Fight Aging! Newsletter, March 28th 2016

FIGHT AGING! NEWSLETTER
March 28th 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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CONTENTS

  • NASA and New Organ Develop the Vascular Tissue Challenge
  • Anders Sandberg on Working Towards Radical Life Extension
  • Arguing a Primary Role for Astrocytes in Neurodegeneration
  • Remember that Professional Ethicists Justify their Wages by Inventing Problems
  • The Reasonable Wager of Cryonics
  • Latest Headlines from Fight Aging!
    • Supplying the Aging Brain with More Energy
    • Dopamine Receptor Level Influences Mouse Lifespan via Behavioral Changes
    • Increased Generation of Mitochondrial Reactive Oxygen Species Tends to Slow Aging in Laboratory Species
    • Cardiovascular Health Correlates with Brain Health
    • Preserved Embryonic Kidney Tissue Grows into New Kidneys in Adult Animals
    • A Correlation Between Periodontitis and Cognitive Decline in Alzheimer's Disease
    • A New Method for Early Detection of Amyloid in Aging Tissues
    • Physical Activity Associates with Improved Brain Health
    • Arguing for Intestinal Dysfunction as an Important Component in Degenerative Aging
    • On Rejuvenation of Muscle Stem Cell Function

NASA AND NEW ORGAN DEVELOP THE VASCULAR TISSUE CHALLENGE
https://www.fightaging.org/archives/2016/03/nasa-and-new-organ-develop-the-vascular-tissue-challenge.php

The news for today is that NASA's Centennial Challenges Program and the Methuselah Foundation's tissue engineering initiative New Organ have joined forces to develop the Vascular Tissue Challenge, which is currently public in a draft form as an RFI. The intent is to divide a 500,000 purse between up to three teams who can advance the state of the art in tissue engineering by reliably producing thick sections of vascularized living tissue.

I'm sure you've all seen the announcements roll in over the past few years as research groups have built small organoids that function correctly for their organ type: slivers of pancreatic tissue, thymus tissue, kidney tissue, and so forth. It has, I think, been amply demonstrated that the research community has the development of methodologies needed to build complex, functional tissue well in hand. There is a great deal that can be done with even such tiny slices of tissue, ranging from integration into tools that speed research to use as matched tissue patches for patients with damaged organs. A little bit of a pancreas or a liver - or a dozen little bits, or more - is actually quite useful in the context of diseases, age-related and otherwise, that cause progressive damage to those organs.

However, not all is roses and rainbows in the field. Growing much larger sections of tissue from the starting point of cells and entirely artificial scaffolds, with the goal of creating whole organs to order, as needed, and matched to the recipient patient, remains to be accomplished. The proliferation of organoids can be contrasted with the absence of larger solid structures. The challenge here, and this has been the blocking issue for a decade, is that the research community cannot yet reliably create tissue that is equipped with the network of tiny blood vessels needed to keep the cells alive and provisioned with nutrients. Thinner tissues can get by without blood vessels, as fluids will diffuse through their structure, but the blood vessels are absolutely required by any tissue much thicker than a centimeter or so.

This is why decellularization of donor organs has taken off: stripping out the cells is is a way to obtain a scaffold, the natural extracellular matrix, that has the intricate blood vessels and the chemical cues to guide newly introduced cell populations to repopulate and rebuild the correct structures. This cannot yet be done for artificial scaffold materials, such as those turned out by 3-D printers, or at least not in anything more than a very early and limited way. Once microvasculature can be produced in engineered tissue in a robust fashion, however, the gate is flung open and the creation of organs in a variety of ways will happen just a few years later at most. Given all of this, vascularization of tissue is an important goal, and a good place to add incentives into the research process.

Draft Vascular Tissue Challenge

The Vascular Tissue Challenge is a 500,000 prize purse to be divided among the first three teams who can successfully create thick, human vascularized organ tissue in an in-vitro environment while maintaining metabolic functionality similar to their in vivo native cells throughout a 30-day survival period. NASA's Centennial Challenges Program is sponsoring this prize to help advance research on human physiology, fundamental space biology, and medicine taking place both on the Earth and the ISS National Laboratory. Specifically, innovations may enable the growth of de novo tissues and organs on orbit which may address the risks related to traumatic bodily injury, improve general crew health, and enhance crew performance on future, long-duration missions.

The Vascular Tissue Challenge rules are currently open for public comment. If interested in this challenge, please provide your feedback.

National Aeronautics and Space Administration (NASA) - Centennial Challenges Program - Vascular Tissue Challenge - Request for Information (RFI)

The Centennial Challenges program is seeking input on a Vascular Tissue challenge being considered for start in 2016. The challenge would require competitors to create a thick tissue with fully functioning vascular systems, similar to the tissue found in the heart, lungs, liver or kidney. This RFI is seeking feedback from potential challengers. Comments must be submitted in electronic form no later than 5:00 pm EDT, April 15, 2016.

The ability to provide oxygen and nutrients to thick human tissue by adequate vascularization of layers of cells to ensure metabolic functions similar to native in-vivo tissues has not been reliably demonstrated. Developing this capability will enable new research initiatives that may bring real solutions to organ disease, skin burns and other medical concerns. NASA's objective for this challenge is to produce viable thick-tissue assays above and beyond the current state of the art technology.

Competitors will be asked to produce an in-vitro vascularized tissue that is more than 1 centimeter in thickness in all dimensions at the launch of the trial and maintains greater than 85% survival of the required parenchymal cells throughout a 30-day period. Tissues must provide adequate blood perfusion without uncontrolled leakage into the bulk tissue to maintain metabolic functionality similar to their in-vivo native cells. Histological measurement of the quality and amount of functional performance will be required to determine survival of parenchymal tissue. Teams must demonstrate 3 successful trials with at least a 75% trial success rate to win an award. In addition to the in-vitro trials, teams must also submit a Spaceflight Experiment Concept that details how they would further advance some aspect of their tissue vascularization research through a microgravity experiment that could be conducted in the U.S. National Laboratory (ISS-NL) onboard the International Space Station.

If you happen to know anyone in the tissue engineering community, please do direct their attention towards this initiative.

ANDERS SANDBERG ON WORKING TOWARDS RADICAL LIFE EXTENSION
https://www.fightaging.org/archives/2016/03/anders-sandberg-on-working-towards-radical-life-extension.php

Anders Sandberg is one of the earlier participants in the modern transhumanist movement, perhaps better thought of as a distributed and shifting set of overlapping interest and advocacy groups rather than a movement per se. The core of the transhumanist ideal is the overcoming of limits, the use of technology to expand the choices available within the human condition. The diverse membership of these groups has spread and prospered over the past twenty years, taking influential roles in biotechnology, aging research, cryonics, artificial intelligence, and other related fields. In a sense it is the ideas that matter: the defeat of aging and age-related disease so as to indefinitely extend healthy life; engineering away all of the other causes of pain and suffering; expanding our intelligence; building intelligence; seeking to be far more than we are today. Those of us who propagate these ideas and work towards their realization are in a way water carriers, passing the value along. The more people who do this, the greater the support for transhumanist goals such as achieving effective medical control over aging, the better the prospects become for all of our futures.

Like many of the other futurists who used the early years of the internet to find one another and form a community to talk about the practicality of their visions for a golden future, Anders Sandberg engineered a career from an interest in transcending the limits of the human condition through technological progress. These days he works with the Future of Humanity Institute, itself an outgrowth of a portion of the transhumanist community. This is in large part an advocacy initiative, clothed as academia, seeking to put forward a vision - with supporting evidence - for a far better future to a public that hasn't really given the topic much thought. To the world at large, tomorrow is anticipated to be much the same as today. It is strange that this is the case in a time of such rapid progress in science and technology, but most people expect to live in a future that looks much the same as the present, barring small changes in fashion and culture. The possibilities are so much greater than that, however. For one, we stand on the verge of being able to treat the causes of aging, and many people alive today will as a consequence live for long enough to see aging entirely defeated, rejuvenation robustly achieved, and their lives and healthspans made unlimited in length. That shortly beyond that lies an explosion of intelligence and culture out into the universe, of a size and scope to make our present world seem the smallest mote by comparison, is almost by the by.

Below find a link to the PDF version of a radio essay by Sandberg presented at BBC Radio 3, one portion of a much broader effort to make more people pay attention to what could be done to make the world a better place, and our lives radically different and less limited as a result.

Desperately seeking eternity (PDF)

People have tried to extend their lives since time immemorial. The oldest great work of literature, the epic of Gilgamesh is partially about the king's search for the herb of immortality. Up until recently we did not have any deep understanding of what ageing truly is, so doing anything about it was hard. That has changed radically in recent decades. We now understand why we age, and can in the lab even slow it down in test animals. Some treatments can prolong animal lifespans by up to 40 per cent whether by removing senescent cells, reducing caloric intake, or influencing certain metabolic pathways. While none of the methods are likely to carry over straight to humans, the fact that we have gone from ageing being an immutable fact to something that can be manipulated is already revolutionary.

Even if the first clinical methods for slowing ageing arrive a few decades ahead, that is still good news for the majority of people living today. Especially since slowed ageing gives you more years of medical progress. While nothing is certain, it looks like in the long run ageing may become just another treatable chronic disease. Some would argue that slowing ageing is all about achieving immortality. But treating ageing directly makes sense simply in terms of health: ageing is a direct contributor to heart disease, diabetes, weakened immune system, Alzheimer's and many other maladies. Life extension cannot give us eternal life: besides ageing, we are killed by diseases, accidents and violence. And if we fix those, we are still finite beings in a universe ruled by probability. Sooner or later we will be unlucky and perish. But we can maybe make this probability so low that it does not matter much in practice. The real issue might be what we would do if we had indefinite lifespans.

Every time someone dies, a library burns. The experiences, skills, and relationships painstakingly built across a lifetime disappear forever. We cannot prevent any particular library from eventually having a fire, but we can make sure the fires are rare. Humans are precious, and that is why we should not wish them to age. Some might say we need a change of generations to keep our culture youthful. Yet, to continue the library metaphor, few people think the way of maintaining a successful culture is to burn the archives and art museums. There are better ways of changing things than killing the old guard. The physicist Max Planck said that science advances one funeral at a time, but in practice many radical new ideas do sweep the scientific world faster than scientists are being replaced. In the social arena we have seen struggles to extend human rights succeeding faster and faster, despite people living longer: compare the time it took for female suffrage to go from academic idea to political practice with the time it took gay rights to make the leap from unthinkable to orthodox. At any rate, if long lives actually do slow social changes there are still better ways of speeding it up than letting people die prematurely. We have term limits in politics: maybe we should have them for professors and CEOs too.

I have met 18 year olds claiming they do not want to live beyond 20 because they will be old and decrepit, while my 105 year old grandmother still potters on since dying is simply not done. Some people find new meaning again and again, others feel suicidal about Sunday afternoons. It is not uncommon to envision one's life as a book, and then assume it must have a beginning, a middle and an end. This is reasonable since we tend to construct our identities as narratives: we often tell stories about who we are, what we have done, and where we are going, so thinking of a life this way comes naturally to us. But a book can be a short pamphlet, a thick epic, or maybe a never-ending fantasy series ... which one would we want to be like?

Many people who wish for radical life extension are afraid of dying. This is a bad motivation: sooner or later they will run out of time anyway, and living just to avoid something is a diminished way of life. They are not hoping for something of value, merely the avoidance of loss. The problem with death is not just that it can be painful, but that it also irreversibly prevents any more experience, any more action. Our social bonds are broken. Pain can be dealt with, but these other factors point at what makes life worth living. We should seek to live longer because we love life. We should wish to experience good things, gain wisdom, and interact with people in important ways. A long and healthy life is quite useful for this.

ARGUING A PRIMARY ROLE FOR ASTROCYTES IN NEURODEGENERATION
https://www.fightaging.org/archives/2016/03/arguing-a-primary-role-for-astrocytes-in-neurodegeneration.php

In the open access paper I'll point out today, the authors provide a high level overview of the evidence that suggests immune cells called astrocytes play a primary role in the progression of age-related neurodegenerative conditions. The immune system of the brain is quite different, somewhat more intricate, and more specialized than its equivalents elsewhere in the body, and those systems are themselves very complex and only partially mapped. The brain is shielded from the sort of haphazard exposure to toxins and pathogens that other tissues must face by the existence of the blood-brain barrier, a shield lining the blood vessels that pass through the brain. The portfolio of tasks carried out by the immune system within that barrier has shifted accordingly. In the brain specialized types of immune cell, neuroglia such as microglia and the aforementioned astrocytes, undertake a very broad range of activities beyond simply sweeping up waste and destroying pathogens, and are tightly integrated into the core functions of the brain. They participate in some of the most important and fundamental neural processes, such as the formation and alteration of connections between neurons, for example.

Most of the common diseases of aging have an inflammatory component. Pathology and degeneration is accelerated by the decline of the immune system into a state of ineffective, constant inflammation. The causes of that decline are discussed elsewhere, and include a sort of misconfiguration perhaps brought on by exposure to persistent pathogens such as cytomegalovirus, and the slow and falling rate of generation of replacement immune cells in adults. Effectively addressing these causes seems a very plausible task for the next couple of decades, based on promising studies in animals from the past few years. In the brain, things are going to be much the same at the high level, but different in the details. A lot of research from recent years points to microglia as the agents of neural inflammation, but the authors here suggest that there is just as much evidence for astrocytes to be involved in the generation of a harmful inflammatory state:

Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System

Since the beginning of the 20th century relentlessly progressive neurological diseases have classically been attributed to a primary neuronal dysfunction. This affirmation applies to Parkinson disease (PD), Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), among others. Therefore, most investigations have been carried out under this belief, leading to the coining of the term "neurodegeneration." In the 90s, a new era began that considered the possibility of a more important role of the so far neglected neuroglia. This led to different findings opposed to the belief of the astrocytes sole function being neuronal structural support.

Astrocytes have been found to have a much more active role that the one predicted by the earlier guessers. Particularly, they are involved in the ions exchange with neurons, they are organized as a syncytium that allows them to interchange information with other astrocytes residing in a defined net through different types of Ca+++ signals while regulating the release of signaling molecules involved in the production of trophic factors, transmitters and transporters that when released to the extracellular medium will modulate the synaptic activity synchronizing the neuronal functions. Also they are involved in the extracellular K+ uptake, in synaptogenesis and gene expression; adapting, at the same time, the permeability of the blood-brain barrier to the neuronal and synaptic needs.

Slowly but relentlessly, the results of several studies have confirmed the existence of an active role played not only by the astrocytes but also by microglia. Mounting evidence suggests that astrocytes modulate microglial response, through the establishment of a complex cross-talk between both types of cells mediated by the production of different chemokines and cytokines. Therefore, we think that the broader term primary degenerative disorders of the central nervous system (PDD CNS) alludes to the complex pathology of these diseases (in contrast to the classic term neurodegeneration). An early astrocytic dysfunction in the PDDs of the CNS has been broadly observed. We advocate that these observations obtained from different degenerative pathologies, but mostly from experimental animal studies, may be the trees from a forest characterized by primary astrocytic dysfunction as the main process starting them.

REMEMBER THAT PROFESSIONAL ETHICISTS JUSTIFY THEIR WAGES BY INVENTING PROBLEMS
https://www.fightaging.org/archives/2016/03/remember-that-professional-ethicists-justify-their-wages-by-inventing-problems.php

To my eyes professional ethics is a self-defeating field, in that it appears to corrode the ethics of those who participate. The basic problem here is one of incentives, an age-old story. The funding and standing for a professional ethicist depends upon finding a continual supply of ethical issues that can be used to justify the continued employment and budget of said ethicist. When it comes to medicine, however, and for most other fields of human endeavor, there is no such supply. All of the true ethical problems in medicine and medical science were solved long ago and the solutions finessed in great detail across centuries of thought and writing. These ethical problems in medicine are few in number and basically boil down to what to do in limited resource triage situations (the best you can), whether or not to harm people deliberately (no), and whether or not to work towards better medicine (yes). Thus a gainfully employed professional ethicist must invent new, not-actually-real problems pretty much from the get-go, or give up and admit that the job is pointless. Natural selection then ensures that we only see those who prefer the money over the integrity.

We can measure the decay in the ethics of professional ethicists by the degree to which they can contort themselves to produce different answers to those I provided for the few legitimate ethical challenges in medicine above. If you spend any time at all following the progression of aging research and efforts to extend healthy human lives, then you will see a great many ethicists demonstrating the decay of their personal ethics in just this fashion. There are any number of salaried ethicists willing to throw their newly invented logs in front of the wheels of progress in this field, and tell us just how terrible it would be to cure age-related disease and lengthen productive and healthy human lives. The processes of aging and the age-related disease it produces are the greatest cause of pain, suffering, and death in the world by a very large margin. The way to remove all of this pain, suffering, and death is to build therapies that can repair the causes of aging, therefore preventing all resulting disease and disability. That will also extend life, because healthy, youthful people have a very low mortality rate. Yet the cadre of professional ethicists weigh their present position against the lives and livelihoods of billions and go right ahead with their flimsy objections.

That this whole situation exists, that institutions responsible for providing and improving technologies have increasingly indulged a parasitical arm that siphons off funding in order to obstruct the processes of improvement, is yet another sign that the world we live in is far from perfect. It also suggests that human nature leaves much room for improvement in the years to come, once such an engineering project becomes possible. In this article we see an example of the type of "ethics" I find so objectionable, though it isn't as though one has to try hard to find other examples:

The Tricky Ethics of Living Longer

Tortoises typically live well past 100 and might be able to survive even longer. In 2006, a giant tortoise thought to be 255 years old died at India's Calcutta Zoo. We humans have yearned throughout history for longevity and even immortality. Science has already helped us live much longer than our ancestors did, by improving hygiene and protecting us from infectious diseases through antibiotics and vaccines. But current research into extending our lives presents an interesting twist. It also raises ethical questions.

I spoke to experts who foresee a coming revolution in medicine, where we treat age instead of disease. To do this, they are trying to figure out how aging works at the molecular level. The goal isn't exactly immortality. Instead, these scientists have noticed that a variety of diseases, from cancers to Alzheimer's, share aging as a major risk factor. Rather than spending a lot of money to treat each disease individually, why not tackle the root cause? What if there was a pill that slowed how our cells age, letting us avoid age-related illnesses - and also likely extending our lives? It's a safe bet that when most of us contemplate the gaping abyss of mortality, we decide we'd like to postpone that fate as long as possible, while remaining mobile, independent, and mentally sharp. If we must die, let us go peacefully in our sleep, at home, when we're at least 100.

But how might such a revolution ripple across society? Life expectancy already varies greatly. It's tied to education, wealth, and even where you live. According to Alexander Capron, an expert in health policy and ethics at the University of Southern California Gould School of Law, life-extending therapies could exacerbate these differences. For example, if these treatments are expensive, or aren't covered by affordable health care plans, only people with disposable cash will have access. This means people with money and resources will have the choice to live longer. Those who don't, won't.

"We can't cherry-pick the costs or savings to focus on," says Patrick Lin, director of the Ethics + Emerging Sciences Group at California Polytechnic State University. Instead, he says,to fairly examine the ethics involved, we should consider impacts both on the individual and society level. "Yes, healthier people may mean lower health costs and more productivity, but that's a partial picture at best. We'd also have to consider the impact of extended lives on, say, Social Security, pensions, job openings given fewer retirements, crime from unemployment, natural resources, urban density, copyright durations, prison sentences, and many, many other effects."

Another effect to consider is how families pass on their legacies, says Nigel Cameron, president of the Center for Policy on Emerging Technologies. Life extension would mean more time with extended family. But it will also mean that inheritance and property will transfer later and less often, which could put more pressure on younger generations to acquire property independently. Lifespan extension could also influence politics and social change, with different age groups pushing for different policies. "There are big generational differences in economic and social interests," Cameron says. "The whole thing becomes much more extended if people live longer, much more competitive."

Still, the research that could lead to life extension is happening, so the conversation about its implications should, too. "Personally, I'm cautiously optimistic about life extension research, but we need to be careful to manage the hype and not ignore the risks," says Lin. "Will we ever become immortal? I don't know, and no one else can see that far, either. But even extending our lives another 20-100 years or more, to start with, is a game-changer."

THE REASONABLE WAGER OF CRYONICS
https://www.fightaging.org/archives/2016/03/the-reasonable-wager-of-cryonics.php

Cryonics has been in the press and the broader online media seemingly more often than not of late. Perhaps it is the season for it. As is the case for many other areas of science and technology in this era of rapid progress, matters in the cryonics industry are on the verge of moving from reasonable but unproven hypothesis to self-evident extrapolation of the uses of a new technology.

The reasonable but unproven hypothesis has been that suitable methods of low-temperature preservation, vitrification being the present standard, will maintain the fine structure of neurons and neural connections sufficiently well that the data of the mind is also preserved. Thus people can be preserved at death, and given the chance at a new life in a future in which restoration becomes technologically feasible. So long as the data is preserved, that restoration remains a possibility. That this data is overwhelmingly static, in the form of encoded structures, is demonstrated by the survival and recovery of cold water drowning victims, among other evidence. The core cryonics hypothesis has held up very well in the face of the past few decades of progress in our understanding of the mechanisms of memory, and progress towards being able to mount initial demonstrations of preserved structure in neural tissue and preserved memory in lower animals.

The phase in which cryonics moves to being an obvious extrapolation of a new medical technology starts when reversible vitrification is used to preserve donor organs indefinitely, removing many of the logistical issues in that industry. When organs are grown from cells to order rather than donated, again reversible vitrification will make the logistics of that tissue engineering a lot easier. This is actually pretty close to realization in the grand scheme of things. Experiments have been carried out in animals with some degree of success, and more researchers are now interested in fixing up the last set of issues in vitrification and thawing protocols that make reversible vitrification hard at present. In a world in which organs are regularly vitrified for storage, then used for transplant years later, it will become pretty obvious to the public at large that storing the brain or the body as a whole is similarly viable.

People who pay more attention to the state of technology still under development are already at that point, of course. If organized well, end of life cryopreservation is a very reasonable wager on the course of the future for someone who will age to death before the advent of sufficiently effective rejuvenation treatments. Few people realize this, unfortunately, and so near all of humanity let themselves fall into oblivion, thinking there is no alternative.

Why Cryonics Makes Sense

We think of the divide between life and death as a distinct boundary, and we believe that at any given point, a person is either definitively alive or definitively dead. Today, dead means the heart has been stopped for 4-6 minutes, because that's how long the brain can go without oxygen before brain death occurs. The brain 'dies' after several minutes without oxygen not because it is immediately destroyed, but because of a cascade of processes that commit it to destruction in the hours that follow restoration of warm blood circulation. Restoring circulation with cool blood instead of warm blood, reopening blocked vessels with high pressure, avoiding excessive oxygenation, and blocking cell death with drugs can prevent this destruction. With new experimental treatments, more than 10 minutes of warm cardiac arrest can now be survived without brain injury. Future technologies for molecular repair may extend the frontiers of resuscitation beyond 60 minutes or more, making today's beliefs about when death occurs obsolete.

In other words, what we think of as "dead" actually means "doomed, under the current circumstances." Someone fifty years ago who suffered from cardiac arrest wasn't dead, they were doomed to die because the medical technology at the time couldn't save them. Today, that person wouldn't be considered dead yet because they wouldn't be doomed yet. Instead, someone today "dies" 4-6 minutes after cardiac arrest, because that happens to be how long someone can currently go before modern technology can no longer help them. Cryonicists view death not as a singular event, but as a process - one that starts when the heart stops beating and ends later at a point called "the information-theoretic criterion for death" when the brain has become so damaged that no amount of present or future technology could restore it to its original state or have any way to retrieve its information.

Here's an interesting way to think about it: Imagine a patient arriving in an ambulance to Hospital A, a typical modern hospital. The patient's heart stopped 15 minutes before the EMTs arrived and he is immediately pronounced dead at the hospital. What if, though, the doctors at Hospital A learned that Hospital B across the street had developed a radical new technology that could revive a patient anytime within 60 minutes after cardiac arrest with no long-term damage? What would the people at Hospital A do? Of course, they would rush the patient across the street to Hospital B to save him. If Hospital B did save the patient, then by definition the patient wouldn't actually have been dead in Hospital A, just pronounced dead because Hospital A viewed him as entirely and without exception doomed.

What cryonicists suggest is that in many cases where today a patient is pronounced dead, they're not dead but rather doomed, and that there is a Hospital B that can save the day - but instead of being in a different place, it's in a different time. It's in the future. That's why cryonicists adamantly assert that cryonics does not deal with dead people - it deals with living people who simply need to be transferred to a future hospital to be saved.

Cryonics and the shifting goal posts of death

The statement "a dead person cannot be revived" seems so obvious that it is hardly worth writing down, but when you look a little deeper, it is not so clear cut. A few decades ago, someone who suffered a cardiac arrest was considered irreversibly dead. Move forward to today, and we routinely bring those people back from the brink. So, in some regards, our definition of what constitutes "dead" has shifted. It is this kind of stance that cryonics researchers often take when faced with dissenters. Their argument, whether you are prepared to run with it or not, is that death has already had its goal posts moved, so who is to say that they cannot be moved again?

Today, brain death, rather than cardiac death, is considered the stamp of finality. But even this, it might be argued, is not entirely infallible. For instance, in 1955, James Lovelock cooled a rat to just above 0°C. Its brain completely stopped its normal business. However, Lovelock managed to reanimate the rodent by warming it back up. Even in a real life situation - cold water drowning - similar findings have been described. A young girl was resuscitated after an astonishing 66 minutes of total submersion in freezing water. After an hour under water, most people would consider the individual irreversibly dead. We now know this is not always the case. Importantly, her memories and personality were still intact. This is not the only case of people "surviving clinical death." Cases like these have spawned a saying in some emergency rooms: "Nobody is dead until warm and dead."

LATEST HEADLINES FROM FIGHT AGING!

SUPPLYING THE AGING BRAIN WITH MORE ENERGY
Monday, March 21, 2016
https://www.fightaging.org/archives/2016/03/supplying-the-aging-brain-with-more-energy.php

A growing dysfunction in energy metabolism, such as might be caused by higher levels of mitochondrial damage in cells, has been implicated in the progression of age-related neurodegenerative conditions. The neurons of the brain collectively require a lot of energy to operate, and thus it is reasonable to consider that disruptions in the processes that provide that energy are significant. Such disruptions are not the root causes of neurodegeneration, however, but rather secondary or later effects of an accumulation of the fundamental cell and tissue damage that causes aging. One possible compensatory approach to therapy, a treatment that doesn't address the root causes but instead tries to modestly slow down their consequences, would involve delivering more energy stores to neurons. The researchers here report on a fairly simple proof of concept in mice:

The human brain has a prodigious demand for energy - 20 to 30% of the body's energy budget. In the course of normal aging, in people with neurodegenerative diseases or mental disorders, or in periods of physiological stress, the supply of sugars to the brain may be reduced. This leads to a reduction in the brain's energy reserves, which in turn can lead to cognitive decline and loss of memory. But new research on mice shows that the brain's energy reserves can be increased with a daily dose of pyruvate, a small energy-rich molecule that sits at the hub of most of the energy pathways inside the cell. These results need to be replicated in human subjects, but could ultimately lead to clinical applications.

"In our new study, we show that long-term dietary supplementation with pyruvate increases the energy reserves in the brain, at least in mice, in the form of the molecules glycogen, creatine, and lactate. The mice became more energetic and increased their explorative activity. It appears that these behavioral changes are directly due to the effect of pyruvate on brain function, since we didn't find that these mice had developed greater muscle force or endurance. For example, chronic supplementation with pyruvate facilitated the spatial learning of middle-aged (6- to 12-months-old) mice, made them more interested in the odor of unfamiliar mice, and stimulated them to perform so-called "rearing", an exploratory behavior where mice stand on their hind legs and investigate their surroundings. The dose necessary to achieve these effects was about 800 mg pyruvate per day - which corresponds to about 10 g per day in humans - given to the mice in normal chow over a period of 2.5 to 6 months. A single large dose of pyruvate injected directly into the blood stream had no detectable effect.

DOPAMINE RECEPTOR LEVEL INFLUENCES MOUSE LIFESPAN VIA BEHAVIORAL CHANGES
Monday, March 21, 2016
https://www.fightaging.org/archives/2016/03/dopamine-receptor-level-influences-mouse-lifespan-via-behavioral-changes.php

An interesting study here shows that lower levels of dopamine D2 receptor (D2R) achieved via genetic engineering in mice lead to a modestly reduced life span. This result appears to be mediated by behavioral changes, such as lesser physical activity, greater food intake, and consequently higher body mass, rather than by any other mechanism.

Dopamine (DA) is known to be implicated in a variety of functions including reward and physical mobility. The DA system has been known to be vulnerable to the effects of aging. Human imaging studies have shown that the rate of D2R loss during aging occurs at approximately 10% per decade. While it is apparent that D2R decreases in both human and rodent brains as a result of physiological deterioration following senescence, the functional consequences of this decline on behavior and lifespan are not fully understood. The D2R ability to modulate reward seeking behavior, motivation, and expectation of a reward, influences feeding behavior. Alterations in the DA reward system can lead to abnormal eating behavior; the down regulation of D2R receptor signaling is thought to reduce sensitivity to reward, providing an incentive to overeat.

An enriched environment (EE) is characterized by sensory, motor and social stimulation relative to standard housing conditions. The incorporation of exercise is an important component of an EE and its benefits have been shown to be a powerful mediator of brain function and behaviour. To determine whether the D2R gene is involved in the mechanism of environmental enrichment, different housing conditions were examined in mice. This study hypothesized that the D2 gene, in the presence of an EE, significantly influenced lifespan, body weight, and locomotor activity.

Results supported the hypothesis. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.

These data provide the first evidence of the role of D2R gene on lifespan in mammals. Mice with normal or reduced expression of the D2 gene and housed in an EE showed significant increases in lifespan. However, mice deficient in D2 failed to benefit from an EE. The D2 gene function appears to be a critical mediator linked to the behavior and lifespan effects associated with an EE. D2's mediating role, however is environment-dependent and was not observed in mice raised in DE conditions. The anti-aging and neuroprotective factors associated with exercise may be the key factor as to why Drd2 +/+ and Drd2 +/- EE mice showed increased lifespan in comparison to their DE cohorts.

INCREASED GENERATION OF MITOCHONDRIAL REACTIVE OXYGEN SPECIES TENDS TO SLOW AGING IN LABORATORY SPECIES
Tuesday, March 22, 2016
https://www.fightaging.org/archives/2016/03/increased-generation-of-mitochondrial-reactive-oxygen-species-tends-to-slow-aging-in-laboratory-species.php

The interactions between molecular damage in cells, repair system activity, the generation of reactive oxygen species (ROS) in mitochondria capable of causing damage, and individual or species longevity are far from simple. The free radical theory of aging and its variants were early and in hindsight overly simplistic views based on the observation that the presence of ROS and their signs of their damage increase with age. However, numerous methods of slowing aging in short-lived animals involve increases in the rate at which mitochondria produce reactive oxygen species. These molecules are signals as well as sources of damage, and an increase can cause repair systems to overcompensate, producing a net gain in cellular maintenance and reduction in overall levels of damage. It isn't just repair: many of the benefits of exercise are also keyed to temporary increases in ROS levels.

Testing the predictions of the Mitochondrial Free Radical Theory of Ageing (MFRTA) has provided a deep understanding of the role of reactive oxygen species (ROS) and mitochondria in the ageing process. However those data, which support MFRTA are in the majority correlative (e.g. increasing oxidative damage with age). In contrast the majority of direct experimental data contradict MFRTA (e.g. changes in ROS levels do not alter longevity as expected). Unfortunately, in the past, ROS measurements have mainly been performed using isolated mitochondria, a method which is prone to experimental artefacts and does not reflect the complexity of the in vivo process. New technology to study different ROS (e.g. superoxide or hydrogen peroxide) in vivo is now available; these new methods combined with state-of-the-art genetic engineering technology will allow a deeper interrogation of, where, when and how free radicals affect ageing and pathological processes. In fact data that combine these new approaches, indicate that boosting mitochondrial ROS in lower animals is a way to extend both healthy and maximum lifespan.

A topic highly debated in the field is the role that mitochondrial ROS play in age related and non-age related pathological processes with a mitochondrial component. Are ROS a cause or a consequence of mitochondrial dysfunction? This is a very important question, which needs to be addressed, since it will affect the treatment of those pathologies. Considering all the available evidence, it is plausible to suggest that ROS can have both positive and negative roles depending on the type of the ROS, when, where and how much is produced. Therefore, we can talk about "Good" and "Bad" ROS. "Good" ROS being low reactivity ROS (i.e. superoxide or hydrogen peroxide) produced at specific places, at specific times and in moderate amounts and "Bad" ROS being highly reactive ROS (or low reactive ROS as hydrogen peroxide or superoxide produced at high concentrations) generated continuously and unspecifically. Experimental evidence suggests that boosting ROS production can contribute to the maintenance of cellular homeostasis and positively affect lifespan when induced correctly, whereas if produced in excess or in an unspecific way, they shorten survival and accelerate the onset of age-related disease.

CARDIOVASCULAR HEALTH CORRELATES WITH BRAIN HEALTH
Tuesday, March 22, 2016
https://www.fightaging.org/archives/2016/03/cardiovascular-health-correlates-with-brain-health.php

Aging is a global phenomenon in the body, so measures of its progression in different organs tend to correlate well. In some cases this is because there is direct causation involved rather than it being a matter of independent processes that spring from the same root causes. The health of the cardiovascular system is demonstrably connected to the health of the brain. For example, the structural failure of small blood vessels in the brain, driven by increased blood pressure and the processes of stiffening in blood vessel walls, destroys small areas of brain tissue on an ongoing basis. The more such destruction, the worse off the individual, and the greater the age-related loss of mental capacity.

Researchers studied a racially diverse group of older adults and found that having more ideal cardiovascular health factors was associated with better brain processing speed at the study's start and less cognitive decline approximately six years later. At the beginning of the study, 1,033 participants in the Northern Manhattan Study (average age 72; 65 percent Hispanic, 19 percent black and 16 percent white), were tested for memory, thinking and brain processing speed. Brain processing speed measures how quickly a person is able to perform tasks that require focused attention. Approximately six years later, 722 participants repeated the cognitive testing, which allowed researchers to measure performance over time.

The researchers found that having more ideal cardiovascular health factors was associated with better brain processing speed at the initial assessment. The association was strongest for being a non-smoker, having ideal fasting glucose and ideal weight. Having more cardiovascular health factors was associated with less decline over time in processing speed, memory and executive functioning. Executive function in the brain is associated with focusing, time management and other cognitive skills. While this study suggests achieving ideal cardiovascular health measures is beneficial to brain function, future studies are needed to determine the value of routinely assessing and treating risk factors, such as high blood pressure, in order to reduce brain function decline.

PRESERVED EMBRYONIC KIDNEY TISSUE GROWS INTO NEW KIDNEYS IN ADULT ANIMALS
Wednesday, March 23, 2016
https://www.fightaging.org/archives/2016/03/preserved-embryonic-kidney-tissue-grows-into-new-kidneys-in-adult-animals.php

This is an interesting approach to organ transplant and regrowth, demonstrated initially in rabbits. The researchers believe it may also provide the basis for xenotransplantation between species, but that remains to be seen:

Researchers have discovered a way of freezing embryonic animal kidneys so that they can later be warmed up and grown into full-size organs without the risk of rejection by their recipient. The team found that when precursor kidney tissue from 16-day-old rabbit embryos is implanted in adult rabbits, it develops into an adult kidney, connecting itself to the host's own blood supply. The host doesn't recognise the organ as strange, and permits it to connect to the blood system. The adult rabbits did not reject the foreign kidneys because the embryonic tissue was transplanted before it had started producing the protein that would alert a host's immune system to foreign cells. Researchers believe that when the protein is eventually produced, it matches that of the host instead.

The team then investigated whether it might be possible to create a biobank of potential organs for transplant. Large organs cannot be frozen to prevent decay because water in them turns to ice as they freeze, destroying delicate call structures. But the embryonic precursor kidneys are much smaller, enabling them to use a cryopreservation process called vitrification that can prevent ice formation by pumping antifreeze into an organ before cooling it to -196 °C. This technique is normally only used to freeze small tissues such as human eggs because it is difficult to get the antifreeze around larger, more complicated organs. The team managed to successfully vitrify and store the precursor kidneys for three months in liquid nitrogen. They then warmed the tissue and transplanted it into adult rabbits. Some 25 per cent of the transplants grew into healthy adult organs in the host - not as high as the 50 per cent success rate they achieved with fresh embryonic tissue, but still good.

The results suggest we may one day be able to create a long-term biobank of animal kidneys that provides an unlimited source of organs for transplanting in people. The team is now trialing a similar experiment between rabbits and goats. More than one kidney could potentially be transplanted into larger animals to make up the mass needed for them to act as a native kidney.

A CORRELATION BETWEEN PERIODONTITIS AND COGNITIVE DECLINE IN ALZHEIMER'S DISEASE
Wednesday, March 23, 2016
https://www.fightaging.org/archives/2016/03/a-correlation-between-periodontitis-and-cognitive-decline-in-alzheimers-disease.php

Periodontitis, an inflammatory condition of the gums, can spread the effects of chronic inflammation elsewhere in the body via the circulatory system. It is associated with the progression of a number of common age-related conditions that have an inflammatory component, such as cardiovascular disease. Thus it is worth keeping an eye on progress towards therapies capable of effectively treating inflammatory gum disease. Researchers here add more evidence for the association of Alzheimer's disease progression with periodontitis:

A new study has found a link between gum disease and greater rates of cognitive decline in people with early stages of Alzheimer's disease. Periodontitis or gum disease is common in older people and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Higher levels of antibodies to periodontal bacteria are associated with an increase in levels of inflammatory molecules elsewhere in the body, which in turn has been linked to greater rates of cognitive decline in Alzheimer's disease in previous studies.

In the observational study, 59 participants with mild to moderate Alzheimer's disease were cognitively assessed and a blood sample was taken to measure inflammatory markers in their blood. The majority of participants were followed-up at six months when all assessments were repeated. The presence of gum disease at baseline was associated with a six-fold increase in the rate of cognitive decline in participants over the six-month follow-up period of the study. Periodontitis at baseline was also associated with a relative increase in the pro-inflammatory state over the six-month follow-up period. The authors conclude that gum disease is associated with an increase in cognitive decline in Alzheimer's disease, possibly via mechanisms linked to the body's inflammatory response.

Growing evidence from a number of studies links the body's inflammatory response to increased rates of cognitive decline, suggesting that it would be worth exploring whether the treatment of gum disease might also benefit the treatment of dementia and Alzheimer's disease. In the UK in 2009, around 80% of adults over 55 had evidence of gum disease, whilst 40% of adults aged over 65-74 (and 60% of those aged over 75) had less than 21 of their original 32 teeth, with half of them reporting gum disease before they lost teeth. "A number of studies have shown that having few teeth, possibly as a consequence of earlier gum disease, is associated with a greater risk of developing dementia. We also believe, based on various research findings, that the presence of teeth with active gum disease results in higher body-wide levels of the sorts of inflammatory molecules which have also been associated with an elevated risk of other outcomes such as cognitive decline or cardiovascular disease."

A NEW METHOD FOR EARLY DETECTION OF AMYLOID IN AGING TISSUES
Thursday, March 24, 2016
https://www.fightaging.org/archives/2016/03/a-new-method-for-early-detection-of-amyloid-in-aging-tissues.php

Better methods of detecting the various forms of amyloid as it builds up in tissues with age should result in greater support for development and availability of the means to remove this unwanted form of metabolic waste. Amyloids are present in every individual to some degree, that presence increasing with age, and are known to cause or be associated with numerous age-related diseases. This is one of the fundamental forms of damage that causes aging, yet amyloid levels are rarely assessed in healthy individuals, or even for patients with diseases that are relevant but something other than full-blown amyloidosis. Ideally everyone, healthy or not, should undergo amyloid clearance therapies - like that developed and trialed by Pentraxin for transthyretin amyloid - every few years starting in middle age or earlier.

Researchers have developed a molecular probe that can detect an array of different amyloid deposits in several human tissues. This new probe is extremely sensitive and was used at very low concentrations to correctly identify every positive amyloidosis sample when compared to the traditional clinical tests. The probe also picked up some amyloidosis signals that the traditional methods were unable to detect. This result means that the new probe could be used to detect amyloidosis before symptoms present, leading to faster and hence more effective treatment.

Aggregates of amyloid proteins form and deposit in different tissues which can affect the normal function. As the disease progresses and amyloid deposits grow, tissues become irreversibly damaged. Amyloid deposits can be found in many different organs leading to a wide range of possible symptoms and making diagnosis challenging. To date, the primary mode of diagnosis for amyloidosis has been the Congo red stain. However, evidence from the team shows that their new probe is much more sensitive, being able to detect small amyloid deposits in samples that were previously determined to be amyloid-free.

According to the U.S. Office of Rare Diseases (ORD) amyloidosis is a rare disease, affecting less than 200,000 people in the U.S.. However, the Amyloidosis Foundation suspects that the figures are underreported and that amyloidosis is not that rare - just rarely diagnosed. A more sensitive diagnostic method would help to uncover the reality of the situation. "Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement. It could also be used to identify new types of amyloids and presymptomatic patients who are at risk of developing the disease."

PHYSICAL ACTIVITY ASSOCIATES WITH IMPROVED BRAIN HEALTH
Thursday, March 24, 2016
https://www.fightaging.org/archives/2016/03/physical-activity-associates-with-improved-brain-health.php

Here is another example of recent data on the relationship between levels of physical activity in later life and the health of the brain. With the advent of low-cost accelerometers and more accurate data on activity, it is becoming clear that even the very modest exercise involved in activities such as cleaning or walking shows correlations with health. To to the degree that this relationship involves causation, the important mechanisms likely relate to the status of the vascular system, the rate at which tiny blood vessels suffer structural failure and destroy small portions of brain tissue. That is driven by the pace of arterial stiffening, progression of hypertension, and other factors that are slowed by regular exercise and sped up by the consequences of a sedentary life style, such as higher levels of chronic inflammation caused by visceral fat tissue.

A new study shows that a variety of physical activities from walking to gardening and dancing can improve brain volume and cut the risk of Alzheimer's disease by 50%. The researchers studied a long-term cohort of patients in the 30-year Cardiovascular Health Study, 876 in all, across four research sites in the United States. These participants had longitudinal memory follow up, which also included standard questionnaires about their physical activity habits. The research participants, age 78 on average, also had MRI scans of the brain analyzed by advanced computer algorithms to measure the volumes of brain structures including those implicated in memory and Alzheimer's such as the hippocampus. The physical activities performed by the participants were correlated to the brain volumes and spanned a wide variety of interests from gardening and dancing to riding an exercise cycle at the gym. Weekly caloric output from these activities was summarized.

The results of the analysis showed that increasing physical activity was correlated with larger brain volumes in the frontal, temporal, and parietal lobes including the hippocampus. Individuals experiencing this brain benefit from increasing their physical activity experienced a 50% reduction in their risk of Alzheimer's dementia. Of the roughly 25% in the sample who had mild cognitive impairment associated with Alzheimer's, increasing physical activity also benefitted their brain volumes.

ARGUING FOR INTESTINAL DYSFUNCTION AS AN IMPORTANT COMPONENT IN DEGENERATIVE AGING
Friday, March 25, 2016
https://www.fightaging.org/archives/2016/03/arguing-for-intestinal-dysfunction-as-an-important-component-in-degenerative-aging.php

Researchers investigating aging in flies have found that loss of intestinal function is a very strong determinant of degeneration and mortality in that species. Interventions that slow that decline, such as by manipulating intestinal stem cell activity or improving intestinal tissue quality control, also reduce mortality and extend life. There has been some discussion over whether this importance of intestinal function in aging is a characteristic unique to flies, and here the authors of this open access paper argue that it is not, and that there should be more targeted investigation in mammals:

A dramatic increase of intestinal permeability occurs in Drosophila melanogaster during aging in normal condition. The assay presented in this article uses a blue food dye to detect increased intestinal permeability in vivo. A blue coloration throughout the body marked the positive individuals, which were referred to as 'smurfs' from then on. Interestingly, the authors showed that genetic or physiological interventions increasing lifespan in flies significantly decreases the proportion of Smurfs compared to the control population at any given chronological age. This apparent link between the age-related increase of intestinal permeability and lifespan led them to more thoroughly analyze the Smurf phenotype. This phenotype allows the identification of individuals that are about to die of natural death amongst a population of synchronized Drosophila melanogaster individuals and those individuals show numerous other hallmarks of aging. Such a stereotyped way to die is unexpected; this could indicate a physiological phenomenon crucial during normal aging. Here we propose to test the hypothesis that such an important phenomenon should be evolutionarily conserved.

We chose to search for such a 'Smurf transition' in two other Drosophila species, Drosophila mojavensis and Drosophila virilis whose last common ancestor with Drosophila melanogaster existed approximately 50 million years ago, the nematode Caenorhabditis elegans whose divergence time with D. melanogaster is around 750 million years, and finally the vertebrate zebrafish Danio rerio, which diverged from D. melanogaster around 850-950 million years ago. We investigated whether Smurf-like animals could be observed in individuals from populations of these evolutionarily distant organisms. For each tested species, we could identify individuals showing extended dye coloration throughout their bodies. Moreover, we observed heterogeneity in a given population with only a fraction of the individuals exhibiting increased dye level outside the intestine. Thus, at least in old animals, it is possible to identify individuals with increased intestinal permeability.

One of the most striking characteristic of Smurf individuals previously described in Drosophila is the high risk of impending death they exhibit compared to their age-matched counterparts in a given population. So we decided to verify whether Smurf individuals were also committed to die in the other organisms we studied in this article. We showed that the proportion of individuals showing increased intestinal permeability grows linearly - or quasi-linearly - as a function of chronological age in these different organisms as it was previously reported in Drosophila melanogaster. Finally, we validated that, similar to what has been shown in D. melanogaster, the Smurf phenotype is a strong indicator of physiological age since it is a harbinger of natural death occurring during normal aging.

Intestinal dysfunction, as measured by the smurf assay in different species, associated to sharp transitions in gene expression and behavior appears to be a conserved hallmark of impending death. If this phase of aging is as broadly present in living organisms as our present study suggests, highly stereotyped molecularly and physiologically as well as sufficient to explain longevity curves, then we think that identifying the very events responsible for entering into this phase or those characterizing the high risk of impending death associated with that phase could answer fundamental questions about aging and lead to treatments able to significantly improve lifespan/healthspan across a broad range of species.

ON REJUVENATION OF MUSCLE STEM CELL FUNCTION
Friday, March 25, 2016
https://www.fightaging.org/archives/2016/03/on-rejuvenation-of-muscle-stem-cell-function.php

This review looks at a range of investigations into the effects of aging on stem cell populations supporting muscle tissue, and various attempts to restore those populations to active duty. Stem cell populations decline with age, becoming less active and more damaged. In recent years, researchers have demonstrated that a variety of approaches can be used to instruct dormant stem cells to be more active: stem cell transplants, altered GDF11 signaling, and so forth.

Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle stem (satellite) and progenitor cells (SMSCs). Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a pre-senescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion.

Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the pre-senescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the pre-senescent state results from loss of autophagy, leading to increased reactive oxygen species (ROS) and epigenetic modification at the CDKN2A locus due to decreased H2Aub, up-regulating cell senescence biomarker p16ink4a. However, the pre-senescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells.

Other work suggests that in humans loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus down regulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to pre-senescence in the very old.