FIGHT AGING! NEWSLETTER
December 21st 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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- Fundraising Victory: 250,000 Raised for SENS Research
- News of Another Potential Family of Senolytic Drugs for Clearance of Senescent Cells in Aging
- The Foster Foundation Makes a Year-End 50,000 SENS Rejuvenation Research Fundraising Challenge
- Methuselah Foundation Funds Leucadia Therapeutics to Work on a New Approach to Alzheimer's Therapy
- Aging: The Longevity Dividend
- Latest Headlines from Fight Aging!
- A Review of the State of Tendon Regeneration
- More Research into the Details of the Harm Done to the Aged Immune System by Cytomegalovirus
- Better Understanding the Role of p53 in Cancer
- Osteoarthritis and Clock Functions in Cartilage Cells
- Decellularization as a Way to Obtain Raw Materials for Bioartificial Organs
- Reviewing FOXO Transcription Factors in Aging and Longevity
- Targeting Macrophage Metabolism to Treat Atherosclerosis
- Ghrelin as a Treatment for Peripheral Artery Disease
- A Small Crowdfunding Project for Work on Metrics of Age
- More Investigation of Bisphosphonates and Reduced Mortality
FUNDRAISING VICTORY: 250,000 RAISED FOR SENS RESEARCH
I'm pleased to announce that the 2015 Fight Aging! matching fundraiser to benefit the SENS Research Foundation has hit the funding goal. Three months ago Fight Aging!, Josh Triplett, Christophe and Dominique Cornuejols, Michael Greve of forever-healthy.org, and Stefan Richter collaborated to create a 125,000 matching fund for SENS donations. We challenged the community to meet that amount by the end of this year: every donation to SENS rejuvenation research before December 31st would pull in a matching amount from the fund. With that total hit here in the middle of December, we have collectively managed to channel 250,000 to the best and most promising research aimed at treating the causes of aging. A quarter of a million in funding can buy a fair amount of early stage research in the life sciences these days. The cost of the tools is falling even as their capabilities grow, and so this is a great time to support medical research. We can make a real difference.
It is important work that we fund with our donations. SENS research programs represent the best chance at significant progress towards rejuvenation therapies in our lifetimes, leading to a range of treatments that work by repairing or clearing the forms of fundamental cell and tissue damage that cause aging and age-related disease. In many cases, SENS-funded research is near the only meaningful work on such therapies, and in those areas SENS Research Foundation programs exist to remove roadblocks and thus enable broader participation and interest in the research community. SENS rejuvenation research has been funded at a low level for a little more than a decade now, long enough for the first results to be visible. In the past couple of years concrete progress has occurred in many of the relevant fields, the fruits of past philanthropic donations.
Most recently, this year saw an important piece of infrastructure technology produced in efforts to clear glucosepane cross-links, for example. In 2014 and 2015 researchers produced technology demonstrations for senescent cell clearance treatments, showing benefits to health in normal aged laboratory mice. A startup company was funded based on one of these technologies. In 2015 another startup, Human Rejuvenation Technologies, received a technology transfer from the SENS Research Foundation with the aim of producing a therapy for atherosclerosis based on programs for clearance of intracellular aggregates. In addition, the first promising trial results in human patients arrived for a treatment that clears transthyretin amyloid from old tissues. Further, methods of repairing mitochondrial DNA damage funded in part by the SENS Research Foundation have moved beyond the laboratory and have been under commercial development since 2013.
The SENS supporters of past years have good reason to be pleased with what has been achieved with their charitable donations, a significant increase in progress towards the tools needed to bring aging under medical control. The SENS Research Foundation and its allies have achieved more than just technological progress, however. Moving forward in the production of medical technology to treat aging has always been as much about persuasion as about research, a matter of having to convince the world that yes, this is possible, plausible, and necessary. People are largely blind when it comes to the costs and suffering caused by aging, and even as recently as a decade ago the medical research community was a hostile environment for anyone who thought to talk openly about treating the causes of aging - to do so was to risk funding and career. This has changed in large part thanks to the efforts of advocates such as the SENS Research Foundation staff, past and present. The present culture of aging research is one in which people debate openly over how best to treat aging; this is a very big deal, and another reason for long-time supporters of the SENS Research Foundation to be pleased at how much has been achieved to date.
NEWS OF ANOTHER POTENTIAL FAMILY OF SENOLYTIC DRUGS FOR CLEARANCE OF SENESCENT CELLS IN AGING
Effective clearance of senescent cells in humans is arguably the form of SENS-style rejuvenation treatment based on repair of cell and tissue damage that is closest to practical implementation. A therapy capable of safely clearing even half of the senescent cells present in all tissues should prove very beneficial - and it is something that can be applied multiple times, as needed, repeatedly turning back this contribution to degenerative aging. As is always the case in these matters, however, only a few research groups are actively working on the problem, and funding is a desert in comparison to other areas of far less interesting research. This is why the research materials I'll point out here, news of a new potential class of senescent cell clearing drugs, still in the early stages of investigation, is worthy of attention rather than being buried by a score of similar announcements. In populous and comparatively well-funded fields such as the treatment of heart disease or arthritis there are far too many potential new drugs under study at an early stage in laboratories and noted in research papers to remark upon each of them. Few of these promising starts in cell cultures will ever get much further than that; there are many possible reasons why good results in cells don't translate to good results in animals. Similarly many of the promising results in animal studies fail on the next stage beyond that. So temper your enthusiasm.
Cells become senescent in response to damage, toxic environments, or as an alternative to self-destruction when they reach the end of their replicative life span. Some are destroyed by the immune system, but enough remain and linger that many tissues are made up of a sizable proportion of senescent cells by late life. These cells behave badly, secreting compounds that alter surrounding cellular activities, spur chronic inflammation, and degrade the extracellular matrix that is fundamental to tissue properties such as elasticity or load-bearing strength. Even partial and uneven clearance of senescent cells has been demonstrated in animal studies to provide lasting benefits to health following a single treatment. Better and more comprehensive clearance should produce greater benefits. That, of course, requires the development of improved methods of clearance.
The research materials quoted below can be taken as a representative sample of the sort of work that should be taking place in many more laboratories, an exploration in search of ever more effective ways to eliminate senescent cells from the body. Inevitably there will be dead ends, surprises, and much more failure than success. That is always the way in research. The way to make progress is to take many chances, invest in many diverse approaches to increase the overall odds of at least one useful result. Perhaps the most useful outcome here is that these results provide another solid demonstration that senescent cell clearance produces meaningful health benefits in aging mice. It is worth remembering that SENS rejuvenation research advocates have been calling for investment in this approach to the treatment of aging for more than a decade now, providing detailed research and development plans along with that advocacy, and were initially mocked for it in many quarters. Only in the last couple of years has the research community directed even a modicum of funding towards senescent cell clearance. There are lessons to be learned here, and one of them is that we could be closer to the defeat of aging than we are today had more people listened back then.
The first broad spectrum drug that can potently kill senescent cells in culture
Researchers are reporting the discovery of the first broad spectrum drug that can potently kill senescent (or aging) cells in culture and effectively clear the cells in animals by specifically targeting a pathway that is critical for the survival of senescent cells. Because senescent cells are believed to play a role in the late effects of radiation on normal tissues and certain age-related diseases, this study has broad implications for future therapies targeting the common biological mechanism that contributes to late tissue injury caused by radiation and aging. Cellular senescence, the loss of cells' ability to divide, normally functions as a tumor suppressive mechanism; however, senescent cells become "toxic" as they accumulate after exposure to radiation and with age. This is because they cause stem cell aging that reduces the ability of tissue regeneration and repair and drive chronic inflammation and oxidative stress. Since chronic inflammation and oxidative stress are thought to be the root cause of some late effects of radiation and many age-related diseases, including radiation-induced long-term bone marrow injury and age-related osteoarthritis and atherosclerosis, eliminating senescent cells has the potential to mitigate radiation-induced late tissue injury and treat many age-related diseases.
In the current study, ABT-263, a molecule initially developed as an anti-cancer therapy, was given orally to either normally aged mice or irradiated mice to induce premature aging of the hematopoietic system, the organs and tissues involved in production of blood. ABT-263 effectively depleted senescent cells, including senescent "stem cells" of the bone marrow and muscle. Depletion of the senescent cells appeared to reduce premature aging of the bone marrow caused by irradiation, and even rejuvenated the function of stem cells in normally aged mice. "Our results demonstrate that clearance of senescent cells by a pharmacological agent is beneficial in part by rejuvenating aged tissue stem cells. Because a decline in tissue stem cell function is associated with exposure to radiation and aging, we believe clearing senescent cells and rejuvenation of tissue stem cells could have a major impact on mitigation of radiation injury and treatment of diseases of aging. ABT-263 was originally developed as an anti-cancer agent. It has toxic side effects that make it inappropriate for development as an agent for diseases of aging. We are investigating next-generation small-molecule drugs that are optimized to clear senescent cells without drug-induced toxicity."
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug.
We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.
THE FOSTER FOUNDATION MAKES A YEAR-END 50,000 SENS REJUVENATION RESEARCH FUNDRAISING CHALLENGE
It has been a great year for SENS rejuvenation biotechnology, both for funding and for results delivered by ongoing research programs. The 2015 fundraising continues apace, with yet another organization taking up the baton to offer a matching fund. Following on from our successful 250,000 Fight Aging! 2015 fundraiser to support the work of the SENS Research Foundation, the Foster Foundation has announced a matching fund of their own. They have put up a 50,000 fund to match all donations to the SENS Research Foundation made between now and the end of the year, just two weeks away. From the latest SENS Research Foundation newsletter:
We are pleased to announce that the Foster Foundation, a longtime supporter of SENS Research Foundation, has offered us a final year end challenge. They will match up to 50,000 raised from December 14th to 31st. Formerly the Rose and Winslow Foster Family Foundation, the Foundation has provided over 150,000 in donations to SRF this year. We thank them for their amazing support of our mission. Help us secure this challenge grant by donating today and helping enable SRF's critical work to end age-related disease.
The rejuvenation research programs running under the auspices of the SENS Research Foundation, and related efforts conducted by a few other organizations, represent the best of current approaches to the treatment of aging. Aging is caused by forms of cell and tissue damage, and therefore the fastest approach to building effective therapies, medical technologies capable of preventing and reversing aging, is to repair this root cause damage. Sadly all too little of modern medical research is focused on this goal, and the mainstream research community has so far only broadly undertaken work for cancer, stem cell therapies, and amyloid clearance, the latter mostly in the course of efforts to treat Alzheimer's disease. These are just three slices of the seven or more broad categories of repair technology needed, and much of the present mainstream work in these fields is either not directed at the treatment of aging, or is not likely to produce meaningful outcomes in terms of repair. This is why non-profit initiatives like the SENS Research Foundation are vital to the future of our health and longevity. Non-profits undertake the work that is overlooked, unprofitable, or unpopular in the existing funding ecosystem, and as a result can unblock logjams and enable progress and adoption of specific lines of research in the broader scientific community.
The SENS Research Foundation can point to success as a patron of mitochondrial repair research over the past eight years or so, helping to build the foundation for allotopic expression - placing backups of mitochondrial genes in the cell nucleus - to the point at which Gensight is now devoting tens of millions to development of the technology. The SENS Research Foundation has also recently funded the startup Oisin Biotechnology to proof and develop a method of senescent cell clearance, and transferred some of the promising results of their lysosomal aggregate clearance research to another startup, Human Rejuvenation Technologies, for the development of treatments for atherosclerosis. They are also in the process of unblocking work on clearance of glucosepane cross-links in humans, funding the development of the tools needed for effective research and development in that area.
These are all programs with concrete results that aim at repair of causes of degenerative aging and age-related disease. Few other organizations can claim to be doing as much with such a modest yearly budget. The more that we can help the SENS Research Foundation to grow, the faster we will see real, working rejuvenation treatments. The clock is ticking and none of us are getting any younger yet - a lot of work is left to accomplish before that starts to happen, and here is the chance to help make it happen.
METHUSELAH FOUNDATION FUNDS LEUCADIA THERAPEUTICS TO WORK ON A NEW APPROACH TO ALZHEIMER'S THERAPY
The Methuselah Foundation has a record of seed funding early stage biotech and medical companies that are undertaking novel work that is (a) relevant to aging or tissue repair and (b) not already in progress to any meaningful degree elsewhere. Funding startups is one way to push forward the state of the art, providing support for research that is almost at or just past the point of initial technology demonstrations in the laboratory. The list of companies funded by the Methuselah Foundation includes the bioprinting company Organovo, an investment that has paid off handsomely in all senses of the phrase, and more recently Oisin Biotechnology, a new initiative focused on senescence cell clearance. The latest investment, announced a few days ago, is focused on getting to an answer on a novel approach to therapies for Alzheimer's disease:
Could a New Approach to Alzheimer's Move Us Closer to a Cure?
Leucadia Therapeutics LLC, a biotechnology company focused on treating and preventing Alzheimer's disease, using patent-pending technology to correct the cause of the disease rather than its effects, and Methuselah Foundation, a public charity incentivizing innovation in regenerative medicine, today announced a joint partnership to develop a novel therapeutic strategy to treat Alzheimer's disease. The company will use this investment to accelerate development of novel therapy with the goal of beginning clinical trials in 2018.
Leucadia Therapeutics Chief Scientific Officer, Douglas Ethell, Ph.D., said, "This is an exciting event for LT as it frees us from fundraising and allows us to focus our efforts on getting into the clinic as soon as possible." Under this agreement, the Methuselah Foundation has made an equity investment in Leucadia Therapeutics LLC. Over the next 3-5 years, Leucadia will develop and test a novel therapeutic device to treat the underlying cause of Alzheimer's disease.
As you can see the release provides no scientific details, but that's fine - information is available elsewhere. The scientist leading this effort, Douglas Ethell, has a background in dementia and stem cell research, and gave a talk on the underpinnings of his new approach at Rejuvenation Biotechnology 2015 entitled "CSF Hydrodynamics at the Cribform Plate: Has the Cause of Alzheimer's Disease Been Under or Over Our Noses All Along?" Unfortunately the video and abstract for this presentation are not yet published online, but we can instead look at a 2014 paper in which Ethell outlines the evidence for his hypothesis that Alzheimer's is caused by an age-dependent decline in drainage of cerebrospinal fluid through narrow passages in the head, a process that may normally assist in removal of unwanted metabolic waste - such as the amyloid associated with Alzheimer's disease.
Disruption of Cerebrospinal Fluid Flow through the Olfactory System May Contribute to Alzheimer's Disease Pathogenesis
Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid-β (Aβ) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa.
Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Aβ removal from those areas - among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis - all of which have been linked to AD risk.
I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Aβ oligomers and other metabolites from the MTL.
Ethell is not the only researcher providing evidence for this sort of idea, that the failure of drainage channels for cerebrospinal fluid is important in the development of dementia, and that these failures are essentially mechanical and structural issues in the same way as, say, stiffening of blood vessels is a mechanical and structural issue. Underlying cellular problems that involve the accumulation of forms of biochemical damage are what give rise to these mechanical and structural failures, but then the proximate issue that causes disease is that the system of tissues no longer pumps or flexes or drains fluid correctly. There are similar hypotheses for the declining integrity of the choroid plexus, a filtration system for cerebrospinal fluid, to be a proximate cause of Alzheimer's disease. It is certainly the case that amyloid levels in the brain appear to be dynamic on a short timescale; there is a lot of support for the view of Alzheimer's disease as the result of a slow failure of a constant, ongoing clearance of metabolic wastes rather than a slow accumulation of metabolic wastes with little clearance.
One of the good points about the failing drainage hypothesis is that it is comparatively cheap to test, and that test is what the Methuselah Foundation is buying here. Any way to restore the declining mechanisms involved, even if forcing the situation without repairing the underlying causes, will suffice for that test. If it the resulting treatment leads to reduced levels of metabolic waste in the brain, which should happen fairly rapidly if those waste levels are dynamic on a short time scale, then the hypothesis is correct. If it doesn't, then it is probably incorrect. This is medical science at its best and most practical.
AGING: THE LONGEVITY DIVIDEND
Some of the researchers involved in the Longevity Dividend initiative have taken the sensible approach of distilling into a new book their view on aging research, the existing evidence, the bounds of the possible in the near future of longevity science, and what should be done to treat aging. They should have done this years ago; it might have greatly helped efforts to lobby for greater funding of favored programs on aging and longevity in the National Institutes of Health. Certainly, the creation of Ending Aging was a very important foundation for the growth of support for SENS research; a well-assembled book is a solid point of reference that keeps on providing worth to those involved in advocacy for the cause it details.
So that said, the Longevity Dividend view is one of aiming for marginal, unambitious gains. It is an outgrowth of the mainstream position in aging research that sees the only viable path ahead as being a slow, expensive process of tinkering with the operation of metabolism so as to slightly slow the aging process - to slightly slow down the accumulation of cell and tissue damage that causes aging. This, of course, will be of little use to the people who are already old, heavily damaged, when the first treatments eventually emerge, and of not that much greater benefit to everyone else. Adding a couple of years to life expectancy doesn't change the big picture all that much at all. Further, the Longevity Dividend typifies the very conservative mindset of Big Government science: change must be small, everything is infused with politics and lobbying of formal hierarchies, and the pace of progress in persuasion is slow and expensive.
So while it is great that there are more researchers out there working to propagate the view that aging can and should be treated - there is still a long way to go yet to persuade the rest of the world to agree with that scientific consensus - in all of this the Longevity Dividend is really the antithesis of the SENS advocacy and rejuvenation research that I see as the most promising way forward. SENS comes as an outside influence on the present funding establishment and its rigid limitations, using philanthropic donations to create radical change, and engineer effective progress towards ways to repair the damage and end aging: to bring aging under medical control and prevent and reverse all age-related disease, not just slow it down a little. In any case, that is my opinion. You can see what you think now that the Longevity Dividend argument is laid out in a coherent fashion and at length:
New book on Aging: The Longevity Dividend from Cold Spring Harbor Laboratory Press
Aging is one of the greatest challenges currently facing society. People are living longer than ever, but many of the later years are fraught with frailty and disease, placing an enormous burden on health-care systems. Understanding the biological changes that occur during aging and developing strategies to address them are therefore urgently needed.
Written and edited by experts in the field, Aging: The Longevity Dividend from the Cold Spring Harbor Perspectives in Medicine collection, examines the biological basis of aging, strategies that may extend health span, and the societal implications of delayed aging. Contributors discuss genetic variants that accelerate or protect against aging, biochemical pathways that modulate longevity (e.g., mTOR), biological consequences of aging (e.g., decline in stem cell function), and various animal models used to study aging processes. They emphasize that age-delaying interventions will yield greater health and vitality than disease-specific treatments. Drugs that may promote health span or longevity (e.g., metformin) and efforts to prevent and treat frailty (e.g., through exercise) are explored.
Aging: The Longevity Dividend, Excerpt from the Foreword (PDF)
With the general realization that the population of our planet is rapidly becoming older, economists, population health experts, epidemiologists, policy planners, physicians, scientists, and others have started considering implications of this "silver tsunami" for the society. At the level of physiological functioning and health maintenance in old age, it became apparent that this increase in longevity will be accompanied by multiple comorbidities in a significant proportion of the older population.
Therefore, developing strategies to maintain optimal health in an increasingly aging population is becoming a global strategic imperative. This book represents the latest concerted and broad effort to shine a light on the potential of biology of aging research to implement what could be a revolutionary change in improving the health span of older adults. It is a culmination of more than 25 years of effort by the editors of this volume to draw broader attention to this issue. Specifically, beginning in 1990, S. Jay Olshansky and colleagues, many of them coauthors of this volume, started to make a powerful case for why and how research into life-span and health-span extension, as part of the larger field of biology of aging, may have a unique potential to provide broad and far-reaching benefits to the aging human population. The effort, aptly named the Longevity Dividend Initiative, has already made substantial headway in the larger community of researchers and is beginning to extend to policy makers and society overall. This book is part of a groundswell of recent activities to help scientists and public advocates of science reach the tipping point and bring about a coherent, conceptually innovative, scientifically based, and publicly as well as industry-supported and sponsored strategy to deal with health issues central to older adults from a revolutionary standpoint.
The argument for the Longevity Dividend is that the payback to society and individuals from extending health span via fundamental interventions based on knowledge of biology of aging will be considerable and broad. This argument, in its entirety, seems intuitively appealing to the point of being a "no-brainer": The current approaches to treating age-related diseases that produce the highest morbidity and mortality in the older adult population are only incrementally effective at increasing life span and minimally effective in increasing health span, defined as the fraction of life span spent in good health and prosperity. In fact, curing all cancers, for example, although desirable, merely replaces cancer with other chronic morbidities such as Alzheimer's, cardiovascular diseases, metabolic diseases, and so on. By contrast, in numerous laboratory animal models, including some studies in nonhuman primates and humans, interventions based on manipulations of nutrient sensing and cellular metabolism have shown not only longevity extension but also significant postponement of multiple age-related diseases (including cancer, Alzheimer's, cardiovascular, and metabolic diseases). This, therefore, is close to, or achieves, health-span extension.
The promise of translating these interventions to human subjects, then, starkly contrasts with current, disease-specific research and treatment approach. Simply put, the choice would come down to the two extremes: (1) the current health-care approach, with most individuals enjoying a relatively long life span but reduced health span with multiple comorbidities and increased, ballooning health-care costs; or (2) the biology-of-aging-based health-span extension, which, if successfully translated to humans, would provide increased health span at a fraction of today's health-care cost, with a vigorous and engaged older adult population and even a potentially productive older workforce.
At present, two key issues stand in the way of broad application of health-span extension to humans. First, we are still not at the point of having applications that are distribution-ready. Second, serious additional roadblocks exist to implementation, including the omnipresent lack of funding for research and, even more so, advanced-stage clinical testing. There also remain ingrained views in society that aging is immutable and/or that intervening in the aging process will produce deleterious and unwanted consequences such as further overpopulation and shortages of resources. Yet the increase in human longevity during the last century was one of humanity's most remarkable medical and technological accomplishments. As valuable as oil, gold, diamonds, fresh water, and clean air may seem, life itself is likely to be our most precious commodity - and we managed to manufacture more of it during the last 150 years than during all of humanity's existence prior to the 19th century.
LATEST HEADLINES FROM FIGHT AGING!
A REVIEW OF THE STATE OF TENDON REGENERATION
Monday, December 14, 2015
This open access review covers, in some detail, the state of development for stem cell therapies aimed at tendon regeneration. This is one of numerous tissues in the human body with normally limited regenerative capacity, and for which stem cell treatments offer the potential for complete healing. Progress towards that goal is, as ever, not as rapid as we'd like, however. Note that the full paper is PDF format only for the moment:
Tendon injuries are a common cause of physical disability. They present a clinical challenge to orthopedic surgeons because injured tendons respond poorly to current treatments without tissue regeneration and the time required for rehabilitation is long. New treatment options are required. Due to its relatively low cellularity and vascularity as well as the change in the tissue microenvironment after injury, tendons form scar tissue and ectopic bone after injury without regenerating the original tendon structure.
Tissue engineering with stem cells offers the potential to replace the injured/damaged tissues with healthy and functional ones. The use of stem cells for tendon tissue engineering is advantageous compared to terminally differentiated cells as stem cells are pluripotent or multipotent, highly proliferative and synthetic, and can provide the appropriate signals to promote tendon regeneration compared to terminally differentiated cells. Moreover, stem cells can also be used as a vehicle for gene therapy and sustained delivery of bioactive factors for tendon repair.
While the application of stem cells for the promotion of tendon healing is promising in small animal models, there have been few well-controlled large animal studies and clinical trials. The follow-up duration in animal studies was usually short (usually 4-12 weeks). Further research on the efficacy and safety of stem cell-based therapy for tendon repair in well-designed large animal models with extended follow-up time and randomized controlled clinical trials is needed.
MORE RESEARCH INTO THE DETAILS OF THE HARM DONE TO THE AGED IMMUNE SYSTEM BY CYTOMEGALOVIRUS
Monday, December 14, 2015
A fraction of the characteristic age-related decline and disarray of the immune system is due to long-term cytomegalovirus (CMV) infection. This herpesvirus is near ubiquitous in the population by the end of life, but for most people there are no immediate or obvious symptoms, or at least not beyond the slow corrosion of the immune system. CMV cannot be cleared from the body, but the immune system appears to devote ever more of its limited resources to this futile battle at the cost of its overall effectiveness. In the research paper noted below, researchers catalog more of the details of this process.
A robust therapy to clear CMV, were one developed, wouldn't fix the damage to the immune system created during the period of infection. One possibly alternative approach is to use targeted cell killing treatments to remove the specialized immune cells and free up space for their replacement, something that has been demonstrated to various degrees in the laboratory, but there is sadly little ongoing work here - the usual story for anything that might make a real difference in aging.
Aging and latent infection with cytomegalovirus (CMV) are thought to be major factors driving the immune system towards immunosenescence, primarily characterized by reduced amounts of naïve T-cells and increased memory T-cells, potentially associated with higher morbidity and mortality. The composition of both major compartments, γδ as well as αβ T-cells, is altered by age and CMV, but detailed knowledge of changes to the γδ subset is currently limited. Here, we have surveyed a population of 73 younger (23-35 years) and 144 older (62-85 years) individuals drawn from the Berlin Aging Study II, investigating the distribution of detailed differentiation phenotypes of both γδ and αβ T-cells.
This study presents a uniquely detailed analysis of the γδ T-cells, in younger and older people with a carefully characterized background. In the same subjects, we also assessed αβ T-cells, and found strong associations of CD8+ αβ T-cells, Vδ1+, other (Vδ1-Vδ2-) with age and also with CMV-seropositivity. The CD4:CD8 ratios were lower in old CMV-seropositive than in seronegative individuals. We found increased Vδ1:Vδ2-ratios associated with CMV in the old, similar to what is reported in cancer, supporting the theory of dual reactivity of γδ T-cells. It remains to be determined whether the increased Vδ1+ compartment in CMV-seropositive individuals might have similar detrimental impact as reported for the survival of melanoma patients. The memory differentiation patterns in the Vδ1+ compartment are similar to the CD8+ αβ T-cells markedly changed by age and amplified by the presence of CMV, suggesting an increased memory compartment of acquired immunity over the life-time and in particular in association with CMV. More functional and longitudinal studies are needed to better understand age-associated immune exhaustion and the role, if any, that a latent CMV infection plays therein due the major investment of immune system resources to maintain control of latent CMV.
BETTER UNDERSTANDING THE ROLE OF P53 IN CANCER
Tuesday, December 15, 2015
The gene p53 is an important tumor suppressor. A loss of function in p53 is involved in many cancers, permitting uncontrolled replication of cells. Here researchers make progress in understanding how this works under the hood, finding links that may help to provide a detail view of how rapamycin and a few other drugs act to reduce cancer risk.
The gene p53 has been described as the "guardian of the genome" due to its prominent role in preventing genetic mutations. More than half of all cancers are thought to originate from p53 mutations or loss of function. New research describes how mutations and or loss of function of the p53 gene activate a protein complex known as mammalian target of rapamycin complex 1 (mTORC1), which helps regulate the energy resources needed for cell proliferation.
mTORC1 is made up of several dozen proteins, and cells use the intracellular membranes of their lysosome as a scaffold to bring all of these proteins together. In response to the need of a normal cell, the p53 gene helps maintain proper levels of a protein known as tuberous sclerosis complex 2 (TSC2) in the lysosome. When p53 is not functioning properly, TCS2 levels in the lysosome drop, and a small protein known as RHEB takes its place. It is this accumulation of RHEB that activates mTORC1 and leads to the abnormal control of cell proliferation. "We have uncovered for the first time the signaling process that leads to excessive growth of cancer when p53 is lost. These protein interactions are like individual links in the chain of events leading to the development of cancer."
OSTEOARTHRITIS AND CLOCK FUNCTIONS IN CARTILAGE CELLS
Tuesday, December 15, 2015
Researchers here link age-related issues with the body clock to the development of osteoarthritis, a degenerative condition of joints. The body clock controls changes in cell and organ activities according to the time of day. This overall system has its reflections in the biochemistry of all types of cells, and, as for many other aspects of cellular biology, the mechanisms involved in clock-related regulation become disarrayed with age. The proximate causes of this disarray are only partially cataloged and explored, long lists of changing protein levels and relationships mapped one by one. The root cause is most likely the well-known forms of cell and tissue damage that cause aging, but - as ever - drawing a line between that damage, through largely unmapped, complicated chains of cause and consequence, to link up with any one specific end result of aging is a challenging, expensive, and time-consuming process. It would be faster to fix the damage and see what happens, a path that would also provide a much greater chance of meaningful therapies resulting from research work.
Researchers have for the first time established that the painful and debilitating symptoms endured by osteoarthritis sufferers are intrinsically linked to the human body clock. Body clocks within cartilage cells - or chondrocytes - control thousands of genes which segregate different biological activities at different times of the day. The body clock, researchers realised, controls the equilibrium between when chondrocyte cells are repaired during rest and when they are worn down through activity. But the research revealed that as we age, our cartilage cell body clocks deteriorate, making the repair function insufficient, which could contribute to osteoarthritis.
The team examined three types of human cartilage under the microscope : normal, mildly affected by osteoarthritis and severely affected. As the osteoarthritis became more severe, the number of cells that express BMAL1 - a protein which controls the body clock - became less and less. And in terms of aging, he found similar reduction of BMAL1 in chondrocytes, which coincided with the reduced 'amplitude' of the body clock (up to 40% weaker in older mice), supporting the theory that aging, at least partially through dysregulation of the chondrocyte clocks, is a major risk factor for osteoarthritis.
DECELLULARIZATION AS A WAY TO OBTAIN RAW MATERIALS FOR BIOARTIFICIAL ORGANS
Wednesday, December 16, 2015
Some of the chemical factories and filters in our bodies could be replaced by any device that performs the same function, and that device doesn't have to look anything like the structures they replace. However, the easiest way to recapitulate the original tissue function is still to use actual tissue, either donor or engineered. Researchers here report that decellularization, removing the cells from donor tissue and replacing them with the recipient's cells, is potentially a way to use discarded donor tissue as the basis for bioartificial organs:
The pancreas is a large gland near the stomach that secretes insulin to regulate the metabolism of glucose and other nutrients. Researchers have been working for years to develop an artificial pancreas in the lab to help the millions of people with type 1 diabetes. But what if the answer is to "recycle" the more than 300 human pancreata from organ donors that aren't currently being used? Researchers now report on the potential to use human pancreata as the "hardware" of a new-generation, bio-artificial pancreas. Currently, about 25 percent of the approximately 1,300 pancreata recovered for transplant cannot be used due to defects and other reasons. "We see these unused organs as potential 'hardware." The 'software' would be the patient's own cells, so that there would be no issues with rejection. We believe this research represents the first critical step toward a fully human-derived artificial pancreas."
The goal of the research was to test the suitability of pancreata from organ donors as a platform for building a new bio-artificial pancreas. First, the discarded organs were washed in a mild detergent to remove all cells, a process that is known as decellularization. A similar procedure is being used by regenerative medicine researchers in efforts to engineer human kidneys, livers and intestine. For the study, 25 human pancreata were processed to remove cells. The researchers found that the framework of blood vessels remained intact after the washing process. In addition, the researchers are the first to report that numerous growth factors were retained in the structures. Some of these proteins are essential in blood vessel formation, cell proliferation and glucose metabolism.
In theory, these organ structures could be re-populated with a patient's own cells. Insulin-producing cells could be generated from the patient's skin cells or could come from the patient's pancreas. Cells to line the organ's blood vessels (endothelial cells) could also come from the patient's pancreas. To test the compatibility of the decellularized structures and new cells, the researchers placed both insulin-producing and endothelial cells on the decellularized structures. In both cases, the organs structures were cell-friendly and allowed the cells to attach, function and maintain their original cell type. Next, to test the ability of the structures to grow new blood vessels, small samples of the cell-coated pancreata structures were implanted in chicken eggs. The structures integrated well with the developing environment of the chicken egg and generated capillaries.
REVIEWING FOXO TRANSCRIPTION FACTORS IN AGING AND LONGEVITY
Wednesday, December 16, 2015
A number of the large FOX family of proteins, in particular the FOXO proteins, appear to play roles in the complex interaction between metabolism and aging. They are thus targets for investigation and potential intervention in that part of the research community interested in trying to slightly slow aging via pharmacology. The plan there is to alter the operation of cellular metabolism in ways that boost existing mechanisms of repair and maintenance, or slow the pace at which the damage that causes aging is generated. The response to calorie restriction is the best understood of such altered states of metabolism, and investigations of the mechanisms involved in calorie restriction have determined much of the present focus on specific genes and proteins for those interested in developing drugs to modestly slow aging. The past decade suggests that attempting to do this is both hard and expensive; at least a billion spent on sirtuin research, for example, produced no useful results in terms of therapies. Even if further billions produce useful drug candidates, they will still be at best as effective as calorie restriction, and while calorie restricted individuals enjoy health benefits they still age and die on much the same schedule as their unrestricted peers. This isn't the road to rejuvenation.
An exciting research area on FOXO transcription factors' impacting on longevity has arisen in recent years. Studies have been conducted to address their upstream regulation, their downstream effectors, and respective signaling pathways in various animal models. Consequently, how these FOXO-mediated programs affect cellular or tissue function and whether there is an effect at an organismal level, has also been scrutinized. Several lines of evidence suggest that FOXOs affect longevity in a pleiotropic fashion, influencing several cell-regulated activities such as stress resistance, metabolism, cell cycle arrest, and apoptosis.
A myriad of future work can be envisioned at this time. The induction of FOXO-mediated programs in tissues with distinct metabolic potential such as brain, muscle, or adipose tissue and with different stages of differentiation or metabolic conditions (nutrition, oxidative stress) will enlarge our knowledge of how FOXO factors affect cellular/organismal lifespan. To further comprehend how FOXOs affect longevity, it is of high importance to understand how human FOXO sequence variants (namely FOXO3A) affect protein expression, its structure, or transcriptional activity. In order to see how these variants translate into physiological profiles, future investigations should address how these variants affect the level of FOXO proteins and their downstream effectors in serum. This approach has been used successfully in patients with vitiligo, in which FOXO3A levels were shown to be decreased when compared with the control group.
Compression of morbidity relates to both extended lifespan and delayed onset of age-related diseases, such as cancer and cardiovascular disorders. The development of molecules targeting aging mechanisms that underlie a number of age-related diseases is an exciting field that is nowadays in its first steps. It is noteworthy that clinical trials to test lifespan extension in humans would be challenging and require markers that can detect difference in aging rate across a short time frame. But given the potential of FOXO proteins to impact on numerous disorders such as cancer, diabetes, neurodegeneration, or immune system dysfunction, novel therapeutic modalities based on FOXOs will most likely take place in the near future.
TARGETING MACROPHAGE METABOLISM TO TREAT ATHEROSCLEROSIS
Thursday, December 17, 2015
Researchers here propose enhancing the cellular operation of the immune cells called macrophages in order to slow the progression of atherosclerosis, a condition in which blood vessel walls become inflamed and damaged, and dangerous fatty plaques grow inside the blood vessels. A number of processes contribute to the progression of atherosclerosis once any initial damage to blood vessel walls exists, and one of the important ones is the behavior of macrophages at the site of damage. These cells are drawn by the presence of oxidatively damaged cholesterol and lipids, ingest them and break them down. Some are overwhelmed by the volume of these damaged molecules, however, becoming what are called foam cells. Many die and their debris contributes to inflammation, and the growth of plaques that narrow blood vessels. This attracts further macrophages in a vicious cycle that ends in disaster when a plaque breaks free and blocks a blood vessel to cause a stroke or heart attack. This research is focused on enhancing the ability of macrophages to deal with cholesterol:
Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis. Macrophage energy metabolism can significantly influence macrophage phenotype, but how this is controlled in foam cells is not known. Bioinformatic pathway analysis predicts that miR-33 represses a cluster of genes controlling cellular energy metabolism that may be important in macrophage cholesterol efflux. We hypothesized that cellular energy status can influence cholesterol efflux from macrophages, and that miR-33 reduces cholesterol efflux via repression of mitochondrial energy metabolism pathways.
In this study, we demonstrated that macrophage cholesterol efflux is regulated by mitochondrial ATP production, and that miR-33 controls a network of genes that synchronize mitochondrial function. Inhibition of mitochondrial ATP synthase markedly reduces macrophage cholesterol efflux capacity, and anti-miR33 required fully functional mitochondria to enhance ABCA1-mediated cholesterol efflux. Specifically, anti-miR33 derepressed the novel target genes PGC-1α, PDK4, and SLC25A25 and boosted mitochondrial respiration and production of ATP. Treatment of atherosclerotic Apoe−/− mice with anti-miR33 oligonucleotides reduced aortic sinus lesion area compared with controls, despite no changes in high-density lipoprotein cholesterol or other circulating lipids. Expression of miR-33a/b was markedly increased in human carotid atherosclerotic plaques compared with normal arteries, and there was a concomitant decrease in mitochondrial regulatory genes PGC-1α, SLC25A25, NRF1, and TFAM, suggesting these genes are associated with advanced atherosclerosis in humans.
This study demonstrates that anti-miR33 therapy derepresses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, works to promote macrophage cholesterol efflux and reduce atherosclerosis.
GHRELIN AS A TREATMENT FOR PERIPHERAL ARTERY DISEASE
Thursday, December 17, 2015
Ghrelin is secreted in the body as a part of the process of hunger, and increased amounts in circulation have a range of sweeping effects on the operation of metabolism. It has been proposed that some portion of the long-term health benefits of calorie restriction and intermittent fasting arise because there are longer periods of hunger and thus longer periods in which there is more circulating ghrelin. For example, ghrelin has been shown to reduce inflammation and promote the development of new immune cells, among many other changes. So read this research in the broader context; I note it because it should be of interest to those who practice dietary restriction of one form or another, not because I believe that the approach here is necessarily going to result in a useful form of therapy:
A new study by a team of researchers suggests that the appetite-regulating hormone ghrelin could be used clinically for the early treatment of critical limb ischemia (CLI), an advanced form of peripheral artery disease. CLI is the severe obstruction of blood flow to the extremities that often requires major amputations and in half of all cases leads to death within five years. Its leading risk factors are diabetes, obesity and age. Using a mouse model of CLI, researchers showed that administering ghrelin daily over two weeks markedly improved blood flow in affected limbs. They found that ghrelin promoted growth of new structurally and functionally normal blood vessels, improved cell survival, and decreased tissue fibrosis.
The findings are exciting as currently there are no drugs treatments for CLI and other techniques are effective in only half of the cases. "Our team has previously shown that ghrelin showed promise for treating the presently incurable lung disease known as pulmonary hypertension, which is caused by blood vessels becoming progressively blocked. This prompted us to investigate whether ghrelin might have a similar effect in CLI." The researchers also studied ghrelin's action at the molecular level in tissue with restricted blood supply and identified that the hormone modulated downstream signalling cascades involved in new blood vessel growth and cell survival.
A SMALL CROWDFUNDING PROJECT FOR WORK ON METRICS OF AGE
Friday, December 18, 2015
Here I'll point out a aging research crowdfunding project at Experiment, focused on carrying out a small project in developing functional metrics of age to help evaluate treatments that might affect the pace or state of aging. The longevity science community has undertaken a growing number of crowdfunding efforts, and I think that this trend is important in the bigger picture of how to make crowdfunding work for scientific research on all scales and for all fields. That part of the community I'm involved with hasn't made much use of Experiment as a platform because it is focused on supporting very small projects, well under 10,000, while we tend to aim to raise much more than that per fundraiser, each supporting a larger discrete project. So it is good to see some inroads here.
In a better world than ours, a stronger scientific community would see every laboratory pulling in additional funds via crowdfunding. In doing so researchers would develop a community of supporters and a better relationship with the broader public, creating a greater understanding of what it is they do in their investigations and the potential of their work. Today next to no-one thinks about or cares about medical research until it is too late, and that has a lot to do with the sparse nature of funding for progress in medicine, I'd say. Changing this state of affairs would bring great benefits. There is also this: traditional philanthropy occupies a very important role in the modern institution of science, as other sources of funding almost never put resources towards the high-risk, early stage, radical new approaches that actually create discoveries. They are only willing to devote funds after the prototypes and proofs exist - which somewhat misses the point of what science is all about and how progress in science and technology happens at the sharp end. Nonetheless, it is what it is, and philanthropic funding is the engine that creates discovery. Opening that up to the public at large can only help.
Harvard Medical School has reported successful aging reversal using genetic and biochemical methods in the labs of Dr. George Church and Dr. David Sinclair. The Church Lab has encouraged us to build a new updated functional test of age. The test will measure functional biomarkers of the lab's subjects compared to their sequenced genomes and of clinical trial subjects elsewhere, estimating the age at which a person physically functions, enabling researchers to validate measurements from genetic and biochemical aging interventions and reliably compare results across subjects, studies and approaches. Our research will determine which biomarkers provide reliable indications of aging level and which test technologies can reliably measure the biomarkers at reasonable cost.
Now that institutions have succeeded in genetically reversing aging in laboratory samples of human cells and biochemically in live mice, we are developing a new system for measuring functional age in order to validate those results in people. Already, there are people whose genetics or lifestyle cause them to age more slowly or faster. Therefore, we already have experience measuring differences in levels of aging, for example tests taken using the H-SCAN function age test developed in 1990. We are developing a successor to that test. We will determine suitable functional age biomarkers and test technology via research and expert advice from Church, Sinclair and others. We will compare that data to the H-SCAN Test's 12 biomarkers and hardware.
Our goal is preparation of a device requirements document that an engineer can use to create a design for the test prototype. The document will contain a list of the functional aging biomarkers to be tested, the range of values to be tested, how each biomarker declines with age, why each biomarker was selected, specifications and sources of testing instruments for each biomarker, integration of the instruments in the device, sequence of tests, and requirements for user interface, software calculations, regulatory agencies, exterior design, connectivity, data security, and installation.
MORE INVESTIGATION OF BISPHOSPHONATES AND REDUCED MORTALITY
Friday, December 18, 2015
You may recall a study a few years back that showed a surprisingly large reduction in mortality and consequent extension of life expectancy for a group of more than a hundred older people taking bisphosphonates, a class of treatment for osteoarthritis. The size of the effect was five years or so, which is on the same order as exercise or calorie restriction in humans, meaning that it is large enough to be suspicious of such a result turning up out of the blue for any existing drug treatment. I would be looking for artifacts in the study data and to want to see both confirmation by other teams and a larger study population. Researchers here are looking at possible mechanisms for this reduced mortality, focusing on zoledronate, one particular bisphosphonate drug:
Researchers have discovered the drug zoledronate is able to extend the lifespan of mesenchymal stem cells by reducing DNA damage. DNA damage is one of the most important mechanisms of ageing where stem cells lose their ability to maintain and repair the tissues in which they live and keep it working correctly. "The drug enhances the repair of the damage in DNA occurring with age in stem cells in the bone. It is also likely to work in other stem cells too. This drug has been shown to delay mortality in patients affected by osteoporosis but until now we didn't know why. These findings provide an explanation as to why it may help people to live longer. Now we want to understand whether the drug can be used to delay or revert the ageing in stem cells in older people and improve the maintenance of tissues such as the heart, the muscle and immune cells, keeping them healthier for longer. We want to understand whether it improves the ability of stem cells to repair those tissues after injury, such as when older patients with cancer undergo radiotherapy."
Approximately 50 per cent of over 75 year-olds have three or more diseases at the same time such as cardiovascular disease, infections, muscle weakness and osteoporosis. In the future it is hoped this drug could be used to treat, prevent or delay the onset of such diseases rather than using a mixture of drugs. "We are hopeful that this research will pave the way for a better cure for cancer patients and keeping older people healthier for longer by reducing the risk of developing multiple age-related diseases."