Fight Aging! Newsletter, January 18th 2016

January 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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  • It is Quite Possible to Create a Senescent Cell Clearance Therapy that is Too Good
  • Visions of Indomitable Macrophages
  • Persistent False Beliefs Hinder Progress Towards the Medical Control of Aging
  • Insight into AMPK and Mitochondria in Aging
  • Assuring a Future for the SENS Research Foundation
  • Latest Headlines from Fight Aging!
    • Extracellular Vesicle Contents Change with Age, Influencing Mechanisms of Bone Growth
    • Articulating the Case for the Longevity Dividend
    • Increased FGF21 Slows Degeneration of the Thymus
    • Are All Protein Aggregates in Aging Exclusively Harmful?
    • Screening for Drugs that Enhance Wound Healing by Spurring Greater Stem Cell Activity
    • The Major Mouse Testing Program: Aiming to Speed Progress in Longevity Science
    • Delivering miRNA-26a to Spur Bone Regrowth
    • Cancer Mortality Continues to Decline Steadily
    • Weight History is Required to Accurately Assess the Effects of Obesity on Mortality Rates
    • An Example of Targeted Cancer Therapy Using Exosomes


Therapies for senescent cell clearance as a treatment for aging are going to be an ongoing concern within the next few years. Multiple different methods have been demonstrated to selectively kill senescent cells in mice, including the genetic engineering approach used a few years ago and the various senolytic drug candidates discovered more recently. These have variable effectiveness in different tissues, with some tissue types retaining all of their senescent cells, suggesting that no initial clinical treatment is going to be perfect. Even these prototypes are, however, clearing as much as a quarter of senescent cells in some tissues. In the case of senolytic drugs this is enough for old mice to display lasting health benefits after even a single treatment.

Why is the destruction of senescent cells an important goal? In short because cellular senescence is a contributing cause of aging. When damaged or faced with a toxic, stressed environment, cells tend to become senescent. A senescent cell stops replicating and secretes signals that both adjust the behavior of surrounding cells, making them more likely to become senescent, and make the senescent cell itself a target for destruction by the immune system. This is probably a defense against cancer, removing from play those cells most likely to become cancerous. Evolution likes reuse, and senescent cells are also transiently involved in wound healing and structural control over embryonic development. Nonetheless, having too many senescent cells is a bad thing, and that is exactly what happens with advancing age: senescent cells that evade destruction linger indefinitely, and their numbers grow over time, especially once the immune system starts to decline in old age. In large numbers senescent cells cause chronic inflammation and their collective signaling actively harms tissue structure and function. Their presence contributes to all of the common age-related diseases via these and a range of other, similar mechanisms. Periodic removal of senescent cells would solve all of these problems.

Senescent cell clearance treatments could be made much more efficient than the prototypes demonstrated so far in mice. That seems inevitable, based on some combination of innovation in delivery methods and innovation in kill mechanisms. We should always expect the first approaches to be weak in comparison to those that come later, with the benefit of more funding and attention. It is, however, quite possible for a therapy to be too good at killing senescent cells. Consider the study from some years back that showed as many as 20% of the skin cells in old baboons exhibited the signature for senescence. Now, what do you imagine would happen to you if 20% of the cells throughout your body died in a matter of a day? It wouldn't be pleasant. Clearing cells isn't a magical clean sweep of a process: a dead cell leaves behind debris and lot of frantic signaling in its last moments, and in volume that can be far worse than just leaving the cells alone. This is a well known problem in the cancer research community, a section of the medical establishment very focused on selectively killing cells. The condition that can result from having a significant number of cells die in a short period of time as the result of treatment is known as tumor lysis syndrome. At the mild end of the spectrum the outcome is sickness and metabolic dysregulation, while severe cases bring kidney failure and death, the systems of blood filtration utterly overwhelmed by a flood of cell debris and toxins.

Thus, naively, a hypothetical highly efficient senescent cell clearance therapy might work just fine in a 40-something adult, with tissues containing comparatively few senescent cells, while having a strong chance of killing patients in their 70s, with tissues containing many more senescent cells and also possessed of less resilient organs. Fortunately this issue is well understood in the research community, so no such highly efficient therapy is ever going to be produced. Approaches that could be this efficient in theory will be diluted or otherwise limited and delivered over a number of spaced treatments, producing a steady or stepped destruction of senescent cells at a safe pace. What that safe pace will turn out to be in humans is an open question, to be answered by experimentation, trials, and further studies, but the mouse data suggests it can be fairly rapid - just not all at once, immediately.


The research I'll point out today is an investigation of some of the detailed mechanisms by which the immune cells called macrophages fail in their tasks and as a result cause the bulk of the pathology of atherosclerosis, a disease in which fatty plaques build up in blood vessels. The cardiovascular system deforms and remodels over the years as a result of these deposits, contributing to hypertension and related issues, but the more dangerous outcome is for sections of a plaque to break off and block blood vessels, leading to serious injury or death due to loss of the oxygen supply to critical tissues.

Atherosclerosis starts with very small-scale irritations of the blood vessel wall caused by the presence of damaged lipid molecules, such as those generated by the small population of dysfunctional cells that have been overtaken by broken mitochondria. This population grows with age as ever more mitochondria become randomly damaged in just the right way to spread within their cell, and so does the level of damaged lipids in the bloodstream, from this and other sources. If that was all there was to atherosclerosis, however, we probably wouldn't consider it a significant threat in comparison to everything else that can fall apart in aging. The small battles fought as cells cleaned up damaged lipids probably wouldn't rise to the level of killing people.

The real reason that atherosclerosis is a dangerous medical condition is that macrophages attempt to clean up the lipids and macrophages are weak. They have a limited capacity to digest damaged lipids and other debris resulting from the presence of damaged lipids in a blood vessel wall. Their cellular recycling mechanisms, the lysosomes, become overwhelmed and the macrophage cells die. That creates more debris, which attracts more macrophages. Small areas of damage can thus spiral out of control into battlegrounds marked by growing inflammation and fatty plaques composed of the remains of countless macrophages, lured in to their doom. None of this would happen if macrophages were indomitable, capable of digesting much, much more of the problem lipids and other wastes.

It is possible to create indomitable macrophages? In principle of course. Somewhere in the future lies the mass production of diamondoid medical nanorobots, each thousands of times more effective than evolved cells at a few specific tasks, such as digesting damaged lipids or macrophage remains. But if thinking of the near future, the bounds of the possible are much more limited. Efforts to alter cells to produce better, artificial operational states that do not appear in nature have proven slow and expensive, and produce largely marginal results where there is any success in this direction. The best outcomes to date have come from coercing cells into adopting existing naturally occurring states and patterns of behavior that are more helpful to the present situation - see stem cell medicine, for example. Trying to build a better macrophage, an entirely new state of cellular operation, by iterating on the present design is not likely to stop atherosclerosis, though with great effort it is probably possible to modestly slow its progression.

To my eyes, the better and more cost-effective approach is that of periodic repair after the SENS model for the treatment of aging, which in this case means cleaning up after this macrophage-induced disaster on a regular basis and before the debris builds up to pathological levels. The approach taken to date is to find natural enzymes capable of breaking down the materials of atherosclerotic lesions and plaques. Graveyards are not seeping lipid compounds, so we know that bacteria in the soil can digest these problem molecules. Somewhere in that vast and largely uncharted range of bacterial species can be found the basis for drugs to clear out damaged lipids and the remains of doomed macrophages. This is in fact the longest running SENS rejuvenation research program, and not so long ago the first candidate bacterial enzymes were licensed to Human Rejuvenation Technologies for commercial development; we'll have to wait and see how that goes.

Repair remains a minority position in the research community, though hopefully not for too much longer as good results from other repair approaches such as senescent cell clearance start to emerge. Most researchers would first seek to build a better macrophage, a model with a more resilient garbage disposal system:

Atherosclerosis is Alzheimer's disease of blood vessels, study suggests

In atherosclerosis, plaque builds up on the inner walls of arteries that deliver blood to the body. Researchers suggest this accumulation is driven, at least in part, by processes similar to the plaque formation implicated in brain diseases such as Alzheimer's and Parkinson's. A look behind the scenes in the process of plaque accumulating in arteries, the new study is the first to show that another buildup is taking place. Immune cells attempting to counteract plaque formation begin to accumulate misshapen proteins. This buildup of protein junk inside the cells interferes with their ability to do their jobs. "In an attempt to fix the damage characteristic of atherosclerosis, immune cells called macrophages go into the lining of the arteries. The macrophage is like a firefighter going into a burning building. But in this case, the firefighter is overcome by the conditions. So another firefighter goes in to save the first and is likewise overcome. And another goes in, and the process continues to build on itself and worsen."

The researchers showed that this protein buildup inside macrophages results from problems with the waste-disposal functions of the cell. They identified a protein called p62 that is responsible for sequestering waste and delivering it to cellular incinerators called lysosomes. To mimic atherosclerosis, the researchers exposed the cells to types of fats known to lead to the condition. The researchers noted that during atherosclerosis, the macrophages' incinerators become dysfunctional. And when cells stop being able to dispose of waste, p62 builds up. In a surprise finding, when p62 is missing and no longer gathers the waste in one place, atherosclerosis in mice becomes even worse.

The researchers also found these protein aggregates and high amounts of p62 in atherosclerotic plaque samples taken from human patients, suggesting these processes are at work in people with plaque building up in the arteries. "That p62 sequesters waste in brain cells was known, and its buildup is a marker for a dysfunctional waste-disposal system. But this is the first evidence that its function in macrophages is playing a role in atherosclerosis." In atherosclerosis, and perhaps in the brain disorders characterized by protein accumulation, such evidence suggests it would be better to focus on ways to fix the cells' waste-disposal system for getting rid of the large protein aggregates, rather than on ways to stop the aggregates from forming.

Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis

The release of proinflammatory cytokines, such as IL-1β, by macrophages increases the size and number of atherosclerotic plaques. Macrophages in atherosclerotic plaques have a defect in autophagy, a process that eliminates dysfunctional proteins, and it has been shown that p62, a chaperone protein involved in autophagy, sequestered polyubiquitinated proteins in cytoplasmic inclusion bodies in macrophages. Macrophages lacking p62 released more IL-1β, and one of the proteins required for the production of IL-1β partially colocalized with these inclusion bodies.

In a mouse model of atherosclerosis, p62 deficiency increased macrophage infiltration in atherosclerotic plaques and exacerbated atherosclerosis. Thus, enhancing the function of p62 to promote the sequestration of polyubiquitinated proteins could prevent macrophages from exacerbating atherosclerosis.


Progress in gathering support for rejuvenation research has long been hampered by a number of widespread false beliefs. Every time we pitch someone unfamiliar with the topic, seeking material assistance in the long process of developing clinical treatments to control aging and thus extend life, the same initial hurdles must be overcome: the false belief that longevity assurance therapies would make people older for longer, not younger for longer; the false belief that overpopulation is inevitable if life spans increase; the false belief that only extremely rich people would benefit or have access to therapies. These are resilient myths, surviving in spite of the fact that they are easily disproved, and despite the fact that scientists explain over and again in detail as to why they won't come to pass.

No-one aiming at the treatment of aging is trying to build treatments that will make old people linger in increasing decrepitude. It isn't even possible to do that with a rejuvenation treatment that repairs damage: aging is an accumulation of damage, and reductions in that damage translate directly into a longer maintenance of youthful physiology. Researches have published countless papers on overpopulation in the general sense to show that what people see as overpopulation is simply poverty resulting from bad choices and bad governance, people choosing to make a wasteland in the midst of plentiful resources. Malthusians predicting vanishing resources have always been wrong; resources are created and replaced the moment that price increases look likely. Where researchers have created models of future population growth under the influence of radical life extension, populations do not grow rapidly. Wealth, security, and longevity produce incentives that reduce population growth.

As to only the wealthy having access: every mass-produced medical technology is initially briefly expensive, and then later affordable, and then later again dirt cheap. You don't have to take my word for it. Go out and look at the price histories of thousands of drugs and other treatments. Treatments to repair the damage that causes aging will be the same for everyone, infusions and injections that are turned out in bulk from pharmacological assembly lines, or available in tens of thousands of clinics where cell samples are needed to produce personalized therapies from a standard template. These treatments will be similar in manufacture and distribution to drugs that today range in cost from near zero to a few thousand. The challenge will be delivery to the third world, because that is a challenge for every technology, not delivery to the average person in the first world. It is nonsensical to think that treating aging will be any different from the past treatment of disease in its logistics.

There are many other resilient persistent false beliefs that impact the ability to talk sensibly about the development of medicine for aging. The idea that multivitamins and antioxidants are a good thing, for example. The supplement industry continues to drown out the voice of the scientific community in this matter. It is done and settled in medical science that high dose vitamins and antioxidants do nothing or cause a modest level of harm, but you wouldn't know that from a tour of any shopping center. When people fixate on supplements, they tend to shy away from consideration of supporting research: doing something, anything, now satisfies the need. Of course it does nothing to actually help matters when it comes to living a longer life, but no-one should claim that we humans are particularly rational or consistent in our approach to life.

The science myths that will not die

Scientists once rallied around the free-radical theory of ageing, including the corollary that antioxidants, molecules that neutralize free radicals, are good for human health. By the 1990s, many people were taking antioxidant supplements, such as vitamin C and β-carotene. It is "one of the few scientific theories to have reached the public: gravity, relativity and that free radicals cause ageing, so one needs to have antioxidants."

Yet in the early 2000s, scientists trying to build on the theory encountered bewildering results: mice genetically engineered to overproduce free radicals lived just as long as normal mice, and those engineered to overproduce antioxidants didn't live any longer than normal. It was the first of an onslaught of negative data, which initially proved difficult to publish. The free-radical theory "was like some sort of creature we were trying to kill. We kept firing bullets into it, and it just wouldn't die." Then, one study in humans showed that antioxidant supplements prevent the health-promoting effects of exercise, and another associated them with higher mortality. None of those results has slowed the global antioxidant market, which ranges from food and beverages to livestock feed additives. It is projected to grow from 2.1 billion in 2013 to 3.1 billion in 2020. "It's a massive racket. The reason the notion of oxidation and ageing hangs around is because it is perpetuated by people making money out of it."

Fears about overpopulation began with Reverend Thomas Malthus in 1798, who predicted that unchecked exponential population growth would lead to famine and poverty. But the human population has not and is not growing exponentially and is unlikely to do so. The world's population is now growing at just half the rate it was before 1965. Today there are an estimated 7.3 billion people, and that is projected to reach 9.7 billion by 2050. Yet beliefs that the rate of population growth will lead to some doomsday scenario have been continually perpetuated.

The world's population also has enough to eat. According to the Food and Agriculture Organization of the United Nations, the rate of global food production outstrips the growth of the population. People grow enough calories in cereals alone to feed between 10 billion and 12 billion people. Yet hunger and malnutrition persist worldwide. This is because about 55% of the food grown is divided between feeding cattle, making fuel and other materials or going to waste. And what remains is not evenly distributed. "Overpopulation is really not overpopulation. It's a question about poverty. Even people who know the facts use it as an excuse not to pay attention to the problems we have right now."


AMP-activated protein kinase (AMPK) is one one of the usual suspects whenever the research community considers calorie restriction, exercise, increased cellular quality control, and other ways to slightly slow the pace of degenerative aging. Search the Fight Aging! archives and you'll find many mentions over the years. In the publicity materials and paper linked below researchers take a modest step forward to better understand why AMPK is important: it appears a lynchpin regulator linking nutrient intake and one of the mechanisms of mitochondrial quality control.

All of the fundamental cellular responses to the environment are linked, and any given protein tends to play many different roles. Thus AMPK is a nutrient sensor, activated by low energy intake, which explains the link to calorie restriction. It also responds to changes that occur with exercise in much the same way, however. Once AMPK is more active, a grand cascade of varied mechanisms are set in motion, and researchers spend a great deal of time sifting through this immense complexity to understand how it produces modest benefits to health and longevity. Many interesting connections have been made. For example, calorie restriction requires functional autophagy in order to extend life, and calorie restriction is associated with raised levels of autophagy. AMPK activation, achieved artificially in absence of environmental changes, increases levels of autophagy. It all ties together in this way, but there is still much to be done to fill in the details.

Autophagy is the name given to a collection of mechanisms that clear out damaged proteins and cellular components, delivering them to locations in the cell capable of breaking down and recycling the parts for later use. One of the more important cellular components are mitochondria, the swarming bacteria-like power plants responsible for creating chemical energy stores, among other tasks. Many lines of evidence link mitochondrial damage to the pace of aging, and mitochondrial dysfunction to age-related disease. Anything that impacts mitochondria is interesting to the aging research community, and here AMPK is shown to have a fairly profound effect:

How the cell's power station survives attacks

Mitochondria, the power generators in our cells, are essential for life. When they are under attack - from poisons, environmental stress or genetic mutations - cells wrench these power stations apart, strip out the damaged pieces and reassemble them into usable mitochondria. Scientists have uncovered an unexpected way in which cells trigger this critical response to threats, offering insight into disorders such as mitochondrial disease, cancer, diabetes and neurodegenerative disease - particularly Parkinson's disease, which is linked to dysfunctional mitochondria.

In an average human cell, anywhere from 100 to 500 mitochondria churn out energy in the form of ATP molecules, which act like batteries to carry power to the rest of the cell. At any given time, one or two mitochondria fragment (fission) or reform (fusion) to cycle out any damaged parts. But when a poison - like cyanide or arsenic - or other dangers threaten the mitochondria, a mass fragmentation takes place. Researchers have known for years that mitochondria undergo this fragmentation when treated with drugs that affect the mitochondria, but the biochemical details of how the mitochondria damage is sensed and how that triggers the rapid fission response has not been clear until now.

Researchers found that when cells are exposed to mitochondria damage, a central cellular fuel gauge, the enzyme AMPK, sends an emergency alert to mitochondria instructing them to break apart into many tiny mitochondrial fragments. Interestingly, AMPK is activated by the widely used diabetes therapeutic metformin, as well as exercise and a restricted diet. The new findings suggest that some of the benefits from these therapies may result from their effects in promoting mitochondrial health. This new role of rapidly triggering mitochondrial fragmentation "really places AMPK at the heart of mitochondria health and long-term well-being."

To uncover exactly what happens in those first few minutes, the team used the gene editing technique CRISPR to delete AMPK in cells and showed that, even when poison or other threats are introduced to the mitochondria, they do not fragment without AMPK. This indicates that AMPK somehow directly acts on mitochondria to induce fragmentation. The group then looked at a way to chemically turn on AMPK without sending attacks to mitochondria. To their surprise, they found that activating AMPK alone was enough to cause the mitochondria to fragment, even without the damage.

AMP-activated protein kinase mediates mitochondrial fission in response to energy stress

Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA-linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress.

Another interesting topic to consider in this context is the ability of cells to rejuvenate their mitochondria completely in response to reprogramming. The creation of induced pluripotent stem cells has been shown to regenerate damaged mitochondria. Either the same or a similar process occurs in the very early stages of embryonic development, as the damage of aging is near-completely wiped away by the internal transformations of the few cells present at the time. Thus there are clearly mechanisms capable of this in the space of states that a cell can adopt, though this doesn't necessarily mean that any of them are accessible to an adult without the accompaniment of severe adverse consequences. Profound cellular transformations are generally not something you'd want to happen to large proportions of your cells at any one time.


The SENS Research Foundation will be seven years old this year. It is one of the very few organizations to aggressively pursue a campaign of research and advocacy aimed at bringing an end to aging and age-related disease, and one of perhaps only two or three at most that focus on rejuvenation research, an approach to the treatment of aging based on repair of the known forms of cell and tissue damage that cause aging. The SENS rejuvenation research project has been very successful over the course of its lifespan to date, moving from nothing more than a vision in the early 2000s to today's network of allied researchers, research programs, new startups, and the first prototype implementations of SENS therapies such as those under development for senescent cell clearance. Over that time the research community has been swayed from its former hostility to any mention of treating aging to much greater support for the goal of enhanced human longevity. To be clear, however, this is still a tiny field. There is a long way to go to produce a SENS research community as large and well supported as the cancer or stem cell research communities.

If you look back a couple of years here at Fight Aging!, you'll find a post on the strategic future of the SENS Research Foundation. The SENS Research Foundation is producing results, persuading researchers, and generating the foundations of new medical technology, and we want to see this successful team continue to achieve its goals. That, however, requires funding. To summarize the older post: half of the 4-5 million yearly budget of the SENS Research Foundation is provided by founder Aubrey de Grey, and those funds come to an end relatively soon. We all owe him a debt of gratitude for what he has achieved in this field with his own money. This is the nature of research and business; every success in finding a source of funding must be treated as a runway and a countdown to the next source of funding.

There are many ways to go from here, and the next decade looks to be a time of great opportunity in funding for longevity science of all sorts, given the large investments that are starting to arrive in the space. Even if, as seems plausible given the recent market activity, we're about to plunge into a couple of years of a bear market, that doesn't dampen the prospects all that much. Given the time taken for any meaningful research effort, the start of a bear market is actually a great time to invest in a research program; it'll just be getting somewhere when the economic picture turns around.


Crowdfunding of scientific research is something that we as a community do quite well. It is a hard problem, and crowdfunding ventures like Experiment are only just starting to make inroads into sustainable platforms. The past few years have seen a slow growth in the community of supporters willing to materially support the SENS Research Foundation every year. So far, as much as a few hundred thousand each year have been raised this way, and I don't see why that number can't keep growing as the public support for longevity science grows.

Investment in SENS Rejuvenation Therapy Startups

Selective, targeted investment worked out very well for the Methuselah Foundation. The Foundation wes an early investor in Organovo a long time back, and that provided a healthy return in the years since. The important thing is to invest in those companies that can also be incubated and supported, so as to provide the best chance of success. The SENS Research Foundation is very well placed to do this. It is in the center of a web of connections to researchers and the Bay Area venture community, and also a source of technologies for new therapies, such as senescent cell and cross-link clearance. The transition from funding a scientific group to seed funding the startup that results from that work is a logical one, and indeed the SENS Research Foundation is already doing this for Oisin Biotechnology and Human Rejuvenation Technologies.

An early stage startup investment is a lottery ticket, of course, even when the investor happens to be well placed to help its progress, but at least it is a lottery ticket that has the side-effect of funding additional research and development regardless of the outcome. Perhaps more important than the risk inherent in any such investment is the timeline: one should expect a biotechnology startup to take five years or longer to come to initial fruition even should it succeed as well as Organovo did. The SENS Research Foundation investments were made last year, so there is a way to go yet.

Deeper Integration with the Non-Profit Funding Ecosystem

A massive non-profit funding ecosystem exists, just as rife with formalism, barriers, and the need for connections as the venture capital ecosystem. There are many different players involved, ranging from high net worth individuals to large foundations to government bodies. Any demonstrably successful non-profit with a yearly budget of only a few million has a lot of room for growth in this space. The folk at the SENS Research Foundation agree, and are looking for a guide:

Job Opportunity: Head of Major Gifts

SENS Research Foundation (SRF) is a 501(c)(3) public charity that is undertaking one of the most ambitious goals in history: ending the human suffering resulting from age-related diseases such as Alzheimer's, diabetes, cancer, and heart disease. Our goal is to apply the principles of regenerative medicine to build a rejuvenation biotechnology industry; what makes us unique is that rather than developing more sophisticated ways to treat disease, we are developing more sophisticated ways to preserve health, and thereby prevent such diseases from ever taking hold.

Since our founding in 2009 we've grown into a significant force for change in medical research. SRF's current annual funding - over 4M - comes roughly one-half from renewable sources and one-half from a multi-year trust which will expire next year. The challenge we now face is to build quickly upon our successes, and to be able to create our truly transformational next generation of research, education and outreach programs without losing momentum. The role of the Head of Major Gifts will be to raise at least 2M/annum in new funding, and to guide us in developing new channels sufficient to create sustainable income of 5-10M/annum, from high net worth individual, foundation, corporate and government sources.

This is a great opportunity for someone coming from a large non-profit, with a packed rolodex and knowledge of the way things work. It represents the option to carve out a name in this space, to become a well-know leader in an organization that is out to change the world for real. There is no greater impact to human life than to speed progress towards the medical control of aging and all age-related disease. It is the largest cause of death and suffering by a wide margin, and every day gained is a hundred thousand lives saved.


Monday, January 11, 2016

Researchers here investigate one of the more complex cell signaling mechanisms, providing evidence to link age-related changes in this mechanism to the development of osteoporosis, the loss of bone mass and strength that occurs with age. There is a growing interest in the research community in alterations to cell signaling that occur with aging. A great deal of this focuses on the changing amounts of various molecules found in the bloodstream, and arises from parabiosis studies that link the circulatory systems of old and young animals, producing benefits to measures of health in the older individual. Researchers have been isolating specific molecules of interest, showing that levels change with aging, and that reversal of those changes produces benefits in old animals.

These changes are most likely secondary reactions to forms of cell and tissue damage that accumulate over a lifespan, but in turn they are proximate causes for a range of undesirable outcomes that include the characteristic decline in stem cell activity that occurs with age. The signals that cells pass between one another are complex and varied. It isn't just a matter of releasing specific molecules into the bloodstream and surrounding tissues. For example, cells also create and emit vesicles, membrane-enclosed packages of molecular machinery that are used for a wide variety of purposes. Just as simple signals vary with age, so too do the number and contents of these vesicles, and here researchers provide evidence to suggest that there is to be found one of the proximate contributing causes to the loss of bone that occurs with age:

The capability of stem cells to regenerate tissue by differentiating into specialized cells has been shown to decrease with age. One organ that is notably affected by this loss in stem cell functionality is the skeleton. Bone is a highly dynamic organ that is constantly remodeled and maintained by the coordinated activity of bone forming osteoblasts and bone excavating osteoclasts. This balance is particularly important at older age, as too high osteoclast activity versus too few osteoblasts is considered to give rise to lower bone strength. The molecular mechanisms by which the imbalance is caused in the elderly are still incompletely understood. However, it is clear, that after skeletal maturation a constant number of mesenchymal stem cells (MSCs) and a reduced number of mature osteoblasts are observed with increasing age. This indicates that the functionality or the osteogenic commitment of MSCs might be impaired. Supportingly, the numbers of pre-osteoblasts, pre-osteoclasts and osteoclasts do not change with age per unit bone length, at least in elderly rats. However, a strong decline of mature osteoblasts has been described, as well as impaired osteoblastogenesis in age associated osteoporosis. This supports the hypothesis that impaired osteoblastogenesis contributes to age-related bone loss and loss of mechanical strength.

Since it has been proposed recently that the systemic environment of young versus elderly individuals can influence stem and progenitor cell functionality in different tissues, such as bone repair, specific focus is put on secreted circulating factors, in particular with regard to extracellular vesicles (EVs), small vesicles released by many if not all cell types. The cargo of EVs, consisting of proteins, mRNAs and non-coding RNAs, including miRNAs, is selectively packaged and delivered to specific recipient cells over short and long distances.

In the present study we set out to determine whether circulating factors, in particular human plasma-derived EVs from the elderly, contribute to the age-dependent loss of stem cell functionality. We observed that vesicles isolated from young donors enhance osteoblastogenesis in vitro compared to elderly-derived EVs. While searching for factors mediating this donor-age-dependent vesicular effect, we identified Galectin-3 to be enriched in EVs from young individuals. Indeed, we found that increased levels of Galectin-3 have a positive impact on the osteogenic differentiation capacity of MSCs and that extracellular vesicles enriched in Galectin-3 enhance osteoblastogenesis of MSCs. We elucidated its molecular mechanism of action by showing that this protein protects β-Catenin from degradation and that its Serine-96 (S96) phosphorylation site is crucial to mediate this effect. Finally, we demonstrated that cell-penetrating peptides fused to a 13 amino acid sequence, mimicking Galectin-3's Serine-96 phosphorylation site, are able to enhance osteoblastogenesis.

Monday, January 11, 2016

To go along with the recent announcement of the Longevity Dividend book, an extended argument for more government funding for the present mainstream approach to aging research, here is a position paper from one the researchers involved in this initiative:

The survival of large segments of human populations to advanced ages is a crowning achievement of improvements in public health and medicine. But, in the 21st century, our continued desire to extend life brings forth a unique dilemma. The risk of death from cardiovascular diseases and many forms of cancer have declined, but even if they continue to do so in the future, the resulting health benefits and enhanced longevities are likely to diminish. It is even possible that healthy life expectancy could decline in the future as major fatal diseases wane. The reason is that the longer we live, the greater is the influence of biological aging on the expression of fatal and disabling diseases. As long as the rates of aging of our bodies continues without amelioration, the progress we make on all major disease fronts must eventually face a point of diminishing returns.

Research in the scientific study of aging has already showed that the aging of our bodies is inherently modifiable, and that a therapeutic intervention that slows aging in people is a plausible target for science and public health. Given the speed with which population aging is progressing and chronic fatal and disabling conditions are challenging health care costs across the globe, the case is now being made in the scientific literature that delayed aging could be one of the most efficient and promising ways to combat disease, extend healthy life, compress morbidity, and reduce health care costs. A consortium of scientists and nonprofit organizations has devised a plan to initiate an accelerated program of scientific research to develop, test for safety and efficacy, and then disseminate a therapeutic intervention to delay aging if proven to be safe and effective; this is referred to as the Longevity Dividend Initiative Consortium (LDIC).

Tuesday, January 12, 2016

Increased production of FGF21 via genetic engineering has been shown to extend life in mice, and calorie restriction appears to also increase FGF21 levels to some degree. Here researchers link FGF21 to the thymus and the immune system in aging. The thymus is an unusual organ in that it atrophies in early adulthood. It plays a limiting role in the pace of production of new immune cells, and thus restoring its structure and activity to youthful levels is an approach to at least partially reversing the age-related decline of the immune system. That might be achieved through tissue engineering or altered levels of FOXN1, among other methods.

A hormone that extends lifespan in mice by 40% is produced by specialized cells in the thymus gland, according to a new study. The team also found that increasing the levels of this hormone, called FGF21, protects against the loss of immune function that comes with age. When functioning normally, the thymus produces new T cells for the immune system, but with age, the thymus becomes fatty and loses its ability to produce new T cells. The researchers studied transgenic mice with elevated levels of FGF21. The team knocked out the gene's function and studied the impact of decreasing levels of FGF21 on the immune system. They found that increasing the levels of FGF21 in old mice protected the thymus from age-related fatty degeneration and increased the ability of the thymus to produce new T cells, while FGF21 deficiency accelerated the degeneration of the thymus in old mice.

FGF21 is produced in the liver as an endocrine hormone. Its levels increase when calories are restricted to allow fats to be burned when glucose levels are low. FGF21 is a metabolic hormone that improves insulin sensitivity and also induces weight loss; therefore it is being studied for its therapeutic effects in type-2 diabetes and obesity. "We found that FGF21 levels in thymic epithelial cells is several fold higher than in the liver - therefore FGF21 acts within the thymus to promote T cell production. Elevating the levels of FGF21 in the elderly or in cancer patients who undergo bone marrow transplantation may be an additional strategy to increase T cell production, and thus bolster immune function." Further studies will focus on understanding how FGF21 protects the thymus from aging, and whether elevating FGF21 pharmacologically can extend the human healthspan and lower the incidence of disease caused by age-related loss of immune function.

Tuesday, January 12, 2016

Over the course of aging, proteins of many different varieties form aggregates in and around cells - this is one of the characteristic differences between old tissue and young tissue, which leads to the SENS rejuvenation research point of view that we should work to remove all of these aggregates. Any difference between old and young tissue should be reverted. Some aggregates are metabolic waste, some are misfolded or damaged protein machinery, and few are well understood at the detail level of their relationship with aging and disease. Where that understanding exists it is pretty clear that aggregates are causing pathology, but the present state of knowledge still leaves the door open to suggestions that at least some of these aggregates are helpful. Their presence perhaps compensates for other forms of age-related damage, or is the result of other compensatory behavior while the aggregates themselves are not particularly harmful. Still they are not present in young tissue, and this should perhaps remain the guide for development of rejuvenation therapies:

We age because the cells in our bodies begin to malfunction over the years. This is the general view that scientists hold of the ageing process. For example, in older people the cells' internal quality control breaks down. This control function usually eliminates proteins that have become unstable and lost their normal three-dimensional structure. These deformed proteins accumulate in the cells in a number of diseases, such as Parkinson's and Alzheimer's. For some researchers, however, the view of the ageing process as a consequence of flawed cell function and disease is too narrow. It ignores the fact that the mentioned so-called prion-like protein accumulations could have a positive effect, too, and therefore should not be referred to as cellular malfunction.

The researchers drew this conclusion based on research on yeast cells. They recently found in these cells a new type of protein aggregate, which appears as the cells get older. As the scientists were able to show, these protein aggregates do not arise as the result of a cell's malfunctioning internal quality control. On the contrary: in yeast cells with such aggregates, quality control functions even better. "It certainly seems that these aggregates help yeast cells to cope with the physiological changes caused by ageing. We are very exited to learn what type of information is stored in these structures." The scientists assume that these age-associated aggregates are formed by several different proteins. The researchers have already identified one prion-like protein that is part of the accumulations. What other proteins are involved and why the aggregates remain in the parent cells during cell division are subjects of further research.

"We're still a fairly small group of scientists who say: aggregate proteins are not pathological - they are neither an accident nor a defect." Rather, these proteins aggregate because it is their normal function. Diseases such as Parkinson's and Alzheimer's only arise when the system becomes imbalanced and too many prion-like proteins accumulate in the wrong place in the cells. "There are two aspects to ageing. Yes, you die at the end of the process, and this is negative. But you die wise. And Alzheimer's is perhaps a bad end to a good thing."

Wednesday, January 13, 2016

The enhancement of stem cell activity is a very broad theme in medical research and development. It encompasses most present stem cell therapies, treatments that largely work through their effects on native stem cell populations, the parabiosis studies in search of blood-borne factors that both influence stem cells and change with age, and research such as the open access paper here, in which more traditional drug screening is used to search for candidates that can increase stem cell activity in a specific tissue of interest:

Advances in adult tissue stem cell biology have led to the idea that pharmacological activation of resident stem cells might represent a therapeutic strategy for tissue repair. Indeed, pharmacological candidates that regulate tissue stem cells have been identified. Here, we asked whether this is a viable strategy for skin repair. Skin is a complex tissue with many endogenous tissue stem cells. These include epidermal stem cells and a population of dermal stem cells called skin-derived precursors (SKPs). Cultured SKPs can clonally reconstitute the dermis and induce hair follicle morphogenesis, suggesting key roles for the endogenous precursors in dermal maintenance and hair follicle biology.

Here, we have tested the idea that increasing the number or self-renewal of endogenous SKPs would enhance skin repair. To do so, we screened libraries of compounds that are used clinically in humans, looking for drugs that enhance SKP self-renewal. We identified two compounds, alprostadil and trimebutine maleate, that increased SKP self-renewal, likely by activating the MEK-ERK pathway. Both compounds enhanced wound healing when applied topically. These findings provide proof of principle for the idea that compounds that regulate SKPs in culture have therapeutic efficacy in vivo, and identify potential drug candidates that can be repositioned for use in humans.

Wednesday, January 13, 2016

The Major Mouse Testing Program is a non-profit initiative setting up to run life span studies for potential age-slowing treatments that the rest of the research community isn't going to get to any time soon. The gold standard of life span studies are those carried out by the Interventions Testing Program at the NIA, but that group is poorly funded, slow, and conservative in their choices. The ITP staff won't be testing senolytic drug candidates or combinations of everything shown to modestly slow aging in mice any time soon, for example. So there is room for others to cut to the chase:

The field of regenerative medicine is becoming increasingly important for the future of healthcare and even how we view aging. With stem cell technology, gene therapy and other longevity technology on the horizon humanity can finally consider living longer, healthier lives. Some drugs already tested have been found to increase mouse lifespan such as metformin and rapamycin. These drugs are even now moving into human clinical trials to see if the above benefits translate into people. However, there are many more promising substances that have never been properly tested and we do not know if they could extend healthy lifespan. How fast science advances depends on how much quality research is being conducted. Currently there are few high impact studies investigating lifespan initiated each year ­ and with so many promising substances to test this is all a painfully slow process. The Major Mouse Testing Project (MMTP) is aiming to help by rapidly testing compounds and speeding up progress.

A significant problem with longevity research and testing in the past has been a lack of robust results. Small animal cohorts and questionable husbandry, combined with poor metrics or protocols, have lead to inconsistent or even conflicting results. In a field as poorly funded as longevity research currently is, we cannot afford to waste money and effort on flawed experiments that do not provide solid evidence of efficacy and high potential for human clinical trials. The Major mouse testing program is working to redress this situation with the help of an international team of dedicated researchers. We hope to deliver the kind of consistent and quality data required to provide definite confirmation of longevity interventions. We plan to initiate large scale testing on already aged mice - the approximate equivalent of a human aged sixty. This means we can produce consistent, accurate and notably faster results to drive progress.

It is also plausible that some interventions, when combined, could have a synergy where the effects are greater than the individual compounds, such as the case with dasatinib and quercetin for the clearance of senescent cells. It is possible there are more synergies to be discovered and this is where the MMTP plans to push forward, not only testing single interventions but also in testing combinations to seek out these powerful synergies. Our researchers are working on a practical solution to test these combinations and at the same time hope to provide the kind of accurate data science demands to prove efficacy.

Thursday, January 14, 2016

Researchers here demonstrate one of a number of approaches to instruct native cells to regenerate more tissue damage than would otherwise have taken place, in this case by delivering a specific microRNA molecule that regulates patterns of gene expression and as a result increases bone regrowth. This is of interest beyond the repair of injuries, as bone mass and strength are progressively lost over the course of aging to produce the condition known as osteoporosis; compensating for this loss will reduce frailty in old age. As the scientific community becomes ever more proficient at cellular programming, this sort of therapy will likely replace the present state of the art in stem cell transplants. Stem cell therapies largely work because the newly introduced cells deliver signals to native cells, but if all of those signals were known and their effects on cells fully understood, the stem cells would not be necessary to achieve beneficial results.

Scientists have developed a polymer sphere that delivers a molecule to bone wounds that tells cells already at the injury site to repair the damage. Using the polymer sphere to introduce the microRNA molecule (miRNA-26a) into cells elevates the job of existing cells to that of injury repair by instructing the cells' healing and bone-building mechanisms to switch on. Using existing cells to repair wounds reduces the need to introduce foreign cells - a very difficult therapy because cells have their own personalities, which can result in the host rejecting the foreign cells, or tumors. The microRNA is time-released, which allows for therapy that lasts for up to a month or longer.

The technology can help grow bone in people with conditions like oral implants, those undergoing bone surgery or joint repair, or people with tooth decay. "The new technology we have been working on opens doors for new therapies using DNA and RNA in regenerative medicine and boosts the possibility of dealing with other challenging human diseases." It's typically very difficult for microRNA to breach the fortress of the cell wall, but the polymer sphere easily enters the cell and delivers the microRNA. Bone repair is especially challenging in patients with healing problems, but researchers were able to heal bone wounds in osteoporotic mice. Millions of patients worldwide suffer from bone loss and associated functional problems, but growing and regenerating high-quality bone for specific applications is still very difficult with current technology. The next step is to study the technology in large animals and evaluate it for use in humans.

Thursday, January 14, 2016

The trend for cancer, like the trend for longevity, is heading slowly in the right direction. Large investments in research produce incremental reductions in cancer mortality, but the shape of this relationship results from the present dominant approaches to cancer treatment, producing therapies that are each limited in their application to only one or a few narrow categories of cancer. Cancer is a spreading tree of variants, and all of the outer branches differ from one another in the details of their cellular biochemistry. Researchers tend to focus on attacking the particular distinctive biochemistry of one branch. This is inefficient and expensive, but it is going to change. The future of cancer treatment will hinge on approaches under development that are capable in principle of application to near all cancers, in particular methods of interfering in the lengthening of telomeres that all cancers rely upon. Once those treatments are a going concern, reduction in cancer mortality will no longer be an incremental trend.

Every year, the American Cancer Society estimates new cancer cases and deaths in the U.S. for the current year and compiles the most recent data on cancer incidence, mortality, and survival. Steady reductions in smoking combined with advances in cancer prevention, early detection, and treatment have resulted in a 23% drop in the cancer death rate since its peak in 1991. Overall cancer incidence is stable in women and declining by 3.1% per year in men (from 2009-2012), with one-half of the drop in men due to recent rapid declines in prostate cancer diagnoses as PSA testing decreases. Cancer mortality continues to decline; over the past decade of data, the rate dropped by 1.8% per year in men and 1.4% per year in women. The decline in cancer death rates over the past two decades is driven by continued decreases in death rates for the four major cancer sites: lung, breast, prostate, and colon/rectum.

Death rates for female breast cancer have declined 36% from peak rates in 1989, while deaths from prostate and colorectal cancers have each dropped about 50% from their peak, a result of improvements in early detection and treatment. Lung cancer death rates declined 38% between 1990 and 2012 among males and 13% between 2002 and 2012 among females due to reduced tobacco use. Even as cancer remains the second leading cause of death nationwide, steep drops in deaths from heart disease have made cancer the leading cause of death in 21 states. Heart disease remains the top cause of death overall in the United States. "We're gratified to see cancer death rates continuing to drop. But the fact that cancer is nonetheless becoming the top cause of death in many populations is a strong reminder that the fight is not over. Cancer is in fact a group of more than 100 diseases, some amenable to treatment; some stubbornly resistant. So while the average American's chances of dying from the disease are significantly lower now than they have been for previous generations, it continues to be all-too-often the reason for shortened lives, and too much pain and suffering."

Friday, January 15, 2016

Researchers here argue that the common study methodology of assessing weight only at a single point in time greatly underestimates the increased mortality rate produced by choosing to become overweight, or worse, obese. The trajectory of weight over time is a significant factor, and being overweight at any time in life increases risk even if that weight is lost later. The longer an individual is overweight, the more damage is done:

Researchers have found that prior studies of the link between obesity and mortality are flawed because they rely on one-time measures of body mass index (BMI) that obscure the health impacts of weight change over time. The new study maintains that most obesity research, which gauges weight at only a single point in time, has underestimated the effects of excess weight on mortality. Studies that fail to distinguish between people who never exceeded normal weight and people of normal weight who were formerly overweight or obese are misleading because they neglect the enduring effects of past obesity and fail to account for the fact that weight loss is often associated with illness. When such a distinction is made, the study finds, adverse health effects grow larger in weight categories above the normal range, and no protective effect of being overweight is observed.

Researchers tested a model that gauged obesity status through individuals' reporting of their lifetime maximum weight, rather than just a "snapshot" survey weight. They found that the death rate for people who were previously overweight, but reported normal weight at the time of survey was 27 percent higher than the rate for people whose weight never exceeded that category. The researchers used data from the large-scale National Health and Nutrition Examination Survey, linking data available from 1988 to 1994 and 1999 to 2010 to death certificate records through 2011. The survey asked respondents to recall their maximum lifetime weight, as well as recording their weight at the time of the survey. Of those in the normal-weight category at the time of the survey, 39 percent had transitioned into that category from higher-weight categories.

The study used statistical criteria to compare the performance of various models, including some that included data on weight histories and others that did not. The researchers found that weight at the time of the survey was a poor predictor of mortality, compared to models using data on lifetime maximum weight. "The disparity in predictive power between these models is related to exceptionally high mortality among those who have lost weight, with the normal-weight category being particularly susceptible to distortions arising from weight loss. These distortions make overweight and obesity appear less harmful by obscuring the benefits of remaining never obese."

Friday, January 15, 2016

The immediate benefits of targeted systems of cancer treatment are fairly straightforward: if a clinic can deliver cell-killing payloads directly to cancer cells, then far lower doses are necessary. This is why the development of targeting methodologies that can reach and accurately distinguish cancer cells is in many ways more important at the present time than the development of actual therapeutics. There are a lot of existing ways to kill cancer cells, and many can be used in a targeted way, reducing their unpleasant and debilitating side-effects in cancer patients while achieving the same or better outcomes.

The cancer drug paclitaxel just got more effective. For the first time, researchers from the have packaged it in containers derived from a patient's own immune system, protecting the drug from being destroyed by the body's own defenses and bringing the entire payload to the tumor. "That means we can use 50 times less of the drug and still get the same results. That matters because we may eventually be able to treat patients with smaller and more accurate doses of powerful chemotherapy drugs resulting in more effective treatment with fewer and milder side effects."

The work is based on exosomes, which are tiny spheres harvested from the white blood cells that protect the body against infection. The exosomes are made of the same material as cell membranes, and the patient's body doesn't recognize them as foreign, which has been one of the toughest issues to overcome in the past decade with using plastics-based nanoparticles as drug-delivery systems. "Exosomes are engineered by nature to be the perfect delivery vehicles. By using exosomes from white blood cells, we wrap the medicine in an invisibility cloak that hides it from the immune system. We don't know exactly how they do it, but the exosomes swarm the cancer cells, completely bypassing any drug resistance they may have and delivering their payload."

In their experiment, the team extracted exosomes from mouse white blood cells and loaded them with paclitaxel. They then tested the treatment - which they call exoPXT - against multiple-drug-resistant cancer cells in petri dishes. The team saw that they needed 50 times less exoPXT to achieve the same cancer-killing effect as formulations of the drug currently being used, such as Taxol. The researchers next tested the therapy in mouse models of drug-resistant lung cancer. They loaded the exosomes with a dye in order to track their progress through the lungs and found that the exosomes were thorough in seeking out and marking cancer cells, making them a surprisingly effective diagnostic tool in addition to being a powerful therapeutic.


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