Fight Aging! Newsletter, April 18th 2016

April 18th 2016

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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  • Don't Get Fat, Don't Stay Fat: Visceral Fat Tissue Will Kill You
  • Working Towards Therapies that Block the Contribution of Cellular Senescence to Aging and Cancer
  • Oxidized Albumin Increases With Age, Contributing to Cellular Senescence and Damage in Blood Vessels
  • The Definition of Regenerative Medicine Includes the Treatment and Reversal of Aging
  • Rejuvenation Biotechnology Update for April 2016
  • Latest Headlines from Fight Aging!
    • George Church on Genetics, Rejuvenation Research, and More
    • The Rider Institute Seeks Funding for DRACO Research
    • Proposing the Deleteriome in Aging
    • Fixated on Present Inequalities Rather than Producing Improvements for All
    • Targeting the Lymphatic System Following Heart Attack
    • The TiRe Database: Is Accelerated Wound Healing Good for Longevity in Mammals?
    • Samumed and Regeneration via Altered Wnt Signaling
    • MHCI Proteins and Loss of Muscle Function in Aging
    • A Reddit /r/science AMA With S. Jay Olshansky
    • FOXO3 Variant Associates with Reduced Cardiovascular Disease Mortality in Humans


Today I'll point out a couple of recent studies covering some of the consequences that result from the long-term damage done by letting yourself become overweight. There are great many such studies, for all the good it seems to do in this era of cheap calories and diminished exercise. When talking about the harms done by excess visceral fat tissue, I'm sure I'm largely preaching to the choir. While I haven't checked, I'm fairly certain that the audience here is well aware of the ways in which we can sabotage our health. Based on the robust evidence from a small mountain of study data, if you want to struggle with illness in later life, spend more on medical services, and die sooner than you would otherwise have done, then the most effective way to engineer that outcome is to take up smoking, stop exercising, and put on weight. Smoking is probably the worst of those, taking everything into account, but when you look at the life expectancy numbers one of the more surprising results is that a sedentary lifestyle and obesity are each about as bad for you as a smoking habit.

How does being fat do enough damage to knock years from your life expectancy? The problems are largely caused by the visceral fat around the organs, rather than by subcutaneous fat deposits. Visceral fat cells are very active, sending all sorts of signals out into the body at large. Some of those trigger the immune system, which leads to raised levels of chronic inflammation. Further, given a high enough sustained intake of calorie and visceral fat deposition, fat cells start dying in large numbers, and this also attracts immune cells and creates inflammation. Recently researchers have noted that DNA fragments from dead fat cells grow in number in the bloodstream with age, again capable of producing inflammation, but also capable of causing abnormal behavior in other cells throughout the body. As you can probably tell, it has been clear for quite some time that inflammation is a primary connection between visceral fat tissue and ill health.

Chronic inflammation will occur in aging no matter how well we take care of our health, at least given the limited capabilities of medical technologies available today, none of which yet meaningfully address the underlying causes of aging. The immune system suffers structural issues after a lifetime of exposure to pathogens, and in addition its cells and sustaining tissues accumulate molecular damage just like all other portions of the body. The result is a weakened immune system that is constantly overactive, inflamed but doing little good in that active state. That is bad enough, but the extra inflammation that comes with excess fat tissue and other outcomes of poor lifestyle choices is a considerable and entirely avoidable additional burden. To be in a state of greater inflammation for years on end is very harmful. Inflammation is demonstrated to raise the risk of suffering all of the common fatal age-related conditions: it speeds progression of the underlying cell and tissue damage that gives rise to those conditions, and then continues to accelerates the pathology of a condition once established, for all the same reasons. This is why the relationships outlined below exist:

Heart failure risk increases with waistline

A body mass index (BMI) over 30 is considered obese, and the connection between obesity and the risk of heart failure has been established in several studies. Now, researchers have conducted a new meta-analysis that shows that a BMI between 25 and 30 kg/m2, which is considered overweight, is also associated with increased risk. "Overweight individuals had a 35 per cent increased risk of heart failure as compared with normal weight individuals, and our findings indicate that overweight should be considered a clear risk factor for heart failure."

Body mass index (BMI) shows the relationship between weight and height and is used internationally as a measure of body fat. The risk of heart failure rose on average by 41 per cent for an increase of five BMI units, and the increase in risk accelerated the further up on the BMI scale you scored. Obesity increased the risk two to three times compared with normal weight. The researchers found no differences between men and women in the analysis, which included 23 studies with a total of almost 650,000 participants. Four studies looked at the link between BMI and the risk of death from heart failure, and the results suggested a 26 per cent higher risk for an increase of 5 BMI units. Meanwhile, the researchers saw that every ten-centimeter increase in waist circumference was linked to a 29 per cent higher risk of heart failure. These analyses were based on twelve studies with a total of just over 360,000 participants.

New study: Waist circumference is stronger predictor of heart disease than BMI

Researchers found that abdominal obesity - or having an apple-shaped body - is a strong predictor of serious heart disease in patients who have type 1 or type 2 diabetes, and haven't displayed any symptoms of heart disease. Apple-shaped bodies are already associated with metabolic syndrome (which includes high blood pressure, high sugar levels and high cholesterol), as well as coronary artery disease and heart failure, but this new study found that waist circumference is also a strong predictor of left ventricular dysfunction in patients. Metabolic syndrome is often accompanied by excess body fat around the abdomen. "This study confirms that having an apple-shaped body - or a high waist circumference - can lead to heart disease, and that reducing your waist size can reduce your risks."

The results of the new research expands on the results of a previously published study called FaCTor-64, which showed that the greater a person's body mass index, the greater their risk of heart disease. FaCTor-64 enrolled patients with diabetes who were considered to be at high risk for heart attacks, strokes, or death but had no evidence of heart disease as of yet. Study participants completed randomized screening for coronary artery disease by CT coronary angiography, then received recommendations to change their care or their lifestyles, or continue routine standard diabetes care, based on their results. They were then followed to track future adverse heart events.


One of the research advocates with the Major Mouse Testing Program recently wrote a popular science article on cellular senescence in aging, and more importantly the growing interest in methods of removing senescent cells. You'll find it linked below. Growing numbers of senescent cells is one of the root causes of degenerative aging, contributing to declining tissue function, progression of age-related disease, and ultimately death. Just this year researchers published results from a study of mice genetically engineered to destroy their own senescent cells, and which lived 25% longer than their unaltered peers. Other drug-based approaches to destroy senescent cells have not yet been used in full life span studies, but have been shown to improve health markedly in rodents, even after a single treatment in old age. Two startup companies are presently in the early stages of working on senescent cell clearance therapies, Oisin Biotechnologies and UNITY Biotechnology, and as more evidence accumulates there will no doubt be other players in this field.

Senescence is a cellular state of arrested replication, and is accompanied by many other altered behaviors, such as secretion of inflammatory and damaging molecules into surrounding tissues, a phenomenon called the senescence-associated secretory phenotype, or SASP. Cells become senescent in response to internal damage or a toxic environment - which can include the SASP of nearby senescent cells. At least initially senescence probably serves to reduce cancer risk, removing the ability to replicate from the cells most likely to suffer cancerous mutational damage. Most senescent cells are destroyed shortly after entering this state, either by their own programmed cell death processes, or by roving immune cells attracted by signals in the SASP. Some linger, however. Growth in the number of these persistent senescent cells occurs throughout life, but speeds up in later years: the level of damage to cells and tissues is higher, so more cells become senescent in response, and at the same time the immune system declines in effectiveness. As the presence of senescent cells increases, their collective SASP becomes a real issue, and actually makes cancer risk and progression worse than would otherwise be the case.

Researchers are still engaged in cataloging all of the ways in which senescent cells interact with important functions in our tissues. This is a slow and expensive process, just like all such work aimed at fleshing out the grand map of human metabolism and how it changes with age. The beauty and simplicity of aiming to destroy senescent cells, however, is that the scientific community doesn't need a full understanding of the detrimental effects, all the way down to the detail level of molecular interactions. All that is needed is to periodically remove these cells and validate the resulting benefits to health and longevity, a much easier prospect, as demonstrated by the numerous approaches presently under development or illustrated in animal studies.

The Two Faces of Aging: Cancer and Cellular Senescence

Aging, inflammation, cancer, and cellular senescence are all intimately interconnected. Deciphering the nature of each thread is a tremendous task, but must be done if preventative and geriatric medicine ever hope to advance. A one-dimensional analysis simply will not suffice. Without a strong understanding of the genetic, epigenetic, intercellular, and intracellular factors at work only an incomplete picture can be formed. However, even with an incomplete picture useful therapeutics can and are being developed. Depending on the context in which they are operating a single gene can have positive or negative effects on an organism's phenotype. Often the gene is exerting both desirable and undesirable influences at the same time. This is called antagonistic pleiotropy. Cellular senescence is a protective measure; it is a response to damage that could potentially turn a healthy cell into a malignant one. By halting its own division a senescent cell removes itself as an immediate tumorigenic threat. Yet the accumulation of senescent, non-dividing cells is implicated in a host of pathologies including, somewhat paradoxically, cancer.

Our bodies are bombarded by insults to their resilient but woefully vincible microscopic machinery. Oxidative stress, DNA damage, telomeric dysfunction, carcinogens, assorted mutations from assorted causes, necessary or unnecessary immunological responses to internal or external factors, all take their toll. In response cells may repair themselves, they may activate an apoptotic pathway to kill themselves, or just stop proliferating. After suffering these slings and arrows, p53 is activated. Not surprisingly, mice carrying a hyperactive form of p53 display high levels of cellular senescence. Abnormalities in p53 are found in most, if not all, cancers. Knocking out p53 altogether produced mice unusually free of tumors, but find themselves prematurely past their prime. There is a clear trade-off here. SASP (senescence-associated secretory phenotype) is associated with chronic inflammation, which itself is implicated in a growing list of common infirmities. Many SASP factors are known to stimulate phenotypes similar to those displayed by aggressive cancer cells.

p53 and mTOR interact with one another in ways that make mTOR inhibitors potentially useful, but since mTOR inhibitors such as metformin and rapamycin have their share of unwanted side effects, more and better drugs capable of destroying senescent cells - known as senolytics - must be explored in greater detail. Starting with a simple premise, namely that senescent cells rely on anti-apoptotic and pro-survival defenses more than their actively replicating counterparts, researchers created a series of experiments to find the Achilles' Heel of senescent cells. After comparing the two different cell states, they designed senolytic siRNAs. Of 39 transcripts selected for knockdown by siRNA transfection, 17 affected the viability of target senescent cells more than healthy cells. Similarly, dasatinib, a cancer drug, and quercitin, a common flavonoid found in common foods, have senolytic properties. The former has a proven proclivity for fat cell progenitors, and the latter is more effective against endothelial cells. Administration together into elderly mice resulted in favorable changes.

There are other senolytic approaches under development. Please embark on your own journey through the gallery of encroaching options for those who would prefer not to become chronically ill, suffer immensely, and, of course, die miserably in a hospital bed soaked with several types of their own excretions - presumably, hopefully, those who claim to be unafraid of death have never seen this image, or naively assume they will never be the star of such a dismal and lamentably normal final act. There is nothing vain about wanting to avoid all the complications that come with time. This research is quickly becoming an economic and humanitarian necessity. The trailblazers who move this research forward will not only find wealth at the end of their path, but the undying gratitude of all life on earth.


Today's open access paper focuses on albumin and is a great example of the role played by oxidation of proteins in aging, the way in which it can act as a link between fundamental damage and secondary damage, and between damage in one location in the body and consequences in another. Oxidation of many common proteins increases with advancing age, firstly because more oxidation is taking place due to damaged or overactive cellular processes, and secondly because the systems intended to clear out oxidized proteins become damaged and less efficient themselves. All proteins are in effect small machines, or interchangeable parts of larger assemblies of machinery, and when altered by oxidative reactions they tend not to work properly, causing a chain of localized malfunctions. Cells react to the presence of this type of damage with increased housekeeping or calls for help to the immune system, but higher levels of such damage can tip matters over into serious dysfunction, chronic inflammation, and the creation of senescent cells, among other consequences, contributing to the progression of aging and age-related diseases.

Oxidation of proteins that are carried far and wide in the blood stream, like albumin, is one of the ways in which localized age-related cellular damage can produce global consequences throughout the body. Take damage to mitochondrial DNA, for example. As we age, a small but significant fraction of our cells become taken over by dysfunctional mitochondria as a result of rare mutational damage to their DNA. Most such damage is repaired very rapidly, but large deletions can cause a form of malfunction that makes mitochondria more resistant to removal by quality control mechanisms. Cells packed full of these broken mitochondria become dysfunctional themselves, exporting reactive oxidizing molecules in large volumes into the surrounding tissues. Some will react with proteins in the bloodstream, and those oxidized proteins will most likely end up stuck in a blood vessel wall somewhere, irritating the local environment. This is how atherosclerosis starts and is reinforced: damaged proteins to start with, followed by an overreaction on the part of local cells, then immune cells pile in, and a growing local disaster zone of inflammation, dying cells, and continued signals for help is created. Ultimately this creates fatty plaques that remodel and narrow blood vessel walls, causing cardiovascular disease at best, and which at worst can fragment to block vital blood vessels, causing death or serious injury.

This unfortunate set of circumstances is one of the reasons why repairing broken mitochondria is an important component of any comprehensive future toolkit of rejuvenation therapies. There are numerous possible approaches to that goal, most of which are either nearly or actually possible today, at least in cell cultures. For a decade or so the SENS Research Foundation has championed allotopic expression, creating copies of mitochondrial genes in the cell nucleus as backups, so that the necessary protein machinery will be created and delivered to mitochondria regardless of damage to the mitochondrial genome. Today Gensight is developing this technology for a single mitochondrial gene, while the SENS Research Foundation is moving more slowly, and with much less funding, towards completing the necessary groundwork for all thirteen genes of interest.

Aging-associated oxidized albumin promotes cellular senescence and endothelial damage

Aging is associated with well-known changes in protein conformation that are involved in aging-related disease. Among this modification, probably the protein oxidation is the most relevant mechanism of pathogenesis in the elderly subjects. Oxidative modifications generally cause loss of catalytic or structural function in the affected proteins; it is likely that the level of oxidatively modified proteins observed during aging will have serious deleterious effects on cellular and organ function. Proteins are major targets for reactive oxygen species (ROS) because of their abundance in biological systems. In addition, proteins are primarily responsible for most functional processes within the cells. The major protein present in the plasma is albumin, which constitutes ~55% of the plasma proteins. As a result, it is most susceptible to suffer an oxidative process. In this manner, the oxidation of albumin may cause endothelial damage. Nevertheless, there are no studies analyzing the effects of oxidized albumin in aging, and as a consequence endothelial damage.

It is now recognized that the oxidative modification of proteins by reactive species, especially ROS, is implicated in the progression of an important number of diseases. Compared to control samples, proteins are more oxidized in tissues of animals and patients suffering from many of the age-related diseases. Cardiovascular diseases show a significantly elevated mortality in elderly patients and have been associated with endothelial cell injury. Furthermore, cardiovascular diseases have been proven to cause a decline in endothelial function. In addition, oxidized proteins have been demonstrated to be a critical contributor to the development of atherosclerosis, contributing to the formation, progression, and complications of atherosclerotic plaques. Noteworthy, in another study, oxidized proteins lead to endothelial dysfunction. As a result, there is great interest in studying new target therapies to prevent or reverse the aging-induced oxidative stress in endothelial cells.

The mechanism by which endothelial cells undergo senescence is still largely unclear and yet to be discovered. Although this mechanism probably involves a multifactorial response, oxidative stress has been proposed as a mediator to explain the process of cellular senescence. Oxidative stress is characterized by excess free radical activity and plays an important role in the oxidation of proteins. Several studies have implicated the oxidation of low-density lipoprotein (LDL) in atherosclerosis. However, there is no evidence that relates the oxidized albumin, which is the most abundant protein in serum, with endothelial injury. Therefore, in this study, we investigated whether aging induced an increase in oxidized protein and whether oxidized albumin may be involved in aging-related endothelial damage.

Endothelial microparticles (EMPs) have been used as biomarkers of cell damage and activation. These are a heterogeneous population of small membrane fragments shed from various cell types. The endothelium is one of the primary targets of circulating microparticles, and microparticles isolated from blood have been considered biomarkers of vascular injury and inflammation. In this study, oxidized albumin-treated human umbilical vein endothelial cells (HUVECs) cause the release of EMPs and an increment of apoptosis levels. These findings support the idea that the endothelial cells are suffering from an endothelial activation, which is an apoptosis phenomenon not observed with native albumin treatment. Recent evidence also suggests that the endothelial cell is damaged as a consequence of cardiovascular disease. Furthermore, released EMPs are considered a marker of endothelial damage in patients. Several studies have demonstrated that adhesion molecules are secreted by activated endothelial cells and contributed to endothelial cell injury. Supporting this, our results demonstrate an increase of VCAM-1 and ICAM-1.

In addition, other studies have indicated the increase of modification proteins may be associated with oxidative stress development in aging. In this regard, there is a wealth of data evidencing the fact that protein modifications cause ROS production. As the results showed, oxidized albumin results in ROS production increment in endothelial cells as well as in the amount of ROS per cell. The enhancement of oxidative stress is considered a key mechanism in cellular senescence development. In this study, the upregulation of ROS induced by oxidized albumin is correlated with an increase in the number of senescent cells. These data support the idea that the oxidized albumin may be considered a cardiovascular risk factor to induce oxidative stress. As a consequence, the cell may suffer senescence processes to prevent a possible damage due to oxidative stress. Research is needed to explore the possibility of utilizing oxidized albumin as a potential therapeutic target.


The staff at the SENS Research Foundation, who coordinate and carry out scientific programs aimed at speeding up progress towards rejuvenation therapies, have for some years referred to their work as a branch of regenerative medicine. When most people think of regenerative medicine, stem cell therapies to treat injuries and age-related diseases are the first thing to spring to mind, but that is just the most visible, energetic, and highly funded part of a much broader field. Wherever there is loss or degeneration in our physiology, a treatment that can even partially reverse that state of affairs, restoring some fraction of normal function to tissues, can reasonably be called a regenerative therapy.

Aging is defined by degeneration and failure. The most straightforward definition and measure of aging is that your risk of death due to intrinsic causes rises over time. Those intrinsic causes are the slow accumulation of molecular damage as a side-effect of the normal operation of cellular metabolism, and a resulting loss of function and resilience in damaged organs and systems. To pick one example, degeneration of the heart and cardiovascular system means an ever greater risk of abrupt failure and consequent death, and that degeneration can be traced back to root causes ranging from cross-links in the extracellular matrix that stiffen arteries, leading to high blood pressure and all of its unpleasant consequences, to growing numbers of senescent cells that produce inflammation and all sorts of other tissue damage, to increasing quiescence and lower rates of activity on the part of the stem cells that maintain heart and blood vessel tissues. These are degenerative changes, marked by decline. Just as delivering stem cells as a therapy can somewhat reverse the loss of tissue maintenance, a way to turn back the clock a little on some of the consequences of that issue, clearing cross-links or senescent cells will help in similar ways. These are all early forms of induced regeneration.

The article linked below skips from one end of the longevity science community, SENS rejuvenation research, to the other, attempts to modestly slow aging with existing drugs. I'm very much more in favor of the former than the latter: the costs are lower and the potential gains far larger. In the middle there is a look at regenerative medicine in the sense of cell therapies and their infrastructure, but it is interesting to see that more people are picking up on the unification of medicine now that the treatment of aging is a realistic prospect for the near future. Aging is not stuck out on the edge on its own, as something somehow out of bounds or different from the treatment of age-related disease. It is all a part of the same tapestry, and the more focus put on aging, the more likely that real progress will be made in bringing the clearly identified causes of aging under medical control.

Regenerative Medicine Comes of Age

Induced pluripotent stem cells (iPSCs) and genome-editing techniques have facilitated manipulation of living organisms in innumerable ways at the cellular and genetic levels, respectively, and will underpin many aspects of regenerative medicine as it continues to evolve. An attitudinal change is also occurring. Experts in regenerative medicine have increasingly begun to embrace the view that comprehensively repairing the damage of aging is a practical and feasible goal. A notable proponent of this view is Aubrey de Grey, Ph.D., a biomedical gerontologist who has pioneered an regenerative medicine approach called Strategies for Engineered Negligible Senescence (SENS). He works to "develop, promote, and ensure widespread access to regenerative medicine solutions to the disabilities and diseases of aging" as CSO and co-founder of the SENS Research Foundation. He is also the editor-in-chief of Rejuvenation Research, published by Mary Ann Liebert.

Dr. de Grey points out that stem cell treatments for age-related conditions such as Parkinson's are already in clinical trials, and immune therapies to remove molecular waste products in the extracellular space, such as amyloid in Alzheimer's, have succeeded in such trials. Recently, there has been progress in animal models in removing toxic cells that the body is failing to kill. The most encouraging work is in cancer immunotherapy, which is rapidly advancing after decades in the doldrums. Many damage-repair strategies are at an early stage of research. Although these strategies look promising, they are handicapped by a lack of funding. If that does not change soon, the scientific community is at risk of failing to capitalize on the relevant technological advances.

For decades, an urge to discern the secrets of unusually long-lived people has animated the work of Nir Barzilai, M.D., a researcher who is currently the director of the Institute for Aging Research at Albert Einstein College of Medicine. The Targeting Aging with MEtformin (TAME) study is focused on the concept that multimorbidities of aging can be delayed by metformin, a commonly used drug for the prevention and treatment of type 2 diabetes. Studies have demonstrated a decreased risk of not only cardiovascular disease but also cancer risk and cancer mortality in type 2 diabetic individuals taking metformin.

The TAME study hypothesis is that delaying aging is the only effective way to delay age-related diseases and compress morbidity. Sponsored by the American Federation for Aging Research, the study will recruit elderly subjects and, in a double-blind, placebo-control study, will test if metformin can put off the onset of multimorbidities including cancer, cardiovascular disease, type 2 diabetes, cognitive decline, and mortality. As the study's principal investigator, Dr. Barzilai hopes to convince the FDA to approve aging, as measured by multiple disease endpoints, as an indication. There is a great benefit for healthy lifespan, not only to the individual, but also for society in the form of cost savings, which is often referred to as the longevity dividend.


The latest edition of the Rejuvenation Biotechnology Update arrived today. This newsletter series is a collaboration between the Methuselah Foundation and SENS Research Foundation, two of the most important organizations involved in advocacy and research to speed the defeat of aging and age-related disease. The newsletter goes out to members of the Methuselah 300, a long-standing group largely made up of ordinary philanthropists of modest means. Over the years these donors have collectively helped to fund many of the important projects carried out at the Methuselah Foundation: the Mprize for longevity science; the initial set of SENS rejuvenation research programs; seed funding tissue engineering startup Organovo and senescent cell clearance startup Oisin Biotechnologies; the establishment of the New Organ prize series; and much more.

If you want to see how everyday people with entirely ordinary incomes can band together to make a real difference to progress in the sciences, look no further than the Methuselah Foundation and the Methuselah 300. This is how it is done: persuade the core supporters, build a network of connections in the research community, and make smart, targeted investments in research and advocacy. On the back of this simple formula, and with the help of hundreds of supporters, the Methuselah Foundation has played a strong role in the significant, pivotal change that has taken place in the aging research community in the past fifteen years. Over the lifetime of the Methuselah Foundation the environment has gone from one in which talking about life extension through medical science was to risk your career to one in which the leaders of the field - and pretty much everyone else - openly advocate for greater human longevity. That didn't happened by chance, and it wasn't inevitable: it took a lot of hard work, both openly and behind the scenes, to bring about this important cultural change.

One of the great secrets of our time is that early stage medical research has become very cheap over the past few decades. The pace of progress in tools and knowledge is staggering. Any number of important, small, discrete projects at the cutting edge of the medical life sciences can be accomplished for a few tens of thousands in funding, given an established lab to work with and smart young researchers to carry out the work. For a few hundred thousand in funding, a biotechnology company can be established, complete their prototype therapy, and carry out animal studies needed to attract greater investment. This is an age of communication, and research funding is in the process of becoming extremely transparent and collaborative: we can choose the projects to learn about and support, and we can see exactly what the organizations we trust to do this for us, such as the Methuselah Foundation and SENS Research Foundation, are doing with our donations. Every twist and turn of the race is there to be cheered on - and make no mistake, it is very much a race. Scientific progress and funding on the one hand, and aging on the other. We'll all win together in the best of worlds, in which rejuvenation therapies are developed soon enough, but lot of work remains in order to get to that goal. So consider joining the Methuselah 300 or donating to support SENS research programs. It is the smart thing to do.

Rejuvenation Biotechnology Update for April 2016 (PDF)

Because it doesn't take a scientist to understand the vital importance of investing in healthy life extension, these newsletters strive to report three significant studies from the past 3-6 months accessibly and approachably, describing how each one fits into the broader landscape of rejuvenation biotechnology research.

Announcing the 500,000 Vascular Tissue Challenge Under Development at NASA and Methuselah Foundation

The deadline for comments is only a few weeks away. The Vascular Tissue Challenge is a 500,000 prize purse to be divided among the first three teams who can successfully create thick, human vascularized organ tissue in an in vitro environment while maintaining metabolic functionality similar to their in vivo native cells throughout a 30-day survival period. NASA's Centennial Challenges Program is sponsoring this prize to help advance research on human physiology, fundamental space biology, and medicine, taking place both on the Earth and the International Space Station National Laboratory. The Vascular Tissue Challenge rules are currently open for public comment. If interested in this challenge, please provide your feedback. We encourage readers to attempt to submit comments even if they received this newsletter after April 15th.

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

Senescent cells have accumulated DNA damage or other abnormalities, have lost the ability to divide, and may create cancer-prone environments locally to where they reside in tissues through the secretion of growth factors, as well as may inflame the immune system through the secretion of cytokines. These cells also appear to have detrimental effects on tissues in which they reside. Senescent cells accumulate in all tissues with age and are a concern to longevity researchers; it is hypothesized that these cells contribute to aging and that removing them from an aged person could have rejuvenation effects. In this study, researchers chose a protein marker of senescent cells, and used a genetic system to induce programmed cell death in their mice when a drug was administered, but only in cells that express the marker at high enough levels to be considered senescent cells. They found that elimination of the senescent cells ameliorated the dysfunction that typically occurs with age in multiple organs and tissues, including fat, cardiomyocytes (heart), and the glomeruli of the kidney (which are involved in filtering the blood). Furthermore, the removal of senescent cells reduced early deaths in the mice and decreased the incidence of cancers, leading to an increase in median life expectancy.

This paper was met with a lot of excitement. The results are indeed impressive, showing that the normal function of several different organs - fat tissue, kidney, heart - can be restored, and healthy lifespan can be prolonged, without apparent side effects, simply by ablating a key subset of senescent cells. This study provides a clear and important piece of evidence to support the idea that senescent cells shorten lifespan, and conversely, that their elimination extends it. With this study, it became clear that, yes, eliminating senescent cells in otherwise healthy aged mice is a net benefit without any apparent downsides. Getting rid of senescent cells is one of the seven key rejuvenation biotechnologies of SENS.

Lanosterol reverses protein aggregation in cataracts.

Cataracts develop due to changes in the lens of the eye, which must be transparent and maintain its optical properties within narrow parameters for proper vision. The major protein which constitutes the lens of the eye is called crystallin, and disruptions to its structure on a molecular level can cause the normally clear lens to become opaque. Currently the only treatment option for cataracts involves surgery. The researchers in this group started by examining some families who had severe cataracts, and found that many of them carried rare gene mutations in the gene that codes for an enzyme called lanosterol synthase. This research group then found that the normal version of lanosterol synthase, but not the mutant versions, were able to prevent the mutant crystallin proteins from forming aggregates. Then they moved to an in vivo study in dogs with age-related cataracts. Cataract scores improved in the dogs treated with lanosterol eye drops.

This is a very interesting result, and of particular relevance is the in vivo portion of the study in dogs, showing that lens clarity could be improved in living organisms with real cataracts by treatment with eye drops alone, with no requirement for surgery. Lanosterol is a naturally occurring compound, which bodes well for its safety if it is effective at doses within the normal range for youthful people without cataracts, and it could potentially be very inexpensive to produce, although the actual price to consumers might be determined more by intellectual property claims and marketing factors rather than by manufacturing costs. Cataracts definitely qualify as an important disease of aging, especially when considering how much impaired vision can affect quality of life and independence.

The mechanism for how lanosterol may reverse cataracts is still uncertain. The authors suggest that the amphipathic (in-between water and oil soluble; like a detergent) nature of lanosterol could allow crystallin proteins which have undergone changes in folding/conformation to return to their normally folded state, which restores clarity of the lens on a macroscopic level. If there is a treatment that works for reversing aging damage, we don't necessarily need to know the mechanism of how it works to benefit from it. However, it might be important to link this new information about lanosterol and cataracts to what occurs in aging. Does lanosterol synthase activity decline with age? How long does lanosterol treatment keep lenses clear? More broadly, a very common theme in diseases of aging is the aggregation of proteins. Removal of crosslinked protein aggregates is one of the main planks of SENS Research Foundation's focus. Protein crosslinking and aggregation is apparently what occurs in cataracts, and according to this study may be at least partially reversible with lanosterol. Could lanosterol, or similar amphipathic molecules, be used to untangle other types of protein aggregates besides crystallin?



George Church is an important figure in the field of genetics, and in recent years has become more vocal in his support for rejuvenation research. He is presently on the advisory board of the SENS Research Foundation, and in this broad article on the near future of medical research you'll find some of his thoughts on aging research:

Aging reversal is a big project both in my lab and in one of our startup companies. This is not about wellness or drugs that affect diseases of aging, which are effects rather than causes; it's trying to get at the causes of aging and reverse them. And there are a fair number of precedents for this in animals, but the idea is to get it transferred to humans.

Reversal of aging: Some examples of this are if you take blood from a young mouse and exchange it with an old mouse. The small molecules, macromolecules, and cells in the blood result in a variety of biomarkers of aging being reversed. You can affect the vasculature, the blood vessels, the nerves, skeletal and cardiac muscles, and there are measures of these that indicate that it's not just prolonging a very aged state or going for longevity; you're actually reversing it.

This is a much better target, in any case, than prolonging longevity because, A, it takes years to decades to even prove that you have extended longevity. Also, if you've done it on somebody that's quite old, the economic consequences are dire; that's the part of your life where you spend huge amounts on medicine and don't improve the quality of life tremendously. If you can reverse it to an age where you essentially don't use any medicine, this will be much more cost effective.


Double-stranded RNA activated caspase oligomerizer (DRACO) is an antiviral technology that works by destroying infected cells rather than directly attacking viral particles themselves, thus disrupting viral replication. It has proven effective against numerous viruses, and should in principal work against near all viral infections in a broad range of species, including the many persistent viral infections that presently lack any effective treatment. The technology finds itself in a similar position to SENS rejuvenation research however, with little support from the funding mainstream, and needing to raise funds from philanthropists to bring the technology to the clinic. Potential radical improvements over the existing status quo are often in this situation, unfortunately. Following on from an initial crowdfunding effort last year, and a growing group of supporters, the Rider Institute is the latest step in the organization of fundraising and advocacy for DRACO research and development:

Currently there are relatively few prophylactics or therapeutics for viruses, and most that do exist are highly virus- or even strain-specific or have undesirable side effects or other disadvantages. We have developed a radically new, broad-spectrum antiviral therapeutic/prophylactic that has the potential to revolutionize the treatment of viral infections. Our Double-stranded RNA Activated Caspase Oligomerizer (DRACO) approach selectively induces apoptosis (cell suicide) in cells containing viral double-stranded RNA (dsRNA). DRACO should recognize virus-infected cells and rapidly kill those cells without harming uninfected cells, thereby terminating the viral infection while minimizing the impact on the host.

When tested in human and animal cells, DRACOs have been nontoxic and effective against 18 different viruses, including rhinovirus (the common cold) and dengue hemorrhagic fever. We have also demonstrated that DRACO is nontoxic in mice and rescues mice from lethal challenges with H1N1 influenza, Amapari arenavirus, Tacaribe arenavirus, and Guama bunyavirus in preliminary trials.

DRACO research has entered what is known as the "Valley of Death." Modest amounts of funding from the National Institutes of Health have enabled the previous proof-of-concept experiments in cells and mice, but that funding grant is now over. Major pharmaceutical companies have the resources and expertise to carry new drugs like DRACO through the manufacturing scale-up, large-scale animal trials, and human trials required for FDA approval. However, before committing any of their own money, those companies want to see that DRACOs have already been shown to be effective against major clinically relevant viruses (such as members of the herpesvirus family), not just the proof-of-concept viruses (such as rhinovirus) that were previously funded by NIH. Thus the Valley of Death is the financial and experimental gap between the previously funded NIH proof-of-concept experiments and the threshold for convincing major pharmaceutical companies to advance DRACOs toward human trials.

We are now raising funds to test and optimize DRACOs against the herpesvirus family, which contains many major clinical viruses such as Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), Cytomegalovirus (CMV), Varicella Zoster Virus (VZV, chickenpox and shingles virus), Epstein-Barr Virus (EBV), and Kaposi's Sarcoma Herpesvirus (KSHV). If we can raise enough funding, we also hope to test and optimize DRACOs against the family of retroviruses, which includes Human Immunodeficiency Virus (HIV) and Human T-Lymphotropic Virus (HTLV). In principle, the DRACO approach should be effective against virtually all known viruses, or potentially even against new viruses that may appear.

This campaign has been set up to raise the funding necessary to bridge the Valley of Death for DRACO research. With your assistance, we hope to raise enough funding to provide a total of 2 million over four years, in order to test and optimize DRACOs against clinically relevant viruses in human cells. If successful, the results of those experiments should persuade pharmaceutical companies and other major sponsors to commit their own resources to advance DRACOs through large-scale animal trials and hopefully human trials. Without your assistance, DRACOs may never progress further, and their potential to revolutionize the treatment of viral infections may remain unfulfilled.


There is considerable growth in omics fields deriving from slices of proteomics, the study of the proteome, the proteins generated by a cell, and genomics, the study of the genome, the DNA that encodes those proteins. This means that the naming convention these days for areas of interest in molecular biochemistry, a particular subsection of the overall set of genes and proteins, is to coin new portmanteau terms ending in -ome and -omics. So here we have an open access paper that attempts a start on unifying on the one hand programmed aging theories in which aging is caused by genetic programs and on the other hand the more mainstream views on aging as an accumulation of damage that occurs as a side-effect of the normal operation of metabolism. In this paper the conceptual collection of genes, proteins, and alterations relevant to the regulation of aging or damage of aging are termed the deleteriome - relating to deleterious changes.

Different theories posit that aging is caused by molecular damage, genetic programs, continued development, hyperfunction, antagonistic pleiotropy alleles, mutations, trade-offs, incomplete repair, etc. Here, I discuss that these ideas can be conceptually unified as they capture particular facets of aging, while being incomplete. Their respective deleterious effects impact fitness at different levels of biological organization, adjusting progression through aging, rather than causing it. Living is associated with a myriad of deleterious processes, both random and deterministic, which are caused by imperfectness, exhibit cumulative properties, and represent the indirect effects of biological functions at all levels, from simple molecules to systems.

From this, I derive the deleteriome, which encompasses cumulative deleterious age-related changes and represents the biological age. This term encompasses molecular damage, consequences of additional deleterious processes, as well as increased disorder at all levels, from simple molecules to cells and organs. The organismal deleteriome consists of the deleteriomes of cells, organs, and systems, which change along roughly synchronized trajectories and may be assessed through biomarkers of aging. Aging is then a progressive decline in fitness due to the increasing deleteriome, adjusted by genetic, environmental, and stochastic processes.

Contributions of various factors to biological aging can be illustrated by the metaphor of an aging car. Here, the length of an organismal lifespan is analogous to the mileage driven over the car's lifespan. It is influenced by the make/model of the car (analogous to the effects of genetics) and road conditions, weather, and fuel quality (representing the effects of environment). Better built cars, like better road conditions, milder weather, and better fuel, will be associated with longevity. In addition, random processes influence lifespan. These stochastic events include internal processes of the car leading to damage accumulation, gradually increasing the chance the car breaks, as well as random events associated with driving (stopping, accelerating, turning, accidents, etc.). For example, a car driven on highways is expected to accrue more miles than when it is driven in city. Likewise, biological aging is influenced by genetics, which is a major contributor when aging is considered across species and genetically heterogeneous populations, environment, and stochastic processes.

As the deleteriome consists of diverse forms of damage and other deleterious processes, it is currently not accessible in its entirety. Difficulty in measurement notwithstanding, the deleteriome may be viewed as a measure of biological age of the cell, organ, or system. This implies that the best markers of aging would be the measures of the deleteriome. Such markers have not been well defined, as the focus of previous research has been on particular age-related changes, such as telomere length, oxidative damage, and expression of a limited number of genes. But such limited assays would be misleading in representing organismal aging and comparison across organisms and cell types. However, recent research shows that the candidate markers that best represent the deleteriome, because they include measurements of many diverse age-related parameters simultaneously, for example, genomewide epigenetic changes, mutations, nontargeted metabolite profiling and gene expression, offer the best predictive models of the progression through aging.


Among the less attractive aspects of human nature are a fixation with what is rather than what can be, the tendency to limit the definition of success and desired outcomes to whatever the best of the present options might be, and a burning desire to tear down those who have more than you rather than work to create more for everyone. Even in an age of rapid, radical change driven by advancing technology, the vast majority of people focus entirely on the distribution of present assets and opportunities, giving little to no thought to the much larger set of assets and opportunities that we could create for tomorrow.

You see this in the vastly greater attention given to any evidence for distributions and correlations in life expectancy between populations today, and the tiny amount of attention and support given to the production of rejuvenation therapies to greatly increase life for everyone at a modest cost. Given the realization of SENS rejuvenation treatments, the first of which are already under development in startup companies, and most of which will take the form of comparatively low-cost, mass-produced infusions, ten year variations in longevity due to lifestyle choices or access to medicine will be swamped, made irrelevant and small.

The study shows that in the U.S., the richest 1 percent of men lives 14.6 years longer on average than the poorest 1 percent of men, while among women in those wealth percentiles, the difference is 10.1 years on average. Over roughly the last 15 years, life expectancy increased by 2.34 years for men and 2.91 years for women who are among the top 5 percent of income earners in America, but by just 0.32 and 0.04 years for men and women in the bottom 5 percent of the income tables. In addition to reporting the size and growth of the income gap, the study finds that the average lifespan varies considerably by region in the U.S. (by as much as 4.5 years), but that the sources of that regional variation are subtle, and, like the aggregate national gap, subject to further investigation. That regional variation in longevity does not seem strongly correlated with factors such as access to health care, environmental issues, income inequality, or the job market. "We don't find those to be as highly correlated with differences in longevity as we find measures of health behavior, such as smoking rates or obesity rates."

The researchers looked at 1.4 billion anonymized income tax filings from the federal government, and combined that with mortality data from the years 2001 through 2014 from the Social Security Administration. This represents the most complete geographic and demographic landscape of mortality in America. Among other things, the growth of the gap in mortality rates - by nearly three years - struck the researchers as noteworthy. To put it in perspective, they note that federal health officials estimate that curing all forms of cancer would add three years to the average lifespan. At the same time, the researchers are quick to point out that the findings cannot immediately be reduced to simple cause-and-effect explanations. For instance, as social scientists have long observed, it is very hard to say whether having wealth leads to better health - or if health, on aggregate, is a prerequisite for accumulating wealth. Most likely, the two interact in complex ways, something the study cannot resolve.

A new puzzle emerging from the study, the authors note, is that differences in lifespan exist along the entire continuum of wealth in the U.S.; it is not as if, say, the top 10 percent of earners cluster around identical average lifespans. "As you go up in the income distribution, life expectancy continues to increase, at every point." And then there are the new geographic patterns in the findings. For instance: Eight of the 10 states with the lowest life expectancies for people in the bottom income quartile form a contiguous belt, curving around from Michigan through Ohio, Indiana, Kentucky, Tennessee, Arkansas, Oklahoma, and Kansas. So while average lifespans for everyone are lower in some Southern states, the poor do not fare worse in those places than they do in other regions. "The Deep South is the lowest-income area in America, but when we're looking at life expectancy conditional on having a low income, it's not worse to be poor in the Deep South than it is in other areas of America. It's just that there are far more poor people living in the South."


Researchers here suggest that regenerative therapies for the heart need to specifically address the lymphatic system in addition to the normal targets, as lymph drainage is as impacted as other processes following a heart attack, and this contributes to the harms done:

Although the blood system is the first to have been explored for the purpose of improving heart function, a study has revealed the potential of a secondary system that had previously received scant attention. The researchers analysed the heart lymphatic system in an animal model. They showed that this system was highly impaired following a myocardial infarction. Using a biotherapy based on the injection of microparticles, they succeeded in regenerating lymphatic vessels in a targeted manner. This treatment promotes lymphatic drainage, thus limiting post-infarct oedema and inflammation. Heart function is thereby improved.

When the heart is no longer able to provide an adequate blood supply to meet the body's needs, we speak of heart failure. This is due to an abnormality of the heart muscle that may be associated with injuries, a filling defect associated with a lung disease, deformation of the heart valves, etc. Fatigue, breathlessness and oedema are the main symptoms. While the blood system is involved in supplying blood to the organs and providing them with oxygen and nutrients, the lymphatic system transports fluids together with cells of the immune system, and drains away cellular wastes. The heart lymphatic system is especially well developed, but its role in cardiovascular diseases had received very little attention until now.

The research team used biodegradable microparticles, containing growth factors, previously developed during work on the creation of blood vessels. The researchers injected rats with a new biotherapy agent, based on the release of an encapsulated growth factor specific for lymphatic vessels (VEGF-C). "When administered to rats, the treatment accelerates the post-infarct cardiac lymphangiogenic response, and improves the lymphatic drainage of the heart in 3 weeks. As a direct effect, it reduces cardiac oedema, inflammation and fibrosis. This work, the result of 4 years of research, shows the strong involvement of this system in cardiovascular diseases. Indeed, research on these lymphatic vessels has only been developed in the last 10 years at most, and their role in physiopathology is often ignored." Lymphangiogenesis (the process that guides the formation of lymphatic vessels) thus represents a significant new therapeutic approach to explore in cases of heart failure and myocardial infarction.


A research team investigating the mechanisms of regeneration has assembled the TiRe (Tissue Repair) database, a catalog of genes known to be involved in skin healing in a variety of mammals. There are several hundred such genes at this point, indicative of the complexity of the processes involved. Among the questions explored in this open access paper is whether or not more rapid healing corresponds with greater longevity in, for example, genetically varied lineages of laboratory mice: is there any overlap in the genes known to be relevant in healing and aging, and what exactly do those relationships mean?

Wound healing is an inherent feature of any multicellular organism and recent years have brought about a huge amount of data regarding regular and abnormal tissue repair. Despite the accumulated knowledge, modulation of wound healing is still a major biomedical challenge, especially in advanced ages. Some species from diverse taxa (such as salamander, axolotl, hydra, and several others) and early mammalian embryos are able to fully regenerate damaged tissues/organs. In mammals, however, this ability is drastically reduced after birth and continues to decline with age. For most organs, this reduced regenerative capacity is in fact a normative response, favoring speed over functional restoration, so that regular tissue repair results in scar formation. Deviations from regular tissue repair may lead to diverse pathological conditions, from slow or ineffective wound healing to hyper-fibroproliferative responses, both of which are often observed in advanced ages. Thus, factors that govern tissue repair are strongly associated with aging and age-related pathologies, and as such are potential targets for intervention in aging.

Is accelerated wound healing "good" for longevity? In an attempt to address this question, we have compared the list of wound healing-associated genes (WHAGs) with those reported as being involved in the control of lifespan. The comparison yielded 17 genetic mouse models of extended lifespan (longevity phenotype), or reduced lifespan (premature aging phenotype), which were also tested for skin wound healing. It is important to note that many studies used the rate of skin wound closure as a biomarker, assuming a priori that slower skin wound healing is indicative of an aging phenotype. Yet, our analysis shows that a slower or faster skin wound healing is indicative of an aging or longevity phenotype, respectively, only when assessed in advanced ages, but not in the young. For example, Agtr1a knockout resulted in slower wound healing in young mice but also in an extended lifespan. In contrast, Cav1 knockout, which accelerated wound closure, was accompanied by reduced longevity.

This means that pro- or anti-longevity effects of genetic interventions manifest in accelerated or delayed skin wound healing only in advanced ages, but not in young animals. Moreover, it seems that the association between the rate of wound healing and longevity is primarily attributed to an overall effect of the target gene on organismal aging rather than to its skin-specific action. This assumption is strongly exemplified by our study on the long-lived ╬▒MUPA mice, which preserve their skin wound healing capacity up to an old age (at least 25 months). In this unique model, the uPa transgene is expressed in the ocular lens and the brain stem but not in the skin, thus excluding the gene-specific effects on wound healing. Overall, the results emphasize that the age factor should be taken into account when evaluating the links between skin wound healing, aging and longevity.

To better understand these links, including older animals in the analysis is encouraged while using only young animals might yield confusing or misleading results. In particular, the opposite effect between the rate of skin wound healing in young age and the effect on life span could be explained by the links between wound healing and cancer, and the role of cancer in the determination of mouse longevity. Indeed, cancer has been considered as "an overhealing wound". This could be especially relevant to mice as cancer is the main cause of death for a variety of murine strains. For example, Tert overexpression in the young leads to accelerated wound healing, a high incidence of cancer, and increased mortality. Another example is the tumor suppressor gene Pten, known to negatively regulate the activity of the PI3K/mTOR pathway, which is involved in various cancers. Knockout of this gene resulted in accelerated wound healing in young age but a decreased lifespan, which is most likely associated with increased tumorigenesis.


This article profiles Samumed, who are producing regenerative therapies based on manipulation of Wnt signaling, presently at various early stages in the pipeline. Wnt signaling is implicated in cancer, aging, and regeneration, but like many protein networks it is involved in a large number of very fundamental cellular processes, making precise control of outcomes a challenge. This is something that the Samumed researchers claim to have solved to a large enough degree to produce drugs that target this pathway, with Wnt-based regenerative treatments in the works for a range of tissues:

Samumed has raised 220 million and is halfway through raising another 100 million. The target Samumed researchers went after was obvious: a gene called Wnt, which stands for "wingless integration site," because when you knock it out in fruit flies, they never grow wings. It's a linchpin in a group of genes that control the growth of a developing fetus - whether you're a fly or a person. Together these genes are known as the Wnt pathway. Trigger the right ones and you might revive old flesh. Some cancers do their dirty work by hijacking Wnt, and blocking it might stop tumors. Most other researchers who had searched for Wnt drugs used one of biomedicine's workhorses: a cell line derived from an aborted fetus in the Netherlands in 1973. Those fetal cells are easy to use in the lab, but over the intervening decades they have become very different from normal cells in humans. The Samumed team opted to look for drug targets in colorectal cancer cells that expressed Wnt, comparing them with healthy colon cells that didn't. It took almost three years. Exactly what did they find? Samumed isn't quite saying. Normally a patent explains which chemicals a drug targets. But in 2013 the Supreme Court said that genes aren't patentable, a ruling Samumed interprets as saying the company can have its patents while keeping those biochemical pathways under wraps.

What the company will show is the animal and human data for its baldness and arthritis treatments. In mice and mini-pigs that have had hair removed, it grows back. Experiments in arthritis involve cutting the ligaments in the knees of rats so that the cartilage is destroyed. Samumed's drug regrows the cartilage, and the rats can walk again. So what happens in people? In March Samumed presented data on the use of its baldness drug, code-named SM04554, in 300 patients. Hair-loss specialists who saw the data were not blown away. Those results aren't big enough to be certain they're not occurring by chance or that men will really feel that the product is making their hair grow back. When it comes to Samumed's valuation - and medicine as a whole - the arthritis data are far more important. The largest study of Samumed's arthritis drug, SM04690, included only 60 patients. Even for small numbers the results line up alluringly: Patients who got SM04690 scored better than those on placebo on two questionnaires that measured how well they functioned and whether their pain improved. On X-rays of patients' knee joints, the space between the bones seemed to have increased, indicating cartilage might really have grown back. Still, again, even Samumed's own consultants say the data are preliminary. More proof will come from a 445-person trial that Samumed aims to complete by the end of the year.

Viewed under the microscope, Samumed looks like a company with a pair of drugs that have not been proved and, if trends in drug discovery hold true, will probably not make it to market. But its investors obviously see something far more wonderful, world-changing and potentially lucrative. If these drugs work, it becomes a better bet that some of Samumed's other medicines will work, too. There's a treatment for scarring of the lung, known as idiopathic pulmonary fibrosis. And for macular degeneration, which causes blindness.


A developmental process responsible for fine-tuning nervous system connections to muscle fibers may inappropriately reactivate in later life, becoming an important contributing cause of the characteristic loss of muscle strength and control that occurs in aging:

Proteins in the family MHCI, or major histocompatibility complex class I, "prune" the connections, or synapses, between motor neurons and muscle fibers. Pruning is necessary during early development because at birth each muscle fiber in humans, mice and other vertebrates receives signals from dozens of neural connections. Proper motor control, however, requires that each muscle fiber receive signals from only a single motor neuron, so without the pruning carried out by MHCI proteins, fine motor control would never emerge. It is not known why more synapses are made during development than are needed. One possibility is that it allows the wiring diagram of the nervous system to be precisely tuned based on the way the circuit is used. MHCI proteins help limit the final number of connections so that communication between neurons and muscles is more precise and efficient than would be possible using just a molecular code that produced a set number of connections.

Researchers also found that MHCI levels can rise again in old age, and that the proteins may resume pruning nerve-muscle synapses - except that in a mature organism there are no extra synapses. The result is that individual muscle fibers become completely "denervated," or detached from nervous system control. Denervated muscle fibers cannot be recruited during muscle contraction, which can leave older people weaker and more susceptible to devastating falls, making independent living difficult. However, the researchers discovered that when MHCI levels were reduced in mice, denervation during aging was largely prevented. The mice actually lacked a protein known as beta-2 microglobulin, which forms a complex with MHCI and is necessary for MHCI expression on the surface of cells. This could be beneficial from a clinical perspective because beta-2 microglobulin is a soluble protein and can be removed from the blood. "Our studies raise the possibility that targeting one protein could help with both motor and cognitive aspects of aging." Because MHCI proteins are important in the immune system, however, such an approach could result in compromised immunity. Future work will include exploring the effectiveness of other approaches to reducing the proteins' synapse-eliminating activity in older nervous systems, ideally while leaving their immune functions intact.


Researcher S. Jay Olshansky is one of the principals behind the Longevity Dividend initiative, a long-running lobbying and advocacy initiative that seeks to push a great deal more government and philanthropic funding into aging research. The specific focus is on modestly slowing aging via near term interventions with the goal of adding five to seven years to healthy life spans over the next few decades, something I regard as far too unambitious. The TAME metformin study is an example of the Longevity Dividend portfolio, for example. Olshanksy is perhaps the canonical example of a researcher who advocates for longevity science, but thinks that radical life extension of decades or more or the outright defeat of aging is not achievable within our lifetimes, and doesn't think that the SENS approach of damage repair is any better than the mainstream approach of slowing aging. His views are well known within the research community, but it is always interesting to see him talk informally on this topic:

I study the upper limits of longevity and ask which populations are living longer and why, and what that means for society. Living a longer life is a monumental achievement of public health and modern medicine - it is exactly what we set out to achieve more than a hundred years ago when life was short. More people today are living to 65, 85, and 100 and beyond than ever before, but it has created a Faustian trade. In exchange for our longer lives, we now live long enough to experience heart disease, cancer, sensory impairments, and Alzheimer's disease. The fact is that our bodies were not "designed" for long-term use. While improved lifestyles can enhance health and quality of life, the aging process marches on unaltered beneath the surface - leading to the diseases and disorders we fear most. My research focuses on investigating ways to extend the period of healthy life and compress sickness and disease as much as possible to the very end. Recently I have teamed with a group of researchers to study the ability of the diabetes drug metformin to do just that; although metformin is just one of many research pathways scientists are pursuing to slow biological aging. My research suggests that slowing down aging will be the next great public health advance in this century because it targets multiple age-related chronic diseases. Importantly, this approach to public health can save far more health care funding than treating one disease at a time. The time has arrived to take a new approach to chronic fatal and disabling diseases.

When will an aging intervention come online? No one can know the answer to this question in advance since it takes years to study the safety and efficacy of potential interventions. However, we're no longer talking about something theoretical here. We can observe decelerated aging today in people that, in many cases, may be your friends, relatives, or even yourself. Centenarians today are in all likelihood living that long because their bodies and minds are not really 100+ years old - they might very well be 10, 20 or even 30 years younger. Scientists are studying the genetics of these long-lived subgroups in order to discover (and perhaps recreate) their genetic advantage for the rest of us. It's an exciting time to be involved in aging science, and I'm optimistic that an intervention that slows aging in people will arrive in time to positively influence most people alive today. However, the short answer is no, we're not ready for metformin as the next equivalent of a baby aspirin. We can't know the answer to this until the research is done and the data thoroughly analyzed. While I would encourage everyone to remain excited about this work, keep in mind that no intervention of this kind should be taken today without approval and evaluation by your personal physician. There is a tendency in this field for the entrepreneurs to try and take over as soon as the science offers a glimmer of hope, so I would urge extreme caution. In the interim, please try and help out the world of aging science by following the work and encouraging the effort.

By 2050 I'd be surprised if we could achieve anything more than a few years of additional healthy life, even with a breakthrough in aging science. This may not sound like much, but keep in mind that in long lived populations, it takes very large reductions in death rates to achieve even a 1 year increase in life expectancy. A 1 year increase in healthy life expectancy is even more difficult to achieve. My personal view here is that if we continue with the current medical model of attacking one disease at a time, we will not see an extension of healthy, but instead, the exact opposite - a prolongation of the period of frailty and disability. This is the very reason we're working so hard now to change the culture of thinking on this topic.

The idea that the first person to live to 150 or 200 or 1,000 or 10,000 years has already being born is hype cooked up by some who want to advocate for radical life extension. All of these numbers are made up out of thin air - they're designed to get the attention of the media, and frankly, this makes it more difficult to get funding for aging science because funders have no interest in creating a new set of challenges that would come with people living for hundreds or thousands of years. Keep in mind that life extension is not the primary goal of aging science; health extension is the primary goal. Aubrey de Grey is a friend, but we do have healthy disagreements. We need this kind of open dialogue in science, and it should be conducted with respect and decorum. Having said that, don't expect radical life extension any time soon. Think about it for a moment. Even if you had an intervention in hand that could make people live for 1,000 years, how could anyone prove that using the tools of science? You would have to wait for 1,000 years to make that statement, which is why I say that anyone making these claims is making up numbers out of thin air. The fact is, even if a genuine magical elixir found its way into anyone's lab, the scientist who discovered it wouldn't know its effect - even if the intervention could talk and declare its effectiveness. Our goals in aging science must be measurable using the tools of science!

I've listened to my friend Aubrey de Grey speak many times. He's quite good, right up until the last 15 minutes when he starts talking about escape velocity and 1,000 year lifespans and made up numbers. It's somewhat difficult to ignore the very point that Aubrey emphasizes. With regard to his effort to reverse or repair the damage caused by aging rather than delaying it, I'm hopeful that he's right. No one can know whether his approach will work until it's tested, which is what I like about Aubrey. He's not selling anything yet - he's operating within the bounds of science and setting forth testable research hypotheses. I think Aubrey's work, or at least the 7 deadlies idea he supports, should be one of the projects pursued by the Longevity Dividend Initiative, but like everyone else, this science would have to survive peer review.

I'm actually pleased that Google's Calico and Venter's Human Longevity have come into the mix. Competition is good; the presence of funds to accelerate aging is good; there are a lot of outstanding scientists already in this field, and I expect we'll soon attract many more. It's the next great frontier of human biology. Having said that, I'm very careful about claims that are made here, which is why I shy away from exaggeration and I think the rest of us should as well. Someone will eventually develop a breakthrough in the field, and when that happens, it will fundamentally change the way in which we think about aging, disease and longevity. Someone will win the race, and perhaps there will be more than one winner, but when that happens, we all win. The fact that there is a race at all is what is so exciting now. While I don't expect 120 is in the cards, I do expect many of us to benefit from an intervention that extends our healthy life and preserves our youthful vigor for a longer period of time. I expect the competition to go on even after the first intervention makes its way into the marketplace. I see a healthy sector moving forward.

This may very well become the next great public health paradigm - we made the case for this in 2008. We are in fact going to high net worth individuals with the suggestion that they can get in on the ground floor of what could prove to be one of the most important accomplishments in medicine in the modern era. Just as Bill Gates has made his impact in public health by attacking infectious diseases in the developing world - and there are very few examples like this - we expect someone to step up to the plate and make a declaration just like President Kennedy did years ago when he decided to send someone to the moon and return them safely. The time has arrived to fundamentally change the way in which we attack disease, and once done, it's fairly easy to make the case that the modern era will have witnessed one of its greatest accomplishments. I don't think the money for this effort will come from governments (not enough funds and too slow); it's going to come from a high net worth individual with a vision and the funds to back it up. The question now is, who will it be?


Researchers recently published evidence for variants in the FOXO3 gene to correlate with modestly reduced mortality due to cardiovascular disease. FOXO3 is one of the very few longevity-associated genes in which the statistical associations have been replicated in different human study populations. In the vast majority of cases there is no replication, which suggests that the genetic contribution to longevity is very complex, made up of thousands of individually tiny contributions that strongly interact with one another and environmental circumstances. This effects in one group of people do not appear in another, even within the same region and heritage:

FoxO3 is an evolutionarily conserved transcription factor in the insulin signaling pathway. It regulates expression of genes controlling a multitude of processes that could enhance health and lifespan. A previous study of American men of Japanese ancestry was the first to find an association of three single nucleotide polymorphisms (SNPs) of FOXO3 with human longevity. The association was replicated in 11 other independent studies of populations of diverse ancestry. The mechanisms by which the protective alleles reduce mortality to promote human longevity are also not known. Identifying the cause of death in longevity-allele carriers vs. noncarriers may provide clues as to why FOXO3 SNPs strongly protect against mortality.

We hypothesized that the longevity-associated FOXO3 genotype would be associated with a sizable risk reduction for mortality and with one or more major age-associated clinical causes of death, such as coronary heart disease (CHD), cancer, and stroke. To test this hypothesis we utilized an extensive, prospectively collected dataset from our long-lived cohort of American men of Japanese ancestry, well characterized for aging phenotypes, drawn from the Honolulu Heart Program prospective cohort study. We genotyped this study population to prospectively assess the following: (i) the effect size of the protective (longevity-associated) FOXO3 genotype on total (all-cause) mortality in 17 years of follow-up; and (ii) the effect of the protective FOXO3 genotype on cause-specific mortality. We then attempted a replication of major findings in a suitable cohort of elderly white and black Americans of both sexes in the Health Aging and Body Composition cohort study, which had 17 years of follow-up.

we demonstrated a large (10%) protective effect against all-cause mortality and 26% for CHD mortality over 17 years of follow-up. The protective effect was, moreover, observed in three genetically different populations. Our study contrasts with the vast majority of prior investigations of FOXO3 variants and longevity, which have been case-control studies that did not quantify risk over time, but rather simply tested for association with an outcome. The magnitude of the impact of an absence of the protective FOXO3 G allele was comparable to the increase in risk of death from smoking a pack of cigarettes a day for 25 years in Japanese men. In black males and females, it was equivalent to having a 20 mmHg higher systolic blood pressure, and in white men and women to a 20 mg dL-1 elevation in fasting blood glucose. The data suggest a possible mediator role for hypertension, which we found to be less prevalent in middle-aged women carrying the FOXO3 G allele.


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