The Methuselah 300 Monument is Unveiled
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The Methuselah Foundation has unveiled the Methuselah 300 monument in the US Virgin Islands, a lasting record of the generous donors of the Methuselah 300 who have helped fund the work of the Methuselah Foundation over the past decade: the M Prize for longevity science; the seed funding of bioprinting company Organovo; the SENS rejuvenation research programs and creation of the SENS Research Foundation; the launch of the New Organ prize series; and much more.

The Methuselah Foundation was the first longevity science initiative that I chose to materially support with my donations and my time. The third post I wrote here at Fight Aging! back in 2004 covers the just-getting-started initiative of the Methuselah 300: aiming to find a group of regular donors to contribute to bold initiatives in aging research. It was an ambitious plan at a time when raising funding to accelerate progress towards rejuvenation therapies was near unheard of, mocked by the press and the scientific establishment where it did happen, and all in all considerably harder than it is today. But why is it now easier to raise funds for rejuvenation research, and why is it now the case that up and coming scientists can talk seriously about treating aging without risking reputation and career? In large part because the Methuselah 300 worked, people joined in to a degree not seen in earlier initiatives with similar aims, the Methuselah Foundation became a going and influential concern within the small aging research community atop the foundation provided by 300 member donations, and the staff and allies of the Methuselah Foundation went on to change the culture of that community, spinning off the SENS Research Foundation along the way, having a hand behind the scenes in many important activities and decisions.

This is something like the eleven thousandth post at Fight Aging!, and a decade has passed since the first member of the Methuselah 300 sent in the first donation to help fund the then small M Prize for longevity science. The reasons for joining the 300 are just the same as they were back then, with the additional guarantee that now it isn't a step into the unknown. You might read Michael Rae's call to action from that time, for example. Joining the Methuselah 300 is a way to make a real difference to the future of health and aging, to materially support an organization with a proven track record of getting things done in longevity science. Just this year, for example, the Methuselah Foundation joined with the SENS Research Foundation in providing seed funding to Oisin Biotech, a startup company aiming to build a viable senescent cell clearance therapy, a technology we hope to see reach the clinic in the near future, the first true rejuvenation therapy capable of removing some of the damage that causes aging and age-related disease.

The Methuselah 300 Monument

In 2005, The Methuselah 300 initiative began with a few brave and dedicated people willing to fight for life itself. These individuals are now honored by a monument in St. Thomas. Their story is presented by the founders of the Methuselah Foundation in the following video. In it, we pay tribute to their continued courage and generosity, which fuels the real hope for extended healthy human life.

Will you join the legacy?

Methuselah Foundation Announces the Official Unveiling of the Methuselah 300 Monument

In 2003, the Methuselah Foundation was formed to take action on a remarkable idea: that the world's greatest scientific and medical minds, given the right spark of innovation, could bring about sweeping changes in the longevity and quality of life for people everywhere. Exciting and innovative ideas find like minds, and the Methuselah Foundation moved quickly to encourage innovative creativity in the fields of medical and longevity research. With the establishment of the first "M Prize", scientific researchers saw this prize as an opportunity to be rewarded for results rather than just research itself, and teams of scientists and doctors began to get on board.

None of this was accomplished alone. Integral to the Methuselah Foundation and it's work are the men and women who early on saw the amazing possibilities the foundation's work could accomplish. These men and women were the foundation of a collective group that came to be known as the 300. Since 2005, 150 dedicated men and women have committed to giving $25,000 over 25 years to help us eradicate needless suffering and extend healthy human life. In the over 10 years since the foundation was formed with the help of these ones, research has reached the point that things once considered impossible are now on the horizon; advances like bio-printing organic material, and the organic generation of new organs.

In the foundation's desire to thank the selfless compassion and generosity of this group who continues to make these things possible, we are pleased to announce the official unveiling of the Methuselah 300 Monument! Just as the original 300 Spartans were later memorialized in a monument at Thermopylae, we have memorialized our own 300 with a unique monument located on a breathtaking hillside in St. Thomas in the U.S. Virgin Islands. The monument total size including surround is 9 feet wide x 17 feet long, and the granite plaques are 4 feet wide by 10 feet long. This monument will draw attention to those who generously give so that other's lives may be extended, or have their quality of life raised by the research the Methuselah foundation continues to inspire and encourage. The monument will be available for all to see by webcam at anytime; seeing not only the names already inscribed, but also the names of future 300 members to be added.

We would also like to extend the invitation for you to become a member of the 300, or support the foundation's work to whatever extent you are able. We will continue working to accomplish our goal of "making 90 the new 50 by 2030"! Will you join us?

Triple Matching of SENS Donations on Giving Tuesday, Coming Up on December 1st
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Giving Tuesday is the Black Friday of the non-profit world, a collaborative event organized across the whole of the non-profit community in which activists and advocates raise awareness, coordinate activities, and inform the decisions that people make about charitable donations at the end of the year. This year Giving Tuesday falls on December 1st. As I'm sure you're all aware, we're in the midst of raising funds for SENS rejuvenation research, the best and most effective of initiatives aimed at bringing aging under medical control. We have a little under $60,000 to go before the end of the year to hit our targets, and I'm pleased to note that if you donate to the SENS Research Foundation on December 1st your donation will be matched threefold - by the Fight Aging! matching fund, the Croeni Foundation, and Aubrey de Grey:

SENS Research Foundation is getting ready to celebrate #GivingTuesday on December 1st. GivingTuesday is now a global event celebrated by supporters of various charities giving to their favorite causes. If you've been planning on contributing to the fight against age-related disease this year, GivingTuesday is a great opportunity to make a difference.

So far, SENS Research Foundation has 3 matching grants set up for GivingTuesday. The first is our FightAging! Challenge which will match every dollar you give us up to $125,000. On GivingTuesday, the first $5,000 we raise will not be doubled or even tripled - it will be quadrupled thanks to the generosity of the Croeni Foundation and Aubrey de Grey. Help us turn $5000 into $20,000 and accelerate the fight against age-related diseases! Donate at on December 1st.

Seize this chance to make a real difference in the future of human health and longevity! The staff and allies of the SENS Research Foundation have demonstrated over the past decade that they can produce real, meaningful results with our donations, pushing forward the state of the art closer to the realization of effective therapies for aging. The potential to fundamentally change the world of medicine is very real: those of us yet to be old have a shot at ensuring that treatments arrive soon enough to prevent us from suffering age-related pain, disability, and frailty. The causes of aging, well-cataloged forms of cell and tissue damage, can in principle be repaired, and the path to doing so is just about as clear as research and development can ever be.

This is the time for it. We stand in the initial years of a revolution in the capabilities and cost of biotechnology. Early stage research in the life sciences has become very cheap; a few tens of thousands of dollars can go a long way in an established laboratory, producing real progress at the cutting edge when spent wisely. Yet much of the necessary, revolutionary work in aging research is only funded by philanthropy, as traditional funding institutions are risk-averse and don't become involved until the prototypes are built, the case proven. In essence all important progress in medicine depends on the early participation of people like you and I, who are both aware of the possibilities, and interested enough in the outcome of greater healthy longevity to help make it happen.

For most people, medical research is invisible. They'll never read about it, never think about it, until it is too late to have made a difference that mattered. Reading this, you have a chance to avoid that scenario. The more that is done now to start the avalanche of rejuvenation biotechnology development, the greater the results decades from now, at a time when aging is encroaching upon your health. Don't let this opportunity slip away: help fund the work of the SENS Research Foundation on the scientific basis needed to bring an end to degenerative aging.

Transthyretin Amyloid May Contribute to the Progression of Cartilage Damage and Osteoarthritis
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Earlier this year researchers published evidence suggesting that rising levels of transthyretin (TTR) amyloid may contribute to age-related damage to cartilage tissue in joints and consequent development of osteoarthritis. Amyloids of various types accumulate in tissue with advancing age, each resulting from a different misfolded protein whose altered properties in that state cause it to form solid deposits. The biochemistry of this process is different in each case, and usually complex and incompletely understood. You don't have to look any further than the field of Alzheimer's research and the still dominant amyloid hypothesis to see that investigations of amyloid biochemistry are enough to keep most of a sizable scientific industry busy for decades. Knowledge of amyloid-β has grown in proportion to the funding and attention directed to the Alzheimer's research community, but for many of the other forms of amyloid it isn't entirely clear as to exactly how their presence contributes to the age-related conditions that correlate with the presence.

In some cases this is because the data is still arriving: researchers were not looking in the right place, or not paying enough attention, or lacked funding for the necessary investigations. TTR amyloidosis is an excellent example of this situation, as until fairly recently the majority of research interest focused on the rare inherited form of the condition, which is caused by genetic mutation and leads to an abnormally rapid accumulation of amyloid. Then it was discovered that a sizable fraction of supercentenarians die due to TTR amyloidosis, the condition called senile systemic amyloidosis in this case to distinguish it from the inherited form. In essence this form of amyloid builds up in the cardiovascular system of the most elderly people, attaining a large enough presence to choke proper function of the heart. Later, in the past couple of years, researchers have found signs of the damage done by TTR amyloid in a range of age-related conditions: as a contributing cause of spinal stenosis; as an unsuspected contribution to heart failure in a much wider group of old people; and now in the progressive destruction of cartilage.

The silver lining here is that promising therapies capable of breaking down TTR amyloid are under development. The more that we see this amyloid involved in age-related degeneration, the happier we should be given ongoing progress towards a basis for effective treatments. The SENS Research Foundation has funded work on catabodies that can degrade TTR amyloid, other groups have made inroads into disrupting amyloid formation, while earlier this year a human trial of small molecule drugs to clear TTR amyloid reported good results.

Transthyretin Deposition in Articular Cartilage: A Novel Mechanism in the Pathogenesis of Osteoarthritis

Amyloid deposits are prevalent in osteoarthritic joints. We undertook this study to define the dominant precursor and to determine whether the deposits affect chondrocyte functions. Amyloid deposition in human normal and osteoarthritic knee cartilage was determined by Congo red staining. Transthyretin (TTR) in cartilage and synovial fluid was analyzed by immunohistochemistry and Western blotting. The effects of recombinant amyloidogenic and nonamyloidogenic TTR variants were tested in human chondrocyte cultures.

Normal cartilage from young donors did not contain detectable amyloid deposits, but 7 of 12 aged normal cartilage samples (58%) and 12 of 12 osteoarthritic cartilage samples (100%) had Congo red staining with green birefringence under polarized light. TTR, which is located predominantly at the cartilage surfaces, was detected in all osteoarthritic cartilage samples and in a majority of aged normal cartilage samples, but not in normal cartilage samples from young donors. Chondrocytes and synoviocytes did not contain significant amounts of TTR messenger RNA. Synovial fluid TTR levels were similar in normal and osteoarthritic knees. In cultured chondrocytes, only an amyloidogenic TTR variant induced cell death as well as the expression of proinflammatory cytokines and extracellular matrix-degrading enzymes. The effects of amyloidogenic TTR on gene expression were mediated in part by Toll-like receptor 4, receptor for advanced glycation end products, and p38 MAPK.

These findings are the first to suggest that TTR amyloid deposition contributes to cell and extracellular matrix damage in articular cartilage in human osteoarthritis and that therapies designed to reduce TTR amyloid formation might be useful.

JAK-STAT Inhibition and Consequent Reduction of SASP as a Mechanism to Lower Inflammation in Aging
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Here I'll point out a paper in which researchers link the suddenly popular JAK-STAT signaling pathway with the harmful activities of senescent cells in old tissues and the rising level of chronic inflammation that contributes to the progression of most age-related diseases. The varied roles of the genes and proteins involved in the JAK-STAT signaling pathway have been studied by a number of research groups of late. There are four Janus kinases (JAK) and at least seven Signal Transducer and Activator of Transcription (STAT) proteins involved in this very small slice of cellular metabolism, and of course their activities influence and are influenced by scores of other mechanisms. Nothing ever happens in isolation inside a cell. The JAK-STAT pathway is of interest because inhibition of some of its components and activities appears to somewhat restore the activity of old stem cell populations, and has also been shown to reduce the growth in chronic inflammation that accompanies aging.

In the open access paper linked below, the authors propose that reductions in inflammation resulting from JAK inhibition occur because the intervention damps down the harmful output of senescent cells. Cellular senescence is a mechanism that removes cells from the cycle of replication in response to damage or stress. It may be an evolved adaptation of a tool of embryonic development that serves to suppress cancer risk, but it unfortunately also produces damage as these cells grow in number - and aging is nothing more than an accumulation of damage and reactions to that damage. Senescent cells generate a disruptive mix of signal molecules known as the senescence-associated secretory phenotype; this alters the behavior of surrounding cells, damages nearby tissue structures, and to the point of this paper, creates inflammation. When few senescent cells are present, as is the case in younger life, there is little harm done. Most are destroyed by the immune system or by their own programmed cell death processes, but over time an ever-increasing number of senescent cells evade these fates to linger indefinitely. In old age a substantial proportion of some tissues are made up of these dysfunctional cells, and tissue function declines as a direct result. Even the cancer suppression falters in the end, with the inflammatory and other effects of SASP promoting cancerous growth more effectively than the removal of cellular replication suppresses it.

The direct approach to cellular senescence is to periodically destroy senescent cells to keep their numbers low. It doesn't matter how exactly they are causing havoc if they can be safely removed. This is the best and fastest path to therapies, but is nonetheless very much a minority concern in the research community. Shortcuts carried out in advance of understanding, even when they work as this destructive approach does, go against the grain of scientific culture. The usual preferred approach is to gather full understanding of what is going on under the hood and then alter the operation of cellular metabolism in targeted ways to reduce undesirable outcomes. Never mind that this is far harder, slower, more expensive, and - for the foreseeable future - less effective. What is important to the research community is that it aligns with the goal of mapping cellular metabolism. Along these lines, it is interesting to note that the paper below, essentially advocating modulation of SASP via JAK inhibition as a desirable approach to therapies, is written by the very same researchers who recently demonstrated improved healthspan via partial elimination of senescent cells.

This is why we need philanthropy and advocacy and organizations like the SENS Research Foundation to get out there and push forward down the fast and effective path. No distractions, no mapping, just straight to the first generation therapies capable of meaningfully treating the causes of aging. It is far from an academic question as to how rapidly effective treatments can be created to address the effects of cellular senescence in aging. Countless lives depend upon this and the other necessary components of a toolkit of rejuvenation therapies. So I'd say that the point to take away from this particular research paper is that it provides one more set of evidence to confirm that, yes, destroying senescent cells to remove SASP as soon as possible is a great idea. In that I'm not in agreement with the authors' summary on possible ways forward:

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

A hallmark of aging is chronic, low-grade, "sterile" inflammation. Elevated proinflammatory cytokines and chemokines are closely associated with mortality and with a variety of age-related diseases, including atherosclerosis, depression, cancers, diabetes, and neurodegenerative diseases. Inflammation also is associated with frailty, a geriatric syndrome characterized by decreased strength and incapacity to respond to stress.

The underlying mechanisms of age-related chronic inflammation, tissue dysfunction, and frailty remain elusive. Cellular senescence, stable arrest of cell growth in replication-competent cells, is a plausible contributor. Senescence can be induced by a number of stimuli and stresses. Senescent cells accumulate with aging in the skin, liver, kidney, the cardiovascular system, and other tissues in various species. The senescence-associated secretory phenotype (SASP), largely comprised of proinflammatory cytokines and chemokines, links senescent cells to age-related inflammation and diseases. We found that elimination of senescent cells delayed the onset of age-related phenotypes and enhanced healthspan. Therefore, senescent cells and the SASP could play a role in age-related pathologies, particularly those that involve systemic inflammation.

The JAK/STAT pathway plays an important role in regulating cytokine production. We hypothesized that it may directly affect the SASP. We demonstrate here that senescent preadipocytes, fat cell progenitors, accumulate in adipose tissue with aging and can contribute to adipose tissue inflammation. We found that JAK inhibitors decrease the SASP in preadipocytes and human umbilical vein endothelial cells (HUVECs). They also decrease age-related adipose tissue and systemic inflammation as well as frailty. Our findings provide insights into the possible contribution of senescent cells to age-related inflammation and, in turn, to age-related pathologies, as well as potential therapeutic targets to alleviate age-related dysfunction.

There are three potential approaches for targeting senescent cells. One is to prevent them from arising by disabling p16- or p53-related processes or other upstream mechanisms that drive the generation of cellular senescence. This approach, however, is likely to induce cancer. The second is to eliminate senescent cells that already have formed. The third is to blunt the proinflammatory nature of the SASP. Mounting evidence suggests that senescent cells can have both harmful and beneficial effects. Therefore, partial suppression of the SASP seems to be a reasonable option, particularly when short-term alleviation of age-related dysfunction might be indicated.

Declaring the Importance of Classifying Aging as a Disease
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To follow on from a recently linked article on the present regulatory state of affairs for aging research, below find another recent call for regulators and administrators to classify aging as a disease. Numerous researchers have issued opinions and position papers on the topic in the past few years, and to understand why this is the case requires an understanding of how regulation impacts the research funding landscape. From a regulatory standpoint aging is not currently considered a medical condition per se. In some classifications, deviation from normality is one of the baseline criteria, and hence universal phenomena like aging are not included, no matter how ugly the end result. In the case of regulation tied to the legal matter of whether or not it is permitted to offer a particular treatment, and in the US the FDA adopts an "all that isn't listed is forbidden" position, the omission of aging as a treatable condition is a big deal. It means that there is no straightforward path to commercialization of potential therapies for aging within the current framework, and this greatly raises the difficulty of obtaining funding for that goal.

Attempts to change this state of affairs are slow, expensive, drawn out affairs of official and unofficial lobbying. You can see one of the approaches presently underway in the forthcoming clinical trial of metformin, a drug highly unlikely to produce meaningful results in my opinion, but which is the thin end of the wedge when it comes to the scientific community trying to force change on the FDA in the matter of aging. The recent increase in calls to classify aging as a disease should be considered in this context: the word "disease" is just shorthand for "something that I'm allowed to try to treat, and can thus raise funding for." Now that slowing aging and the medical control of aging are accepted as a plausible, possible near future goal by much larger fractions of the research community, the regulatory straitjacket is becoming ever more uncomfortable.

In the case of the World Health Organization's International Statistical Classification of Diseases and Related Health Problems the situation is still all about money, but in this case the benefits sought are a little more indirect. Adding aging to the WHO classification scheme is a way to induce various bureaucracies around the world to direct thought, funding, and verbiage to aging in the context of possible treatments. This falls somewhere between an attempt to amplify advocacy for the treatment of aging and an attempt to expand government research funding, such as the National Institute on Aging budget, via existing mechanisms requiring adherence to the WHO classifications.

For my part, I think that striving to change the regulatory system from within is just another way of implicitly endorsing its existence. None of the vast costs imposed on medical research and development by FDA bureaucrats will go away if aging officially becomes a disease. The better way forward would be for researchers in the US to develop relationships with developers elsewhere in the world, such as the more advanced Asia-Pacific nations in which medical regulation isn't so overbearing and costly: commercialize elsewhere, and deliver services and therapies to the market via medical tourism. The result will be more new treatments, delivered more rapidly, and at lower cost. If the FDA continues to pile on the costs and time for regulatory acceptance of new therapies, more than doubled in the past ten years, alternative commercial ecosystems will develop. Not before time, to my eyes, and it is a pity that this process is not further along now. The best path ahead is to make the FDA and its ilk irrelevant, to bypass the broken system and grasp greater freedom, not to support the present bureaucratic suppression of medical research by spending years to slightly change its parameters.

Why Classifying Aging As A Disease Is Of Crucial Importance To Humanity

Most people have probably heard many times the idea that one can "grow old gracefully" and in a healthy way. This message is perpetuated by the fitness and health industry and pension companies love to show the image of happy, relatively healthy 65-year-olds who can finally escape dreaded work and do what they enjoy in life, for at least a few years before a period of serious disability and death. It is true that some people live over a century and delay many specific pathologies. I also agree that it is a more desirable scenario to die frail at 100 than earlier, but the fact is that what we define as biological aging is in itself a pathological problem, a problem that still suffers from a lack of research. While not every age-related change is studied, the damages can be broadly classified into categories, and specific biomolecular problems can be directly targeted.

While there is a small decrease in function between 20 and 40, the human body still remains "very healthy" until mid 40s when disease correlated to the aging process overtakes accidents/suicides as most common cause of death. Keeping the human body biologically under 50 years old would take away the vast majority of all disease, and even if biologically young people were obese and smoked, there would likely only be a small number of cases where these "unhealthy" habits caused lethal health problems. The problem with WHO and governmental programs is that these systemic pathologies destroying the body and generating ill health in the elderly are not yet considered to be a disease. I have worked trying to change this paradigm. Earlier this year I coauthored "It is time to classify biological aging as a disease", and Alex Zhavoronkov and his company In Silico Medicine have recently published a paper on this issue, to persuade the World Health Organisation to classify aging as a disease as a part of the International Statistical Classification of Diseases and Related Health Problems (ICD-11).

When I was a child I was told wrinkles signified wisdom and life experience, but didn't impact one's health in any way. Nowadays my brain is wired to spot the pathologies behind them; skins laxity and jowls linked to blood sugar crosslinking and destruction of collagen, dysfunction of matrix metalloproteinases and subsequent extracellular matrix degradation. Wrinkled skin is not simply a cosmetic issue, as senile skin is failing to perform its duties properly, similar to burned and scarred skin. Many old people become easily dehydrated, are less able to cope with temperature fluctuations, and they injure and bruise themselves easily due to the loss of components making up the main skin layer, the dermis. Skin aging in itself is yet not classified as a disease, but lesions have pathological names, and photo-aging caused by sun exposure, which shares molecular pathologies with intrinsic skin aging, is considered a pathological condition. What is humanity gaining by this hypocrisy?