Is the Present Human Life Span Enough?
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Is the present human life span enough? This was the topic for a recent debate, wherein Aubrey de Grey of the SENS Research Foundation and Brian Kennedy of the Buck Institute were matched against Ian Ground of Newcastle University and Paul Root Wolpe of the Emory Center for Ethics. Obviously my answer to the question is a resounding no; we should absolutely be doing far more than we are to eliminate aging and extend healthy life spans to the greatest degree possible. I am in a minority for holding that view, however. A growing minority, but a minority nonetheless. Two thirds of the population, when asked, say that yes, the present length of life is just fine. For my money, I think this is simply that most people live in the moment, within the bounds of what is, and give little thought to what might be different. If the wall is white and has always been white, you'll only get blank stares if you ask people what color it should be. What is familiar is equated with what is best, or sufficient, or good. Most people see the future as more of the present, just a different day with different fashions. Managing to hold this state of mind whilst standing amidst the fastest pace of progress in history is a feat, but clearly we humans are up to it.

Perhaps the most interesting aspect of the position that present length of life is sufficient is that near all of the people who think this way, will if asked, also say that cancer, heart disease, Alzheimer's, and other well-known age-related conditions should be cured. This is inconsistent, to say the least, as these conditions are caused by aging. They, and the other failure modes of organs and tissues that have been given formal names, are what kill people. Aging is the wear and tear that gives rise to these conditions, but these are not separate things. The only way to prevent age-related disease is to control the processes of aging - such as through periodic repair of damage after the SENS model - so as to indefinitely sustain function and health. If function and health are sustained, then life is lengthened. It is impossible to decouple aging from health.

The next time you find someone who thinks that the present length of life is fine, ask them what disease they want to suffer and die from. What is an acceptable way to decay into death? Heart disease? Kidney failure? How about neurodegeneration, the loss of the mind? My guess is that they don't want to suffer any of the above, and have hazy notions of an easy death at the end of life. Modern societies have pushed the ugly realities of what it means to age to death out of mind, behind curtains and into nursing homes and hospitals. That ugly reality for near everyone is pain and degeneration, the loss of function over time, and a very unpleasant end. Again, the only way to prevent that is to control the underlying processes of damage that cause aging and disease, and by doing so extend health and life. There is no picking that apart. It is only through ignorance of how things actually work in our biology that people can hold the strange and inconsistent positions that they do on aging, medicine, and longevity.

Lifespans are Long Enough

What if we didn't have to grow old and die? The average American can expect to live for 78.8 years, an improvement over the days before clean water and vaccines, when life expectancy was closer to 50, but still not long enough for most of us. So researchers around the world have been working on arresting the process of aging through biotechnology and finding cures to diseases like Alzheimer's and cancer. What are the ethical and social consequences of radically increasing lifespans? Should we accept a "natural" end, or should we find a cure to aging?

Is 78.8 Years Long Enough to Live?

First to argue in favor of the motion that "Lifespans are long enough" was professor of bioethics and director of the Emory Center for Ethics, Paul Root Wolpe. He said: "We all want to live longer. Maybe even forever. But I think the quest for immortality is a narcissistic fantasy. It's about us. It's about me. It's not about what's good for society." As Wolpe saw it, the question is not about whether it's possible to extend life but whether it's desirable. He viewed making the pursuit of indefinitely long life a goal in and of itself as wrong-headed. "Will life extension make the world a better place, a kinder place? Has extended life expectancy made it better? I don't think so," Wolpe said.

First to debate against the motion that lifespans are long enough was Aubrey de Grey, chief science officer of SENS Research Foundation. "I believe that the defeat of aging is the most important challenge facing humanity," he declared. "I'm going to start with this question about the alleged conflict between individual desire and societal good." De Grey compared the issue to people not wanting themselves or anyone else to get Alzheimer's disease. "It's a societal good because we don't like each other to get sick any more than we want to get sick," he said. De Grey doesn't believe that future problems are anywhere near as horrifying as the problem we have today. He said: "Let me tell you exactly how bad the problem that we have today actually is. Worldwide roughly 150- to 160,000 people die each day. And more than two-thirds of those people die of aging. It's crazy. In the industrialized world, we're talking more like 90 percent of all deaths. Let's actually do something about it."

Philosopher Ian Ground of Newcastle University and Secretary of the British Wittgenstein Society supported the motion that lifespans are long enough. Ground questioned the wisdom of having an indefinitely long life that could be led with no thought about its ending or decline. He urged us to consider a decision like committing to a certain career, person or place. People can't do everything, marry everybody or live everywhere, Ground said. We become particular people by making those choices, and must recognize that with natural capacities come natural limitations, he added.

The final panelist, who argued against the motion "Lifespans Are Long Enough," was Brian Kennedy, CEO and president of the Buck Institute for Research on Aging. Kennedy addressed speculation from the previous three speakers about what life might be like if we lived to 150, from how society would change to the prospect of boredom. "Maybe we're going to be bored. Well, you know, if you ask me: 'Do I want to have cancer at 75? Do I want to have Alzheimer's disease at 85? Or do I want to be bored at 110?' I know which one I'm going to take," said Kennedy.

In the end, the team arguing against the motion "Lifespans Are Long Enough" won, according to the audience. The post-debate score results were 40 percent for the proposition, 49 percent against and 11 percent undecided.

The SENS Rejuvenation Biotechnology Companies
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After the laboratory, the next stage of development in rejuvenation therapies involves the founding of biotechnology startups. There is no clear-cut point at which research stops being non-profit in the laboratory and starts being for-profit in a venture-funded startup. Every research team eyeballs the time and cost needed to get to the next level, something ready for the first human trial. Once that comes down to a gap that can be crossed with the combination of a seed round and angel investment round - say half a million to a million dollars and a year or two of work with a couple of clearly identifiable goals and go/no-go decisions - then the adventurous will make the leap. As I'm sure you've noticed it looks like a bear market is getting underway, but what better time to pull in investment for a project that might take a couple of years of heads-down work out of the limelight to reach the next stage? Bear markets only last a year or two, so by the time a new biotech startup has completed its first stage work successfully, it'll be ready to catch the headwinds of the next bull market.

Numerous lines of SENS rejuvenation research are, piece by piece, leaving the laboratory for the startup world. This is the success that we as a community have achieved with our years of charitable support for research aimed at advancing the state of the art. Whenever a new SENS-related biotechnology startup launches, bear in mind that a diverse group of people, investors and researchers, have looked at the technology and said "yes, we think can get a prototype therapy for human trials done in a couple of years." It is an important sign of progress, and one that is hard to fake: people with meaningful amounts of money on the line made those calls. You should expect our community to transition in part from one of fellow traveler non-profits and research groups to one made up equally of a network of startups, entrepreneurs, and investors of various stripes, from occasional angels to professionals at venture funds.

Here is a short list of interesting companies I am aware of that are working on SENS-related therapies at various stages, some very new, some years old, and proceeding at differing paces and with different strategies for development. They are not the only companies of interest to people who follow this space: I am omitting Arigos Biomedical, Organovo, and BioViva, among others, but the companies I list below are all very clearly working on aspects of SENS rejuvenation biotechnology. I'm certain there are others that I don't know about at this point - I am certainly far from well connected. I foresee a future in which in addition to the important work still ongoing in the laboratory, we can help to support a incubator-like environment of friendly companies under the SENS umbrella, helping one another succeed, each focused on one slice of the rejuvenation therapies needed to bring an end to aging. Those that succeed will act as guides for the growth of others: in diversity there is the greater chance of finding winning strategies. Importantly, among these companies today there are lot of people who are in this primarily to get the therapies built and out there and available. They are long-term SENS supporters. If they strike it rich, a good portion of that wealth is going to be reinvested in the next cycle of research development because, like us, they have a good idea of which of the two of life and money is more important. That is what success will look like once things become more commercial.


I've posted on the topic of Gensight in the past. This is a French company with tens of millions in venture funding that is built on technology for allotopic expression of mitochondrial genes originally partly funded by the SENS Research Foundation. They are focused on generating a robust commercial implementation for one mitochondrial gene, initially to deploy gene therapies to treat hereditary mitochondrial disease. Creating such a robust implementation is an important foundation for a future effort in which all mitochondrial genes can be backed up to the cell nucleus, and thus the contribution of mitochondrial DNA damage to aging can be eliminated.

Human Rejuvenation Technologies

Human Rejuvenation Technologies is a venture run by philanthropist Jason Hope, who you may recall funded a sizable chunk of the ongoing work on glucosepane cross-link breaking at the SENS Research Foundation back a few years ago. Glucosepane cross-link breaker drug candidates seem to be a few years in the future yet, so Human Rejuvenation Technologies is instead working with a drug candidate for clearing a form of metabolic waste key to plaque formation in atherosclerosis. This candidate is one of the results produced by the long-running SENS Research Foundation LysoSENS program.

Ichor Therapeutics

Ichor Therapeutics has been around for a couple of years, and has done a good job in setting a sustainable lab business on the side. The interesting work here, however, is the continuation of SENS research programs aimed at removing the buildup of A2E, one of the components of lipofuscin that builds up in cells and interferes with cellular garbage disposal. Unusually among the forms of cellular damage, even those involving buildup of metabolic waste such as lipofusin, A2E is linked very directly and solidly to some forms of age-related disease that involve retinal degeneration. In most cases the fundamental damage that causes aging is separated from the end stage of disease by lengthy and barely understood chains of cause and consequence, but here it is very clear that getting rid of A2E is a good thing.

Oisin Biotechnology

Oisin Biotechnology are developing a senescent cell clearance therapy, an approach to treating aging that has definitely arrived with a splash: there are multiple methods demonstrated in mice, and a number of different groups at the point of launching commercial development efforts. Oisin was funded more than a year ago by the Methuselah Foundation and SENS Research Foundation, and you'll be hearing much more about them in the year ahead, I predict.

Pentraxin Therapeutics

Pentraxin Therapeutics is the oldest and slowest of these companies, founded way back in 2001. The SENS-relevant work started in 2008 or 2009 with a partnership with GlaxoSmithKline to develop a treatment to clear transthyretin amyloid, a form of metabolic waste that builds up with age and is linked to cardiovascular disease, osteoarthritis, and death by heart failure in the oldest human beings. A human trial recently produced very positive results, showing significant clearance of amyloid in patients, and this is consequently probably the furthest advanced of all SENS technologies. Unfortunately it is also the most locked up within the slow regulatory system and a Big Pharma partnership. It is hard to say what is going to happen next here, but don't hold your breath expecting to see anything in the clinic soon.

Unity Biotechnology

Unity Biotechnology has emerged from the first successful efforts to clear senescent cells via gene therapy, back in 2011, as well as ongoing programs such as those of the Campisi laboratory. They have a sizable staff for a startup, good venture backing, and are developing treatments based on these methods, but which will be more suitable for use in human patients. You no doubt saw the full court press in the media put on by the various organizational backers of Unity earlier this week. It is great to see such a large number of people pushing the SENS line of damage repair as the approach to treatment of aging. As more companies reach the point of gaining support from deep pockets in the venture community, we will see more of this media attention for SENS-like rejuvenation therapies.

Enhanced Proteasomal Activity Restores Declining Self-Renewal in Aging Neural Stem Cells
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The proteasome is a type of cellular structure tasked with breaking down damaged and unwanted proteins, its activities one part of a broad variety of maintenance mechanisms found inside the living cell. Today I'll point out the latest of a number of studies from recent years to investigate the underlying reasons for associations between declining cellular maintenance and specific aspects of degenerative aging. The researchers noted here have linked proteasomal activity to the vitality of neural stem cells. They show that both decline in aging, but the stem cells can be restored to more youthful vigor when proteasomes are artificially induced to pick up the slack once more.

Stem cells maintain tissues by providing a source of new cells and signals that influence cellular behavior. Even in the brain, stem cell populations deliver a supply of new neurons over time, and this is one of the sources of neural plasticity, the ability of the brain to change, learn, adapt, and (to a limited degree) repair itself. The activity of stem cell populations declines with advancing age, however, most likely a reaction to rising levels of cell and tissue damage. Less activity serves to reduce the risk of death by cancer, but at the cost of a faster decline into frailty and organ failure, the result of failing tissue maintenance. In the brain, this means a progressive loss of neural plasticity, and this is thought to contribute meaningfully to the development of neurodegenerative conditions. It probably has subtle and profound effects on the state of the human mind as well, beyond those caused by obvious structural failures in brain tissue, though that is far harder to prove one way or another.

As is the case for stem cell activity, proteasomal activity is also known to decrease in older tissues. All mechanisms of cellular maintenance go the same way, unfortunately, and this is a recurring theme in aging research. There are many who view aging as at least in part a garbage catastrophe: a downward spiral led by broken mechanisms and a growing inability to keep up. Many models of enhanced longevity have greater maintenance activities than their less fortunate peers. Naked mole rats for example, have very effective proteasomes. Aging is the accumulation of cell and tissue damage, and even repair systems get damaged - though in likelihood these age-related declines are not the direct results of damage, but rather mediated by a complex web of interacting signals and protein levels. For much of the past decade, some researchers have looked towards boosted maintenance, including increased proteasomal activity, as a possible way to slow the onset of aging or treat degenerative conditions. Despite a lot of research and many published papers, little concrete progress towards clinical translation of research has occurred on this front, however.

Essential role of proteasomes in maintaining self-renewal in neural progenitor cells

The breakdown of protein homeostasis has been suggested to be tightly associated with the aging process, because all cells have to keep a dynamic balance between protein synthesis and degradation in order to maintain their integrity and normal functions. In fast-proliferating cells, it is particularly crucial to recycle obsolete macromolecules to provide the raw materials for synthesis of subcellular compartments and molecules to satisfy the requirement of rapid proliferation and/or differentiation. Such a self-renewal ability of cells, however, is gradually compromised and eventually diminished with age. Hallmarks of aged cells include increased accumulation of hyper-oxidative, misfolded, or abnormally-aggregated proteins, all of which result from the dysfunctional cell clearance mechanisms, especially the protein degradation pathway.

The proteasome-dependent degradation is one of such cellular clearance mechanisms for retaining intracellular protein homeostasis, which targets and subsequently degrades damaged, misfolded or redundant proteins. The dysfunction of proteasomes, in turn, may contribute to the occurrence of many aging-related diseases. Various studies have shown that proteasomal activity might be compromised during the aging process in both animals and cells, given that its decrease has been found in a variety of aged tissues in humans, non-human mammals, and even in lower organisms such as fruit flies.

In this study, we investigated the role of proteasomes in self-renewal of neural progenitor cells (NPCs). Through both in vivo and in vitro analyses, we found that the expression of proteasomes was progressively decreased during aging. Likewise, proliferation and self-renewal of NPCs were also impaired in aged mice, suggesting that the down-regulation of proteasomes might be responsible for this senescent phenotype. We previously increased proteasomal activity in bone marrow stem cells by exogenously applying the proteasome activator 18α-GA or genetically over-expressing the β-subunit PSMB5, and found that both methods could effectively improve cell integrity and ameliorate replicative senescence, in addition to enhancements of cell survival and neuronal differentiation following the brain transplantation of PSMB5-overexpressing bone marrow stem cells. In the current study, we observed similar effects of 18α-GA on NPCs.

Lowering proteasomal activity by loss-of-function manipulations mimicked the senescence of NPCs both in vitro and in vivo; conversely, enhancing proteasomal activity restored and improved self-renewal in aged NPCs. These results collectively indicate that proteasomes work as a key regulator in promoting self-renewal of NPCs. This potentially provides a promising therapeutic target for age-dependent neurodegenerative diseases.

25% Median Life Extension in Mice via Senescent Cell Clearance, Unity Biotechnology Founded to Develop Therapies
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With today's news, it certainly seems that senescent cell clearance has come of age as an approach to treating aging and age-related conditions. Some of the leading folk in the cellular senescence research community today published the results from a very encouraging life span study, extending life in mice via a method of removing senescent cells. This is much the same approach employed in one of the first tests of senescent cell clearance, carried out in accelerated aging mice a few years ago, but in this case normal mice were used, leaving no room to doubt the relevance of the results. The researchers have founded a new company, Unity Biotechnology, to develop therapies for the clinic based on this technology. Clearance of senescent cells has been advocated as a part of the SENS vision for the medical control of aging for more than a decade now, and it is very encouraging to see the research and development community at last coming round to this view and making tangible progress.

Senescent cells have removed themselves from the cycle of replication in reaction to cell and tissue damage, or a local tissue environment that seems likely to result in cancer. Their numbers accumulate with age. Most are destroyed by the immune system or their own programmed cell death mechanisms, but enough linger for the long term for their growing presence to be one of the contributing causes of the aging process. These cells behave badly, secreting harmful signals that degrade tissue function, generate inflammation, and alter the behavior of surrounding cells as well. Near every common age-related condition is accelerated and made worse by the presence of large numbers of senescent cells. We would be better off without them, aging would be slowed by the regular removal of these errant cells, and the therapies to make that possible are on the near horizon.

The mouse lifespan study is the important news here, as it demonstrates meaningful extension of median life span through removal of senescent cells, the first such study carried out in normal mice for this SENS-style rejuvenation technology. This sort of very direct and easily understood result has a way of waking up far more of the public than the other very convincing evidence of past years. So it looks like Oisin Biotechnology, seed funded last year by the Methuselah Foundation and SENS Research Foundation to bring a senescent cell clearance therapy to market, now has earnest competition. Insofar as the competitive urge in business and biotechnology speeds progress and produces better results, let the games begin, I say.

Scientists Can Now Radically Expand the Lifespan of Mice - and Humans May Be Next

Researchers have made this decade's biggest breakthrough in understanding the complex world of physical aging. The researchers found that systematically removing a category of living, stagnant cells (ones which can no longer reproduce) extends the lives of otherwise normal mice by 25 percent. Better yet, scouring these cells actually pushed back the process of aging, slowing the onset of various age-related illnesses like cataracts, heart and kidney deterioration, and even tumor formation. "It's not just that we're making these mice live longer; they're actually stay healthier longer too. That's important, because if you were going to equate this to people, well, you don't want to just extend the years of life that people are miserable or hospitalized."

By rewriting a tiny portion of the mouse genetic code, the team developed a genetic line of mice with cells that could, under the right circumstances, produce a powerful protein called caspase when they start secreting p16. Caspase acts essentially as a self-destruct button; when it's manufactured in a cell, that cell rapidly dies. So what exactly are these circumstances where the p16 secreting cells start to create caspase and self-destruct? Well, only in the presence of a specific medicine the scientists could give the mice. With their highly-specific genetic tweak, the scientists had created a drug-initiated killswitch for senescent cells. In today's paper, the team reported what happened when the researchers turned on that killswitch in middle-aged mice, effectively scrubbing clean the mice of senescent cells.

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16Ink4a-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16Ink4a-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16Ink4a-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.

Unity Biotechnology Launches with a Focus on Preventing and Reversing Diseases of Aging

Unity will initially focus on cellular senescence, a biological mechanism theorized to be a key driver of many age-related diseases, including osteoarthritis, glaucoma and atherosclerosis. "Imagine drugs that could prevent, maybe even cure, arthritis or heart disease or loss of eyesight. It's an incredible aspiration. If we can translate this biology into medicines, our children might grow up in significantly better health as they age. There will be many obstacles to overcome, but our team is committed and inspired to achieve our mission. This has been a long journey, and we're at the point now where we can start making medicines to achieve in humans what we've achieved in mice. I can't wait to see what happens as we move into the clinic."

To close this post, and once again, I think it well worth remembering that SENS rejuvenation biotechnology advocates and supporters have been calling for exactly this approach to treating aging for more than a decade. That call was made based on the evidence arising from many fields of medical research, and from a considered perspective of aging as a process of damage accumulation, one that can be most effectively treated by repair of that damage. The presence of senescent cells is a form of damage. SENS was not so long ago derided and considered out on the fringe for putting forward that position, but for several years now it has been very clear that the SENS viewpoint was right all along. I strongly encourage anyone who remains on the fence about the validity of the SENS proposals for the treatment of aging to reexamine his or her position on the science.

Recent Research on Muscles, Stem Cells, and Aging
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Today I thought I'd point out a few recent papers and publicity materials on muscle aging. A large chunk of the research into stem cell aging and changes in cell metabolism with aging focus on muscle tissue. In part this is a feedback loop: the better understood models and types of cell are found in or associated with muscle tissue. Therefore more researchers use this as a starting point, and therefore the knowledge grows faster than is the case for other tissue types. It doesn't hurt that muscle tissue is easily sampled and examined in people and animals, unlike the cell populations of internal organs. That reduces the cost across the board for many types of study, and researchers are very conscious of cost - there is no such thing as a laboratory with enough funding for optimal progress. Measured by deeds rather than words, our society places very little value on medical research, or indeed research at all for that matter. The investment that goes into building the scientific understanding necessary to produce better medicine is minuscule in the grand scheme of things. Thus a core skill for any scientist to be able to do more with less, because less is absolutely the state of things.

Muscle mass and strength diminishes with aging. It is called sarcopenia in those who suffer this loss to a significantly greater degree, and there has been an ongoing effort for the past decade to formally define this condition within the US regulatory system. That this process is still underway, and with no end in sight, is a sign of just how much that system holds back progress. It thus remains illegal to try to commercialize therapies for sarcopenia, and that is felt all the way back down the chain of research and development in the form of reduced availability of funding. There are many mechanisms involved in muscle degeneration in aging, ranging from the characteristic reduction in stem cell activity in old tissues to the effects of chronic inflammation, passing through mitochondrial dysfunction and numerous other metabolic changes that impair aspects of muscle growth or operation. As is always the case, definitively linking the observed changes into lines of cause and consequence is a challenge. Clinics will be repairing aging with SENS rejuvenation therapies long before the research community can produce a comprehensive, detailed model of aging that traces every step from fundamental damage through to final end stage of disease.

You may find the research linked here interesting, but remember that it's a thin slice of a large and diverse selection of scientific initiatives. These are small snapshots in an evolving album relating to muscle aging, and that in turn is but a small part of the larger field.

Regenerating damaged muscle after a heart attack

Researchers used human embryonic stem cells to create a kind of cell, called a cardiac mesoderm cell, which has the ability to turn into cardiomyocytes, fibroblasts, smooth muscle, and endothelial cells. All these types of cells play an important role in helping repair a damaged heart. As those embryonic cells were in the process of changing into cardiac mesoderms, the team was able to identify two key markers on the cell surface. The markers, called CD13 and ROR2, pinpointed the cells that were likely to be the most efficient at changing into the kind of cells needed to repair damaged heart tissue. The researchers then transplanted those cells into an animal model and found that not only did many of the cells survive but they also produced the cells needed to regenerate heart muscle and vessels.

"In a major heart attack, a person loses an estimated 1 billion heart cells, which results in permanent scar tissue in the heart muscle. Our findings seek to unlock some of the mysteries of heart regeneration in order to move the possibility of cardiovascular cell therapies forward. We have now found a way to identify the right type of stem cells that create heart cells that successfully engraft when transplanted and generate muscle tissue in the heart, which means we're one step closer to developing cell-based therapies for people living with heart disease."

The ins and outs of muscle stem cell aging

Skeletal muscle has a remarkable capacity to regenerate by virtue of its resident stem cells (satellite cells). This capacity declines with aging, although whether this is due to extrinsic changes in the environment and/or to cell-intrinsic mechanisms associated to aging has been a matter of intense debate. Furthermore, while some groups support that satellite cell aging is reversible by a youthful environment, others support cell-autonomous irreversible changes, even in the presence of youthful factors. Indeed, whereas the parabiosis paradigm has unveiled the environment as responsible for the satellite cell functional decline, satellite cell transplantation studies support cell-intrinsic deficits with aging.

In this review, we try to shed light on the potential causes underlying these discrepancies. We propose that the experimental paradigm used to interrogate intrinsic and extrinsic regulation of stem cell function may be a part of the problem. The assays deployed are not equivalent and may overburden specific cellular regulatory processes and thus probe different aspects of satellite cell properties. Finally, distinct subsets of satellite cells may be under different modes of molecular control and mobilized preferentially in one paradigm than in the other. A better understanding of how satellite cells molecularly adapt during aging and their context-dependent deployment during injury and transplantation will lead to the development of efficacious compensating strategies that maintain stem cell fitness and tissue homeostasis throughout life.

Hypothesis on Skeletal Muscle Aging: Mitochondrial Adenine Nucleotide Translocator Decreases Reactive Oxygen Species Production While Preserving Coupling Efficiency

Mitochondrial membrane potential is the major regulator of mitochondrial functions, including coupling efficiency and production of reactive oxygen species (ROS). Both functions are crucial for cell bioenergetics. We previously presented evidences for a specific modulation of adenine nucleotide translocase (ANT) appearing during aging that results in a decrease in membrane potential - and therefore ROS production - but surprisingly increases coupling efficiency under conditions of low ATP turnover. Careful study of the bioenergetic parameters of isolated mitochondria from skeletal muscles of aged and young rats revealed a remodeling at the level of the phosphorylation system, in the absence of alteration of the inner mitochondrial membrane (uncoupling) or respiratory chain complexes regulation.

For equivalent ATP turnover (cellular ATP demand), coupling efficiency is even higher in aged muscle mitochondria, due to the down-regulation of inner membrane proton leak caused by the decrease in membrane potential. In the framework of the radical theory of aging, these modifications in ANT function may be the result of oxidative damage caused by intra mitochondrial ROS and may appear like a virtuous circle where ROS induce a mechanism that reduces their production, without causing uncoupling, and even leading in improved efficiency. Because of the importance of ROS as therapeutic targets, this new mechanism deserves further studies.

Mitochondrial Quality Control and Muscle Mass Maintenance

Loss of muscle mass and force occurs in many diseases such as disuse/inactivity, diabetes, cancer, renal, and cardiac failure and in aging - sarcopenia. In these catabolic conditions the mitochondrial content, morphology and function are greatly affected. The changes of mitochondrial network influence the production of reactive oxygen species (ROS) that play an important role in muscle function. Moreover, dysfunctional mitochondria trigger catabolic signaling pathways which feed-forward to the nucleus to promote the activation of muscle atrophy. Exercise, on the other hand, improves mitochondrial function by activating mitochondrial biogenesis and mitophagy, possibly playing an important part in the beneficial effects of physical activity in several diseases. Optimized mitochondrial function is strictly maintained by the coordinated activation of different mitochondrial quality control pathways. In this review we outline the current knowledge linking mitochondria-dependent signaling pathways to muscle homeostasis in aging and disease and the resulting implications for the development of novel therapeutic approaches to prevent muscle loss.