To this end, we developed a bioactive therapy of sustained release of the morphogen Sonic hedgehog (Shh) and the anti-inflammatory cytokine interleukin-10 (IL-10) from a coacervate delivery vehicle. This is combined with a structural therapy consisting of a biodegradable polyethylene glycol (PEG) hydrogel, harnessing the benefits of both components. Upon injection into the hearts of rats after heart attack, we found that each component synergistically improved the benefit of the other. Furthermore, their combination was critical to preserve heart function. These findings indicate that, when combined, growth factor delivery and an injectable hydrogel represent a promising therapeutic approach for treatment after heart attack.


The Rejuvenation Biotechnology 2015 conference started yesterday, hosted by the SENS Research Foundation in San Francisco. This is the second in a conference series intended to help build the bridges between scientists and developers, the lab and the industry. We are nearing the point at which some first generation rejuvenation therapies based on the SENS vision of damage repair become ready for practical clinical development. Senescent cell clearance has been demonstrated to some degree via drugs in mice, and at least one startup company has been seed funded to create a first pass at a viable therapy for humans. Similarly allotopic expression to eliminate the consequences of mitochondrial DNA damage is under commercial development already for inherited mitochondrial diseases, and once robustly deployed that technology will need comparatively little adaptation to be used as a therapy for aging.

A smooth hand-off from laboratory to developer doesn't just magically happen, however, no matter how compelling the potential therapy. It requires network, connections, and a two-way flow of education and awareness. Even the obvious steps in creating technological progress must be organized well in advance. Given all of this, the focus of the Rejuvenation Biotechnology conference series is as much on business and economics as it is on the science of rejuvenation and the programs taking place in the laboratory. The message is being delivered to a broad audience of movers and shakers in the business community: opportunity is knocking, the potential to treat aging as a medical condition is near. Be ready, and better yet, invest in speeding development, because your competitors are going to wake up one day soon and do exactly that. Those who get there first are going to make a lot of money selling treatments that are applicable to everyone, and which greatly improve health for everyone.

It is usually the case that good coverage of SENS conferences only emerges after the fact, alongside video of the presentations, but this year there is a little liveblogging taking place:

Live blogging from RB2015  - Rejuvenation Biotechnology Conference

Fantastic keynote talk by Chas Bountra, Structural Genomics Consortium Oxford Chief Scientist. We must transform the way we discover medicines. The biggest challenge is identifying proteins we need to modulate. Too much secrecy and competition are slowing down drug discovery. As an example, take cancer in the UK: in the next 12 months, 315,000 people will be diagnosed. That is one person every 19 seconds. Half of us in the room will get diagnosed with cancer in our lifetime. The way we discover drugs is too costly, too risky, and too slow: available for solid tumors produced an increase in overall survival by only 2.1 months, and only 30 out of 71 drugs for solid tumors produced clinically meaningful improvements. Average cost per drug launched: 12Bn. In 2003 there were 529 molecules in development for cancer (phase 1-3 clinical trials). In 2013 they looked at what happened to them: 45 made it to market, 95 were still in development, 389 have been terminated (took to the clinic and terminated). It's also very slow. It took 6-30 years to take an idea into patients.

Too much secrecy, competition, duplication and wastage. We bring together multiple clinicians, academic groups, pharma companies, patient groups and CROs. We're funded by government, private, philantropic and charity funds. We're working to come up with new targets so the industry can take the molecules to the markeplace. We're trying to create a new ecosystem, which will generate more novel, more effective medicine, more quickly, and more affordably. Let's remember that, regrettably, all of us will be patients one day.

RB2015  -  Liam Grover: Designing materials to maximise regeneration

We develop novel methods for tissue regeneration by considering the biology at the implant site in addition to the influence it will have on a biomaterial. Cell response is important, but many overlook the fact that cell response is guided through the extracellular matrix, and matrix assembly is often ignored. Material/tissue interactions have not been fully exploited in regenerative medicine, and critically the translation of "simple materials" to the clinic has a lower cost in effort and money than the translation of cell therapies - meaning a larger short-term economic payback.

Keynote Address: Science and Technology for Diplomacy

Frances Colón is the Acting Science and Technology Adviser to the Secretary of State, United States Department of State. In an animated talk spanning science, technology, diplomacy and policy, Frances provided an inside look at the intersection between science and politics.

Colón was asked about how the State plans to deal with issues that are perceived as 'non-crisis' issues, such as aging. She stated that 90% of the issues they deal with are crises like infectious outbreaks and simply do not have the bandwidth to tackle these other issues, despite the fact that the older population is growing rapidly across the globe. Her advice was to speak loudly, clearly and frequently (from diverse communities) to US Congressmen and organizations like the NSF. Speaking as a scientist in the aging field, I concur with my collegues here and hope that age-related diseases make it on the to-do list of public policy makers.

An attendee noted that getting a policy initiated with the current Obama administration may be our best best since he has actively gone after a 'non-crisis' issue like climate change. Finally, Colón encourages scientists to be vocal about their work and passions - so that our collective voice grows louder and can lead to real policy change.


Researchers have found a genetic alteration that slows the progression and fatal consequences of atherosclerosis in a mouse lineage engineered to have an accelerated progression of the disease. As is usually the case in such studies, the primary goal is insight into disease mechanisms, gathering knowledge that may later aid in the development of therapies. It is not necessarily the case that finding a way to slow atherosclerosis in an animal model has relevance to the actual condition: there are many examples of promising research results turning out to be a roundabout way of fixing the breakage in the animal model lineage that causes individuals to develop the condition rapidly and reliably. In normal individuals it then turns out to be useless. This is more often the case in poorly understood areas of biochemistry, given that as knowledge is gained it becomes easier to sift out the more relevant mechanisms, those applicable to the real condition.

Atherosclerosis is a particular unpleasant and prevalent cardiovascular condition that in and of itself causes few overt symptoms until it suddenly kills you. It is an outgrowth of cardiovascular dysfunction in general, however, and is thus usually accompanied by all of the other signs of degeneration in heart and blood vessels: tissue stiffness, hypertension, heart failure, and so forth. The physical damage of atherosclerosis consists of fatty deposits and inflammatory injuries in blood vessel walls, spawned at least in part by the effects of oxidized LDL cholesterol on cell populations in blood vessels, but the increasing stiffness of blood vessel walls and resulting increased pressure of blood flow doesn't help matters by putting additional stresses on these tissues. It is thought that mitochondrial DNA damage is the original cause of much that damaged cholesterol, while the accumulation of persistent cross-links in the extracellular matrix are a primary culprit in blood vessel stiffness.

Once the fatty deposits of atherosclerosis get started, they grow in a positive feedback loop: the damage spurs inflammation, attracting macrophages that attempt to clean up the waste, but which ingest too much fat and become foam cells. These in turn cause more inflammation, produce more fatty debris, and attract more macrophages. The role of inflammation here means that any treatment that reduces the chronic inflammation accompanying aging is likely to be beneficial, but it can't solve the problem. All it can do is slow things down a bit. Prior to the development of self-sustaining fatty deposits, serious damage to blood vessel walls, and restructuring of blood vessels and the heart in response to stiffness and hypertension, it is in principle possible to prevent atherosclerosis and arterial stiffness from ever developing through some combination of SENS therapies targeting mitochondrial DNA damage and cross-links. All the more reason to develop these therapies, but those people already old when they arrive will also need means of safely clearing out the fatty debris of atherosclerotic plaques. That is what kills, when a section finally breaks off to clog a vital blood vessel.

The link below is to the abstract as the full paper, while open access, is still only available in PDF format. It is an interesting look at some of the mechanisms driving the progression of atherosclerosis, and a good example of the way in which most medical research focuses on intervening in later stages of the disease. The proposed intervention here doesn't treat the root causes of the condition at all, but rather seeks to slow down the feedback loop of its later development. As a strategy this will always be less effective and more costly, but here as elsewhere it remains the primary approach for the research community.

RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality

Atherosclerosis is one of the major causes of human death in modern society. A high blood cholesterol level resulting from cholesterol metabolism dysfunction is a key known contributing factor for premature atherosclerosis. Using a mouse model of high blood cholesterol, we show that a specific activation marker of a programmed necrosis mediated by the kinase receptor-interacting protein 3 (RIP3) can be detected in the core of atherosclerotic plaques. Mice lacking the RIP3 gene showed a significant reduction of proinflammatory monocytes in the blood and delayed mortality. This study suggests that RIP3-mediated necrotic cell death is part of a self-amplifying proinflammatory cycle that contributes to the premature death of animals with the pro-atherosclerosis trait.

Monocyte cells enter atherosclerotic plaques and subsequently differentiate into macrophages, which, after engulfing cholesterol crystals and becoming foam cells, die in situ to form the necrotic core of the plaques. These dead cells then send out damage-associated molecular patter (DAMP) signals to attract and mobilize more monocytes, completing a vicious cycle that accelerates disease progression. Thus the particular mode of death of these macrophages - apoptosis or necrosis - can be a critical determinant for the initiation of inflammation, because necrotic death releases the cellular contents that constitute the DAMP signal to the blood stream, whereas apoptotic cell debris is engulfed by macrophages without leaking out of the cell.

Recently, the molecular mechanism of a form of programmed cell death termed "necroptosis" was characterized. This form of cell death can be triggered by the TNF family of cytokines and by ligands of Toll-like receptors 3 and 4. The activated TNF receptor recruits receptor-interacting kinase 1 (RIP1) which in turn binds and activates a closely related kinase, RIP3, to form a necrosis-inducing protein complex. The activated RIP3 is marked by phosphorylation that allows it to bind and activate its downstream effector, a pseudokinase known as "mixed lineage kinase domain-like protein," MLKL. MLKL then is phosphorylated by RIP3 and shifts into an oligomerized state that allows it to form membrane-disrupting pores, ultimately resulting in necrotic death.

After we developed a monoclonal antibody that specifically recognizes the phosphorylated RIP3, we studied the role of necroptosis in atherosclerotic plaque areas by using this antibody to probe the signal of necroptosis activation. We further investigated the role of necroptosis in systematic inflammation by analyzing a panel of proinflammatory cytokines and immune cells in ApoE single-knockout and ApoE/RIP3 double-knockout mice. Finally, we addressed the consequences of necroptosis in the animals by comparing the lifespans of ApoE single-knockout and ApoE/RIP3 double-knockout mice fed either a high-cholesterol or a normal diet. It is clear that high blood cholesterol in the ApoE single-knockout mice is sufficient to cause atherosclerotic plaque formation, even without the systematic inflammation contributed by RIP3-mediated necrosis. However, disease progression, as measured by plaque area and thickness, was significantly slowed in the absence of necroptosis. We believe this slowing of disease progression results from an interruption of the vicious cycle of necroptosis-induced inflammation in lesion sites such as atherosclerotic plaques.

The most interesting result from this study is that mice without RIP3-mediated cell death not only manifested much less severe lesions in multiple tissues but also had significantly delayed mortality. What causes necroptosis in the atherosclerotic plaques remains to be determined. It is likely that cholesterol crystals and local higher concentrations of inflammatory cytokines contribute to the death of macrophages. Nevertheless, by using the small molecules specifically targeting necroptosis, which are being developed, it should be possible to alleviate the symptoms and prolong the lives of patients suffering from atherosclerosis.


Monday, August 17, 2015

As a companion piece to last week's post on the miserable, parasitic institution of modern bioethics, here are a few apropos comments from Steven Pinker:

Have you had a friend or relative who died prematurely or endured years of suffering from a physical or psychiatric disease, such as cancer, heart disease, Alzheimer's, Huntington's, Parkinson's, or schizophrenia? Of course you have: the cost of disease is felt by every living human. The Global Burden of Disease Project has tried to quantify it by estimating the number of years lost to premature death or compromised by disability. In 2010 it was 2.5 billion, which means that about a third of potential human life and flourishing goes to waste. The toll from crime, wars, and genocides does not come anywhere close.

Physical suffering and early death have long been considered an ineluctable part of the human condition. But human ingenuity is changing that apparent fate. Advances in drugs, surgery, and epidemiology have brought reductions in years lost to more recalcitrant diseases in every age range and in richer as well as poorer countries. As the treatments get cheaper and poor countries get richer, these gains will spread. Biomedical research, then, promises vast increases in life, health, and flourishing. Just imagine how much happier you would be if a prematurely deceased loved one were alive, or a debilitated one were vigorous -- and multiply that good by several billion, in perpetuity. Given this potential bonanza, the primary moral goal for today's bioethics can be summarized in a single sentence. Get out of the way. A truly ethical bioethics should not bog down research in red tape, moratoria, or threats of prosecution based on nebulous but sweeping principles such as "dignity," "sacredness," or "social justice." Nor should it thwart research that has likely benefits now or in the near future by sowing panic about speculative harms in the distant future.

Some say that it's simple prudence to pause and consider the long-term implications of research before it rushes headlong into changing the human condition. But this is an illusion. First, slowing down research has a massive human cost. Even a one-year delay in implementing an effective treatment could spell death, suffering, or disability for millions of people. Second, technological prediction beyond a horizon of a few years is so futile that any policy based on it is almost certain to do more harm than good. Biomedical advances will always be incremental and hard-won, and foreseeable harms can be dealt with as they arise. The human body is staggeringly complex, vulnerable to entropy, shaped by evolution for youthful vigor at the expense of longevity, and governed by intricate feedback loops which ensure that any intervention will be compensated for by other parts of the system. Biomedical research will always be closer to Sisyphus than a runaway train -- and the last thing we need is a lobby of so-called ethicists helping to push the rock down the hill.

Monday, August 17, 2015

Here I'll point out a long article that ties together technological advances that increase human longevity with some of the broader modern issues of progress, change, and opposition to progress that are important in modern societies.

Stagnation and stasis are ever the goal of much of our politics: a thousand Canutes standing athwart the tide. People are reflexively conservative, even in times of great change brought on by technological progress, and that is reflected in regulation and other forms of obstruction that slow down beneficial change. Nowhere is this more apparent than in medicine, one of the most heavily regulated areas of research and development. We are in the midst of a biotechnology revolution, capabilities advancing by leaps and bounds in the laboratory, and costs plummeting, yet the delivery of new clinical therapies is becoming slower and more expensive year after year. The costs imposed by regulation have doubled in the past decade, and for no good reason.

Stasis is the path to destruction, the eventual collapse of a society under the weight of regulation and coercive redistribution. Continued and accelerating progress is the path to a golden future, and medical technologies to enhance longevity while also defeating age-related frailty and disease will play an important role in putting us on this road:

Technological progress, particularly radical extension of the human lifespan through periodic rejuvenation that can restore the body to a more youthful condition, is also the only hope for remedying unsustainable expenditures of national governments, which are presently primarily intended to support people's income and healthcare needs in old age. Rejuvenation biotechnology of the sort championed by Dr. Aubrey de Grey's SENS Research Foundation could be developed with sufficient investment into the research, and could become disseminated by biotechnology entrepreneurs, ensuring that older people do not become decrepit or incapable of productive work as they age.

Many people who receive rejuvenation treatments will not want to retire - at least not from all work - if they still feel the vitality of youth. They will seek out activities to support human well-being and high living standards, even if they have saved enough money to consider it unnecessary to take a regular 8-to-5 job. With the vitality of youth combined with the experience of age, these people will be able to make sophisticated, persistent contributions to human civilization and will tend to plan for the longer term, as compared to most people today.

Fortunately, there are glimmers of hope that the path of gradual embrace of ever-accelerating progress will be the one taken in the early-21st-century Western world. The best outcome would be for an existing elite to facilitate mechanisms for its own evolution by offering people of merit but from humble backgrounds a place in real decision-making. Some of that evolution can occur through market competition - new, upstart businesses displacing incumbents and gradually amassing significant resources themselves. The best instantiation of this in the United States today is the Silicon Valley entrepreneurial culture - which, incidentally, now tends to finance longevity research.

These developments are evidence that the United States today is characterized not by one elite, but by several - and the old "Paper Belt" elite is clearly in conflict with the new Silicon Valley elite. Differences in the breadth of vision among elites matter. For instance, breakthroughs in human longevity could actually be a great boon for medical providers and the first pharmaceutical companies that offer effective products/treatments. Even the most ambitious proponents of life extension do not think it possible to develop a magic immortality pill. Rather, the treatments involved (which will be quite expensive at first) would require periodic regeneration of the cells and tissues within a person's body - essentially resetting the biological clock every decade or so, while further innovation uncovers ways to reverse the damage more cheaply, safely, and effectively. This is a field ripe with opportunities for enterprising doctors, researchers, and engineers (while, at the same time, certainly endangering many extant business models). Some government officials, if they are sufficiently perceptive, could also be persuaded to support these changes - if only because they could prevent a catastrophic collapse of Social Security and Medicare.

The key to achieving a freer, more prosperous, and longer-lived future is to educate both elites and the general public to accurately weigh the opportunities and risks of emerging technologies. Too many individuals today, both elites and ordinary people, view technological progress with suspicion, conjuring in their minds every possible dystopian scenario and every possible malfunction, inconvenience, lost possibility, moral reservation, or aesthetic dislike they can muster against breakthroughs in life extension, artificial intelligence, robotics, autonomous vehicles, genetic engineering, nanotechnology, and many other areas of advancement that could vastly benefit us all. If we have a modicum of technological progress, the West might be able to muddle through the next several decades. If we have an acceleration of technological progress, the West will leave its current problems in the dust.

Tuesday, August 18, 2015

Here I'll point out a review of some of the species researchers use in the study of aging, coupled with a call to expand that list to fill in known gaps and shortcomings. Despite the large differences between lower animals and humans, aging is a near universal phenomenon. It originated in its presently dominant form very early in the evolution of life, and thus many relevant cellular mechanisms are the same or at least very similar even in widely divergent species. Since lower animals used in aging research are short-lived, it is far less costly to conduct exploratory life span experiments and alterations of metabolism. Nonetheless, there are sizable challenges inherent in trying to learn about human aging via the investigation of insects and worms, and here it is proposed the some of these problems can be overcome by adding additional points of comparison, such as hydra, sea urchins, sea squirts, and the like:

Although the nematode, the fruit fly models, and yeast have led to major advances in aging research, the gaps that exist in these models make a compelling case for additional, potentially invertebrate, model systems to identify longevity genes, whose roles have yet to be studied, and to investigate the role of additional cellular pathways in aging.

Both the nematode and the fruit fly models have critical shortcomings including the following: (a) both nematode and fruit fly belong to Ecdysozoa, a superphylum, which has undergone extensive gene loss since their divergence from their common ancestor with humans and thus a large fraction of human orthologs are missing; (b) larvae from these two species can enter a non-aging stage in response to stress, which suggests that modulation of lifespan observed in corresponding adult organisms may be mediated by stress response mechanisms that have no equivalent in humans; (c) except for the Drosophila gut, the somatic adult tissues of these two organisms have limited regenerative capabilities with scarce to null cell proliferation; finally, (d) nematodes and fruit flies poorly mimic the processes involving stem cell renewal and tissue repair mechanisms that maintain tissue homeostasis in mammals. Thus, new invertebrate models with proliferating cells in the adult, as well as in those with extensive regenerative capacity, have the potential to be informative on the perils of life-long cell division and mechanisms of tissue regeneration and homeostasis.

Given this background, researchers have begun to make new inroads in the study of aging and longevity in several new model systems. We provide here a brief outline of the advantages of several of the newest invertebrate model systems for the study of aging. Although we continue to witness remarkable progress in aging research using invertebrate models, major limitations and challenges remain in the use of these new models for research in aging biology. These limitations include: (a) technologies to mass culture cells from these models are still lacking; (b) progress has been slow in fine tuning genetic and molecular tools and methodologies, including RNAi and transgenic approaches, for use in these models; (c) very few age-related phenotypes that are functions of specific cellular and molecular pathways in these systems have been identified; and, (d) information on cellular, molecular, and physiological mechanisms in tissue aging and homeostasis, including the role of stem cells and senescence, is still very meager in these new model systems.

Tuesday, August 18, 2015

There is considerable debate over the origin and ongoing role of post-reproductive life span in evolution. If evolution is driven by reproductive success, why do the individuals of some species live on far past the capacity to reproduce? Our own species is an exceptional example of the type; we are very long-lived in comparison to other mammals, and have a long period of post-reproductive life. Why is this the case? You might look at the grandmother hypothesis for one possible answer to that question, thought it is far from being the only answer. In general one should expect anything involving biology to be intricate, complex, and composed of many separate mechanisms. In this paper researchers explore the concept that post-reproductive lifespans might serve as an aid to adaptation, for example. It is a good reminder that much of the debate over the evolution of aging is quite abstract and technical, based on the use of models and the limitations and bounds of effectiveness of those models:

Post-reproductive lifespan is a life history trait that is typical of some mammals, and is especially developed in humans who can live for decades after having given birth to their last offspring. To our knowledge, the role that survival beyond the last reproductive age may play in population genetics models of adaptive evolution has not been investigated yet. This is probably because models with ideally infinite census size are insensitive to the presence of post-reproductive individuals.

It is well known that post-reproductive lifespan reduces the population effective size, which is a parameter inversely proportional to the genetic change in a finite population due to random sampling of gametes through generations; i.e. drift. The classic model for populations without age structure suggests that a reduction in effective size goes to the detriment of fixation chances of a beneficial mutation. Hence, one would intuitively be led to infer that a more prolonged post-reproductive lifespan slows adaptive evolution in a population. In the present paper, we will show that this intuition is wrong and explain why it is so.

We compare two separate, stationary populations living in a constant environment that are equivalent except for the average time their respective members spend in the post-reproductive stage of life. Using a recently derived approximation, we show that fixation of a beneficial mutation is more likely in the population with greater post-reproductive longevity. This finding is surprising, as the population with more prolonged post-reproductive lifespan has smaller effective size and the classic population-genetic model would suggest that decreasing effective size reduces fixation chances of beneficial mutations. Yet, as we explain, in the age-structured case, when effective size gets smaller because of longer post-reproductive lifespan but census size is kept equal, a beneficial mutation has a higher likelihood to get fixed because it finds itself at higher initial frequency.

Wednesday, August 19, 2015

Our community began to crowdfund projects in longevity science, such as the ongoing SENS research programs, long before Kickstarter and the rest of the young crowdfunding industry came into being. It is inevitable and helpful that people will take the lessons of for-profit crowdfunding and try to apply them to general research funding at the small scale, as is happening at Experiment, and also inevitable that crowdfunding platforms devoted to aging and longevity research will arise, such as LabCures and now the newly launched is a project of the Life Extension Advocacy Foundation non-profit company, and is a mission driven crowdfunding platform dedicated solely to longevity research projects. We believe that centralizing and enhancing such efforts will create a strong community of contributors and researches who will help extend healthy human lifespans, both through both direct funding as well as shifting public perception in favor of this important humanitarian goal. Conquering the negative effects of aging is one of the oldest dreams of humanity, and now through the steady progress of science, we are poised to fulfill that dream.

Whether this occurs in 20 years or 200 is largely a question of funding. The best way to accelerate this process is by mobilizing those who desire the option of a longer and healthier life into a cohesive social force - crowdfunding relevant research and advocating for its benefits to society. On researchers post projects related to longevity or age related disease, and receive funds from contributors to fulfill their goals. Contributors, in turn, are able to exercise agency in the development of potentially life changing research, as well as receiving rewards specified by the project creators. We care about the success of and will actively support every project on our site; you won't just be one in a crowd. As we grow, the fruits of our success will be focused on furthering our shared mission.

Wednesday, August 19, 2015

The first project up at the newly launched longevity science crowdfunding site is a mitochondrial research program to be carried out by a SENS Research Foundation scientist. This follows on from a crowdfunded initial stage in 2013 and continuing research from the past couple of years. The project is effectively an extension and expansion of the work of Gensight on allotopic expression of mitochondrial genes to cover all of the genes of interest in the mitochondria. When successful this will offer a way to bypass and eliminate the contribution of mitochondrial DNA damage to degenerative aging.

This is also a big experiment for the SENS Research Foundation: does this form of fundraising, styled after Kickstarter and Experiment, work for our community? Does it help to pull in new donors and present our goals to people who haven't yet heard of this research? Is it more or less effective than the ad-hoc methods we've used over the past decade? Further, are we at the point at which the community can run multiple distinct fundraising programs each year and still be successful in all of them? The only way to find the limits of fundraising is to keep pushing. Personally, I just pledged a few hundred dollars.

At the SENS Research Foundation, we are in the early stages of creating an innovative system to repair these mitochondrial mutations. If this project is successful we will have demonstrated, for the first time, a mechanism that can provide your cells with a modified backup copy of the entire mitochondrial genome. This genome would then reside within the protective confines of the cell's nucleus, thereby mitigating damage to the mitochondrial genome. In fact, during the long course of evolution, this gradual transfer of genetic information into the nucleus has already occurred with the majority of mitochondrial genome, leaving behind a mere 13 genes within the mitochondria. Demonstrating the effectiveness of this technology would be a major milestone in the prevention and reversal of aging in the human body.

We are also developing a unique method for guiding the products of these nuclear encoded mitochondrial genes back into the mitochondria, where they can then properly function. Over the last decade, engineering this last step has been the major bottleneck in achieving effective results. In our novel system, the mRNA from an engineered mitochondrial gene is guided back to the mitochondrial surface, where it is then translated into a protein by the organelle's co-translational import system. Once imported, it is then incorporated into the correct location within the inner mitochondrial membrane. Our precise targeting is achieved by adding a specific sequence "tag" to both ends of the mRNA. These tags then serve to guide the information containing mRNA molecule to the mitochondrial surface. Our prior research indicates that our system of tagging yields in a significantly higher efficiency of import to mitochondria than any previously published research.

In the first part of this project we will use cells that have been derived from a patient with a rare mitochondrial disease that are completely null for the mitochondrial ATP8 gene i.e. they make no ATP8 protein. We will attempt to effectively fix these cells by inserting our better engineered versions of ATP8 into the nuclear genome, rather than the mitochondrial genome, and then use our tagging system to help guide the functional protein back into the mitochondria. During the second part of this project we will then proceed to translate this technology to the remaining 12 mitochondrial genes. We have already begun recoding several of these genes in the form of cDNA constructs that can then be used to transfect our test cells.

Thursday, August 20, 2015

In the research noted below, scientists have made initial inroads into the induced dedifferentiation of human cells. This is an attempt to recapture the behavior of tissues in highly regenerative species such as salamanders, and success here may be a step towards generating much greater regeneration of injuries and aged tissues suffering a lack of maintenance. Over the past decade considerable effort has gone into better understanding the precise mechanisms by which species such as salamanders and zebrafish can fully regenerate limbs and organ tissue. Part of the answer appears to be a different relationship between immune cells called macrophages and tissue regeneration, and the dynamics of cellular senescence may also play a role, but of primary interest is that the cells in these species respond to injury by dedifferentiating to form a blastema capable of regrowth. It remains to be seen whether this process can be safely recreated in humans:

A research team has adapted the astonishing capacity of animals such as newts to regenerate lost tissues and organs caused when they have a limb severed. Cells in newts can change in response to injury - a process known as dedifferentiation. The cells aggregate and return to a stem cell-like state to allow them to increase in numbers and generate the specialised cells needed for new tissue formation. But this form of tissue regeneration does not occur in humans, so the researchers recreated similar conditions in the laboratory by growing human cells as 3D aggregates.

The scientists cultivate the spheroid clusters of cells, which are just visible to the naked eye, in tiny cavities. The process involves reverting cells to an embryonic state. In doing so, the cells eat their own constituents and consequently reduce in size. "Using this technique, we have shown that human cells can also be dedifferentiated to an early embryonic stage. They are then capable of generating new tissues. We were able to use pharmaceuticals to induce cell self-eating effects and stimulate dedifferentiation though not as effectively as 3D culture, so we need to do more work on this. The next stage is to find out more about the dedifferentiation process so that we can find the right treatment to encourage tissue repair in the damaged joint. That is our aim."

Thursday, August 20, 2015

Researchers here show that a greater number of senescent cells in skin correlates with a greater loss of skin elasticity. As we age, skin becomes less elastic. Damage to the structures of the extracellular matrix that determines this and other physical properties of tissue occurs due to a number of processes, such as cross-linking and the activities of senescent cells. Developing methods to remove cross-links and clear senescent cells would allow the production of therapies to reverse these and numerous other issues associated with aging:

Senescent cells are more prevalent in aged human skin compared to young, but evidence that senescent cells are linked to other biomarkers of aging is scarce. We counted cells positive for the tumor suppressor and senescence associated protein p16INK4a in sun-protected upper-inner arm skin biopsies from 178 participants (aged 45-81 years) of the Leiden Longevity Study. Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adjusting for chronological age and other potential confounders.

The numbers of epidermal and dermal p16INK4a positive cells were significantly associated with age-associated elastic fiber morphologic characteristics, such as longer and a greater number of elastic fibers. The p16INK4a positive epidermal cells (identified as primarily melanocytes) were also significantly associated with more facial wrinkles and a higher perceived age. Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology.

In conclusion, p16INK4a positive cell numbers in sun-protected human arm skin are indicative of both local elastic fiber morphology and the extent of aging visible in the face.

Friday, August 21, 2015

Here is one of many studies to show a strong association between regular physical activity throughout life and better health and longevity when reaching old age. Human epidemiological studies like this one can largely only show correlation due to the way in which they are structured, but the equivalent life span studies in animals do show causation, in that the explanation for this correlation is that exercise acts to extend healthy life span:

We examined whether physical activity in early adulthood, late midlife, and old age as well as cumulative physical activity history are associated with changes in physical functioning and mortality in old age. Data are from 1,149 participants aged 65 years or older enrolled in the InCHIANTI study who were followed up from 1998-2000 to 2007-2008. At baseline, participants recalled their physical activity levels at ages 20-40, 40-60, and in the previous year, and they were categorized as physically inactive, moderately active, and physically active. Physical performance was assessed with the Short Physical Performance Battery and self-reported mobility disability was evaluated at the 3-, 6- and 9-year follow-up. Mortality follow-up was assessed until the end of 2010.

Physical inactivity at baseline was associated with greater decline in Short Physical Performance Battery score and greater rate of incident mobility disability (hazard ratio 4.66) and mortality (hazard ratio 2.18) compared to physically active participants at baseline. Being physically active throughout adulthood was associated with smaller decline in physical performance as well as with lower risk of incident mobility disability and premature death compared with those who had been less active during their adult life. We conclude that higher cumulative physical activity over the life course was associated with less decline in physical performance and reduced rate of incident mobility disability and mortality in older ages.

Friday, August 21, 2015

Researchers here fill in some of the gaps regarding the action of the INDY gene on longevity in nematode worms, suggesting that its effects largely arise due to its influence on the nematode version of AMPK, now also well known to be involved in the relationship between metabolism and natural variations in longevity. INDY (I'm Not Dead Yet) was one of the earliest longevity genes to be discovered, uncovered in fly studies. It is a mark of the complexity of cellular biochemistry, in which every system interacts with every other system, that researchers are still tracing mechanisms and signals to establish how exactly manipulations of INDY work to extend longevity.

Reduced expression of the Indy gene in Drosophila melanogaster promotes longevity in most studies. The underlying mechanisms recapitulate multiple characteristics of caloric restriction, i.e. reduced in body fat, insulin like proteins, and increased mitochondrial biogenesis, along with the activation of FOXO and the co-transcriptional regulator PGC-1α. Interestingly, food intake in the long lived, Indy mutant flies is not reduced. Knocking down the Indy homolog CeNAC2 in C. elegans also promotes a moderate increase in lifespan in one study, while another study failed to observe the phenotype. Whether or not the knockdown of CeNAC2 really promotes longevity and by which mechanism remains unclear.

Therefore, the aim of this study was to determine the role of the C. elegans INDY homolog CeNAC2 in life span regulation and to delineate possible molecular mechanisms. siRNA against Indy/CeNAC2 was used to reduce expression of Indy/CeNAC2. Mean life span was assessed in four independents, as well as whole body fat content and AMPK activation. Moreover, the effect of Indy/CeNAC2 knockdown in C. elegans with inactivating variants of AMPK (TG38) was studied.

Knockdown of Indy/CeNAC2 increased life span by 22±3 % compared to control siRNA treated C. elegans, together with a decrease in whole body fat content by ~50%. Indy/CeNAC2 reduction also increased the activation of the intracellular energy sensor AMPK/aak2. In worms without functional AMPK/aak2, life span was not extended when Indy/CeNAC2 was reduced. Inhibition of glycolysis with deoxyglucose, an intervention known to increase AMPK/aak2 activity and life span, did not promote longevity when Indy/CeNAC2 was knocked down. Together, these data indicate that reducing the expression of Indy/CeNAC2 increases life span in C. elegans, an effect mediated at least in part by AMPK/aak2.


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