Fight Aging! Newsletter, July 13th 2015

July 13th 2015

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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  • More on Beta-2 Microglobulin Blood Levels and Aging, Resulting From Parabiosis Research
  • Measuring the Processes of Aging in Younger Adults
  • Gensight: Developing a Mitochondrial Repair Therapy
  • Investigating the Proximate Causes of Defective Antibody Production in the Aged Immune System
  • Recent Reviews Covering the Role of Glial Cells in Aging
  • Latest Headlines from Fight Aging!
    • SkQ1 Improves Impaired Skin Healing in Old Mice
    • Spurring Regrowth of Axons in Damaged Nerves
    • Reassessing Smooth Muscle Cells in Atherosclerosis
    • Greater Incremental Damage to Brain Tissue Means a Greater Risk of Stroke and Death
    • A Popular Press Article on the Work of the Buck Institute
    • Yet Another Theory on the Human Gender Gap in Longevity
    • Reviewing Negligible Senescence in Sea Urchins
    • mTOR Regulates Some of the Bad Behavior of Senescent Cells
    • Thymus Organoids Restore Immune Function in Mice
    • One Tiny Slice of the Benefits of Exercise: Slower Tendon Aging


Over the past couple of years, researchers have been involved in cataloging differences in signaling molecules in the blood when comparing old and young mice. This is an outgrowth of heterochronic parabiosis studies, in which an old and a young individual have their circulatory systems joined and the results observed. The effects are improved health, regeneration, and aspects of cell biology such as stem cell activity in the old individual, and opposing negative impacts on the young individual. This was in the news recently with a focus on TGF-β signaling and stem cell activity in the brain, but the other part of that research involves β2 microglobulin (B2M), which is front and center in the publicity materials linked below.

The orthodox theory is that stem cell activity declines with age in reaction to growing levels of tissue damage, and this happens because it reduces cancer risk, with life span emerging from the processes of natural selection as a balance between death by cancer on the one hand and death by loss of tissue maintenance and organ function on the other. The evidence to date suggests that in mammals at least this is far from a finely balanced outcome and that there is a in fact a fair amount of room to boost cell activity and regeneration in old age without greatly increasing cancer incidence.

Thus researchers are greatly interested in finding ways to restore stem cell activity in the old, and turn back loss of tissue maintenance. There is a good chance that much of this declining activity is caused, proximately at least, by changes in cell signaling over the course of aging, and especially in levels of signal molecules carried in the blood stream - which comes back to parabiosis as an investigative tool. If specific signals important in age-related decline of function can be identified, then changing their levels can form the basis for therapies.

The root cause of loss of function with age is still cell and tissue damage, however, and the best goal is to repair that damage and thus have the signaling changes revert themselves, not interfere at a higher level, even if it happens to turn out that there are benefits to be had. Even if you can improve greatly on today's medicine by restoring stem cell activity, with a backup provided by next generation targeted cancer therapies, then there is still the harm caused by forms of damage such as mitochondrial dysfunction and waste products such as cross-links and amyloid. That will still kill us if left untreated, stem cells or no stem cells.

Age-related cognitive decline tied to immune-system molecule

Connecting the circulatory system of a young mouse to that of an old mouse can reverse the declines in learning ability that typically emerge as mice age. Over the course of their long-term research on so-called young blood, however, the researchers had noted an opposite effect: blood from older animals appears to contain "pro-aging factors" that suppress neurogenesis - the sprouting of new brain cells in regions important for memory - which in turn can contribute to cognitive decline.

Beta-2 microglobulin, or B2M, levels steadily rise with age in mice, and are also higher in young mice in which the circulatory system is joined to that of an older mouse. B2M is a component of a larger molecule called MHC I (major histocompatibility complex class I), which plays a major role in the adaptive immune system. These findings were confirmed in humans, in whom B2M levels rose with age in both blood and in the cerebrospinal fluid (CSF) that bathes the brain. When B2M was administered to young mice, either via the circulatory system or directly into the brain, the mice performed poorly on tests of learning and memory compared to untreated mice, and neurogenesis was also suppressed in these mice.

These experiments were complemented by genetic manipulations in which some mice were engineered to lack a gene known as Tap1, which is crucial for the MHC I complex to make its way to the cell surface. In these mice, administration of B2M in young mice had no significant effect, either in tests of learning or in assessments of neurogenesis. The group also bred mice missing the gene for B2M itself. These mice performed better than their normal counterparts on learning tests well into old age, and their brains did not exhibit the decline in neurogenesis typically seen in aged mice.

The effects on learning observed in the B2M-administration experiments were reversible: 30 days after the B2M injections, the treated mice performed as well on tests as untreated mice, indicating that B2M-induced cognitive decline in humans could potentially be treated with targeted drugs. "From a translational perspective, we are interested in developing antibodies or small molecules to target this protein late in life. Since B2M goes up with age in blood, CSF, and also in the brain itself, this allows us multiple avenues in which to target this protein therapeutically."

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner.

B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.


A recent open access paper describing efforts to measure degenerative aging in people in their twenties and thirties age bracket has been doing the rounds in the media. It is interesting to see people making an effort to create definitive measurements of aging in earlier age groups. The signs should certainly be there to see, given discriminating enough biotechnologies: the underlying damage that causes aging occurs at all ages. I'm also very much in favor of anything that might make the younger people in the audience feel more like they have skin in the game. In my experience one of the great ironies in persuading people to care about aging, to speak out for the cause and help fund research, is that the young think it isn't their problem, and the old think that there is no point in helping given that meaningful results will only arrive in the decades ahead. Everyone looks to their own lawn and little beyond.

Nonetheless, the young age too. Aging is a process of damage accumulation, accelerating to greater obvious results in later life due to interactions between damage that cause problems greater than the sum of the parts, and also due to declining repair and maintenance mechanisms. Damage feeds on damage in any machine: the more of it there is, the faster it arrives, and old, damaged machines see a rapid decline in mean time to failure. There are numerous types of cellular and molecular damage at the roots of aging, some of which can be repaired by our cells, were they operating at best capacity, and others that cannot. Aging is thus caused by a mix of two types of harm. On the one hand there is a slow and relentless accumulation of some types of defect: consider cross-links in the extracellular matrix that cannot be broken down by any of the enzymes we produce, generated as comparatively rare byproducts of metabolic operation, or mitochondrial mutations that can evade cellular quality control mechanisms and result in a growing population of dysfunctional cells packed with dysfunctional mitochondria. On the other hand there is a constant, ongoing, rapid creation of other types of defect that is matched by an equally rapid and capable set of repair processes. Unfortunately that repair effort itself winds down over time, allowing damage to get ever further ahead. Here you might think of plain old tissue maintenance by stem cell populations, as the decline of stem cell activity in aging is an important concern in medical research these days.

I think that much further work would need to be done in order to validate that the methods of measuring aging used by these researchers hold up well enough, and in fact correlate usefully with outcomes. Telomere length in particular is very flaky as usually measured in white blood cells, prone to all sorts of interesting and apparently contradictory outcomes in various different studies.

Researchers learn to measure aging process in young adults

Researchers introduced a panel of 18 biological measures that may be combined to determine whether people are aging faster or slower than their peers. The data comes from the Dunedin Study, a landmark longitudinal study that has tracked more than a thousand people born in 1972-73 in the same town from birth to the present. Health measures like blood pressure and liver function have been taken regularly, along with interviews and other assessments. "We set out to measure aging in these relatively young people. Most studies of aging look at seniors, but if we want to be able to prevent age-related disease, we're going to have to start studying aging in young people."

The progress of aging shows in human organs just as it does in eyes, joints and hair, but sooner. So as part of their regular reassessment of the study population at age 38 in 2011, the team measured the functions of kidneys, liver, lungs, metabolic and immune systems. They also measured HDL cholesterol, cardiorespiratory fitness, lung function and the length of the telomeres -- protective caps at the end of chromosomes that have been found to shorten with age. The study also measures dental health and the condition of the tiny blood vessels at the back of the eyes, which are a proxy for the brain's blood vessels.

Based on a subset of these biomarkers, the research team set a "biological age" for each participant, which ranged from under 30 to nearly 60 in the 38-year-olds. The researchers then went back into the archival data for each subject and looked at 18 biomarkers that were measured when the participants were age 26, and again when they were 32 and 38. From this, they drew a slope for each variable, and then the 18 slopes were added for each study subject to determine that individual's pace of aging.

Most participants clustered around an aging rate of one year per year, but others were found to be aging as fast as three years per chronological year. Many were aging at zero years per year, in effect staying younger than their age. As the team expected, those who were biologically older at age 38 also appeared to have been aging at a faster pace. A biological age of 40, for example, meant that person was aging at a rate of 1.2 years per year over the 12 years the study examined.

Quantification of biological aging in young adults

At present, much research on aging is being carried out with animals and older humans. Paradoxically, these seemingly sensible strategies pose translational difficulties. The difficulty with studying aging in old humans is that many of them already have age-related diseases. Age-related changes to physiology accumulate from early life, affecting organ systems years before disease diagnosis. Thus, intervention to reverse or delay the march toward age-related diseases must be scheduled while people are still young. Early interventions to slow aging can be tested in model organisms. The difficulty with these nonhuman models is that they do not typically capture the complex multifactorial risks and exposures that shape human aging. Moreover, whereas animals' brief lives make it feasible to study animal aging in the laboratory, humans' lives span many years. A solution is to study human aging in the first half of the life course, when individuals are starting to diverge in their aging trajectories, before most diseases (and regimens to manage them) become established. The main obstacle to studying aging before old age - and before the onset of age-related diseases - is the absence of methods to quantify the Pace of Aging in young humans.

We studied aging in a population-representative 1972-1973 birth cohort of 1,037 young adults followed from birth to age 38 y with 95% retention: the Dunedin Study. When they were 38 y old, we examined their physiologies to test whether this young population would show evidence of individual variation in aging despite remaining free of age-related disease. We next tested the hypothesis that cohort members with "older" physiologies at age 38 had actually been aging faster than their same chronologically aged peers who retained "younger" physiologies; specifically, we tested whether indicators of the integrity of their cardiovascular, metabolic, and immune systems, their kidneys, livers, gums, and lungs, and their DNA had deteriorated more rapidly according to measurements taken repeatedly since a baseline 12 y earlier at age 26. We further tested whether, by midlife, young adults who were aging more rapidly already exhibited deficits in their physical functioning, showed signs of early cognitive decline, and looked older to independent observers.

We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their "biological aging" (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

I absolutely disagree with the author's position that intervention to reverse aging and age-related disease must happen while people are young. It will be certainly be much easier to achieve medical control of aging when people are young, as therapies will then have to successfully repair far less damage and a much smaller variety of damage. But, and this is crucial, the whole point of developing methods of repair for the causes of aging rather than methods of merely slowing it down is so that the old can be rescued - so that we create rejuvenation. This is no small point: it is a core part of the plan for SENS and other repair-based rejuvenation strategies.


In this post I'll point out Gensight, a company creating medical biotechnologies that are relevant to the goal of human rejuvenation, and which is about to undertake an IPO in order to pull in more significant funding for ongoing development. This company has over the past couple of years developed mitochondrial repair technologies based on research at the Corral-Debrinski lab in Paris partly funded by the SENS Research Foundation. This is a great example of what we'd like to see result from the Foundation's intervention in fields of research that need more support in order to move forward.

So the area of interest here is mitochondrial damage and how to remove the consequences of that damage. What does this mean? Mitochondria are the power plants of the cell, working to produce chemical energy stores in the form of adenosine triphosphate (ATP) molecules, though like every cellular component they play a role in many processes beyond their primary function. Evolution likes reuse. Each cell contains a herd of hundreds of mitochondria, which multiply like bacteria, sometimes fuse together, swap component parts of their machinery between one another, and are culled when worn or broken by cellular quality control mechanisms. Mitochondria are the descendants of ancient symbiotic bacteria and carry the remnants of that origin in the form of a small number of genes encoded in mitochondrial DNA. There were originally many more genes, but over evolutionary time they were either lost or migrated to the cell nucleus to reside in the nuclear DNA.

DNA is fragile and a cell is basically a balloon of constant chemical reactions. DNA gets damaged all the time, but the array of repair mechanisms that work to restore that damage are highly efficient: very little slips past. They are far more efficient in the cell nucleus than in mitochondria, however. Further, mitochondrial DNA seems to be more prone to damage for reasons that may include the fairly energetic chemical reactions required to build ATP, or may be an artifact of the way in which mitochondria multiply by division. There is still some debate on this front. What is known is that some forms of mitochondrial DNA damage can bypass quality control, leading very quickly to an entire cell being overtaken by dysfunctional mitochondria with the same broken DNA, unable to properly generate ATP by the usual path, and as a result the cell starts to export harmful, reactive molecules into the surrounding tissue. Enough of these cells and functional damage starts to accrue in tissues and organs: this is one of the contributing causes of degenerative aging.

What to do about this? The strategies are fairly obvious at a high level: replace the broken DNA, or supply new mitochondria, or supply the missing proteins that the broken genes encoded. There are many variants that mix and match between these themes, some are better than others, and some are quite far along in development. The SENS Research Foundation approach is allotopic expression: use gene therapy to put copies of all of the remaining mitochondrial genes into the cell nucleus and then work out how to get the protein produced from that genetic blueprint back to the mitochondria where it is needed - it is that second portion of the work that is the hard part.

Gensight is working on a variant of this approach, but like most groups producing technology of interest to our goals they are not actually focused on aging and longevity at all. Instead Gensight produce their technology to treat inherited mitochondrial disease in which a necessary mitochondrial gene is missing or damaged in wide swathes of a patient's tissues. They are primarily focused on Leber's hereditary optic neuropathy (LHON), a degenerative blindness condition that has been a proving ground for research into mitochondrial repair over the past decade or so. You might recall that the SENS Research Foundation collaborated with Marisol Corral-Debrinski back in the day, helping to fund research on the technology that Gensight is now developing for clinical application.

So the good news here is that a solid, young biotech company with quite a lot of funding is having a serious go at producing a robust platform for repairing the consequences of mitochondrial DNA damage. The next step to follow on from Gensight's progress in reducing this all to practice will be to adapt the core technology to work for all mitochondrial genes of interest, those whose damage is involved in degenerative aging. Given the way companies, business cycles, and intellectual property licensing tend to work out, and allowing some time for the standard confusion and occasional failure, I imagine that start to be underway in earnest somewhere between 2020 and 2025. If we're lucky, someone else will start work on a similar approach to mitochondrial damage in aging before then, however: commercially successful research tends to attract competing scientific programs.

Gensight scouts a $100M IPO for its ocular gene therapies

Parisian drug developer Gensight Biologics is swinging for a 100 million U.S. IPO to fund its work on potential one-time treatments for serious retinal diseases, angling to take advantage of a bullish market for biotechs. Gensight's top prospect is GS010, a treatment for certain forms of the rare Leber hereditary optical neuropathy, or LHON, which leads to sudden and irreversible loss of sight in teenagers and young adults. The treatment works by fixing a DNA glitch that leads to LHON, using a harmless virus to deliver a corrective copy of the ND4 gene. Gensight completed a Phase Ib study on GS010 this year, the company said, and plans to push its top prospect straight to Phase III in the second half with data expected in 2017.

Mitochondrial Targeting Sequence (MTS)

Our MTS technology platform enables efficient expression of a mitochondrial gene by nuclear deoxyribonucleic acid, or DNA, and delivery of messenger ribonucleic acid, or mRNA, to polysomes located at the mitochondrial surface. This allows for the synthesis, internalization and proper localization of the mitochondrial protein.

Mitochondrial DNA mutations, whether inherited or acquired, lead to impairment of the electron transport chain functioning. Impaired electron transport, in turn, leads to decreased adenosine triphosphate, or ATP, production, overall reduced energy supply to the cells, formation of damaging free-radicals, and altered calcium metabolism. These toxic consequences lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death. This cycle of increasing oxidative damage insidiously damages neurons, including those in the retina, over a period of years, eventually leading to neuronal cell death.

LHON originates from mutations in three NADH Dehydrogenase mitochondrial genes: ND1, ND4 and ND6. Because ND4 mutations account for more than 75% of the LHON population in North America and Europe, we chose to first focus on this specific mutation. We have demonstrated the feasibility of using the MTS technology platform for the treatment of LHON due to the ND4 gene mutation in animal studies. We plan to use our MTS technology platform to address other LHON mutations and have already initiated a research program for our next potential product candidate, GS011, which targets the ND1 gene mutation. We believe that our MTS technology platform can also be used to address diseases outside of ophthalmology that involve defects of the mitochondrion, such as neurodegenerative disorders.


In the open access paper linked below, researchers outline the proximate cause for one aspect of the characteristic decline in immune function that accompanies aging, in this case the failure to produce sufficient numbers of antibodies in response to the presence of pathogens. Along the way they find an approach that can partially reverse this degeneration, though it remains far from clear as to nature of the root causes and how those root causes lead to the proximate cause.

The progressive failure of the immune system is an important component of age-related frailty, and the more that can be done to turn it back, the better. Here the focus is on humoral immunity and specifically the generation of antibodies by B cells. Portions of the immune system are responsible for digesting the component parts of pathogens such as viruses and microbes, breaking them down into antigens, then presenting those antigens to the antibody manufacturing process. Antibodies are proteins constructed to match and bind to those antigens, let loose in vast numbers so that they can either flag the matching pathogens for destruction by other parts of the immune system, or directly interfere in some vital machinery essential to the pathogen's activities.

It is well known that the aged immune system produces an ever smaller output of antibodies when challenged. This is a part of the reason why vaccinations become ineffective in the elderly, for example. It is worth keeping an eye on research efforts to explain and potentially reverse this decline, but bear in mind that the immune system is enormously complex. Talking about even one narrow portion of the whole - manufacturing antibodies in this case - means considering the roles of many different cell types, mechanisms within cells, and an intricate chain of activities leading from the arrival of a pathogen to matching antibody production, wherein imbalance or failure at any point leads to a worse outcome. You should probably click through and take a look at the diagram that accompanies the abstract before reading on:

Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging

The extent of humoral immunity, or immunity provided by antibodies, decreases with age in both mice and humans. This decrease in humoral immunity translates into increased frequency and severity of infectious diseases in aged individuals. Furthermore, vaccination of the elderly provides inadequate protection against most infectious diseases, leaving these individuals vulnerable to a number of diseases.

The production of antibodies results from a complex interaction of B cells with T follicular helper (TFH) cells in the germinal center (GC) reaction. After differentiation, TFH cells migrate to the B cell follicle and provide help to B cells via costimulation and cytokine production. Mice lacking TFH cells, or their key effector molecules, have severely defective antibody production in response to T-dependent antigens.

T follicular regulatory (TFR) cells are a recently defined specialized subset of effector T regulatory cells (Tregs) that inhibit antibody production. TFR cells originate from natural Tregs in contrast to TFH cells, which develop from naive CD4+ T cell precursors. Programmed cell death protein-1 (PD-1) expression on TFR cells limits both the differentiation and effector function of TFR cells. How TFR cells exert their suppressive effects is not yet clear.

We have demonstrated that the ratio of TFH/TFR cells is an important factor in humoral immunity and that this ratio dictates the magnitude of antibody responses. Therefore, successful humoral immunity is a delicate balance between stimulatory TFH cells and inhibitory TFR cells and not simply a result of the total number of TFH cells. TFR cells appear to be specialized in their suppression of the GC reaction because non-TFR Tregs do not have the same suppressive capacity. We demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. We find increases in both TFH and TFR cells, with a proportionally greater increase in TFR cells. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo.

Together, our studies provide insights into mechanisms for defective antibody production in aging. We find an over-representation of functionally competent suppressive TFR cells in aged mice, most likely resulting from enhanced differentiation of TFR cells. However, expansion of memory TFR cells may also contribute. In addition, we find that TFH cells are generated following immunization of aged mice, but these aged TFH cells fail to elicit strong antigen-specific B cell responses in vivo. Aged TFH cells express higher levels of PD-1 and PD-1 blockade can improve TFH cell function. Thus, the substantial increase in fully suppressive TFR cells, combined with the decrease in antigen-specific responses of TFH cells, results in a significant defect in antibody production in aged mice. Although other mechanisms, such as defects in clonality and/or naive T or B cell numbers also may contribute, our data point to alterations in TFH cell activity and TFR cell proportions as being a key mechanism that impairs antibody production in aging. Therefore, approaches that downmodulate TFR cells may provide a strategy for improving humoral immune responses in the elderly.


Glial cells perform many vital tasks in the brain and other nervous system tissues, and age-related changes in their behavior are a part of the progression of neurodegenerative conditions. In the last couple of months a fair number of very readable review papers on this topic have been published. If you are interested in learning more about this aspect of the brain, now is your chance; take a look at the reviews referenced below.

There are many varied types of glia, each with a different role. Some provide structure and nutrients so as to support neurons, others appear essential to activities such as the formation of synaptic connections, or undertake immune system functions such as the destruction of invading pathogens. Much of the focus in the study of glia falls upon microglia, which carry out immune functions, and astrocytes, which have a very broad portfolio of responsibilities and contributions: near every aspect of the brain's operation is influenced by or dependent upon their activities. In the study of the aging brain, rising levels of chronic inflammation and dysfunction of specific mechanisms are both topics of interest. Microglia mediate inflammation, while many neural mechanisms disrupted in the progression of neurodegenerative disorders involve astrocytes in one way or another.

Neuroinflammation: good, bad, or indifferent?

Under non-diseased conditions, central nervous system (CNS) homeostasis is maintained by an intricate crosstalk between glia and neurons. For example, astrocytes play a key role in neurogenesis, metabolism, and regulating neuronal activity at the tripartite synapse. Microglia are continuously surveying their microenvironments for foreign antigens and are important phagocytes, playing roles in synaptic pruning and clearance of apoptotic debris. However, in response to CNS infection or injury, these glial cells become activated and contribute to ensuing inflammatory processes, in either a beneficial or detrimental manner, depending on the nature, intensity, and duration of the insult. Yet, another wrinkle to this paradigm is the fact that many immune-related molecules can possess secondary functions in the CNS, which expands their portfolio of action.

It is now evident that many diseases affecting the CNS have some inflammatory component, either as a primary cause or secondary outcome of tissue damage. Much work remains to be done to identify the critical mediators and cell types involved; however, this will prove to be a challenging task given the complexities already uncovered with regard to the timing, context, and crosstalk between individual inflammatory molecules. Nonetheless, harnessing inflammation to promote CNS healing/regeneration remains an area of active investigation.

New advances on glial activation in health and disease

In addition to being the support cells of the central nervous system (CNS), astrocytes are now recognized as active players in the regulation of synaptic function, neural repair, and CNS immunity. Astrocytes are among the most structurally complex cells in the brain, and activation of these cells has been shown in a wide spectrum of CNS injuries and diseases. Over the past decade, research has begun to elucidate the role of astrocyte activation and changes in astrocyte morphology in the progression of neural pathologies, which has led to glial-specific interventions for drug development. Future therapies for CNS infection, injury, and neurodegenerative disease are now aimed at targeting astrocyte responses to such insults.

Impact of age-related neuroglial cell responses on hippocampal deterioration

Aging is one of the greatest risk factors for the development of sporadic age-related neurodegenerative diseases and neuroinflammation is a common feature of this disease phenotype. In the immunoprivileged brain, neuroglial cells, which mediate neuroinflammatory responses, are influenced by the physiological factors in the microenvironment of the central nervous system (CNS). These physiological factors include but are not limited to cell-to-cell communication involving cell adhesion molecules, neuronal electrical activity and neurotransmitter and neuromodulator action. However, despite this dynamic control of neuroglial activity, in the healthy aged brain there is an alteration in the underlying neuroinflammatory response notably seen in the hippocampus, typified by astrocyte/microglia activation and increased pro-inflammatory cytokine production and signaling. These changes may occur without any overt concurrent pathology, however, they typically correlate with deteriorations in hippocamapal or cognitive function.

Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.

Glia: guardians, gluttons, or guides for the maintenance of neuronal connectivity?

An emerging aspect of neuronal-glial interactions is the connection glial cells have to synapses. Mounting research now suggests a far more intimate relationship than previously recognized. Moreover, the current evidence implicating synapse loss in neurodegenerative disease is overwhelming, but the role of glia in the process of synaptic degeneration has only recently been considered in earnest. Each main class of glial cell, including astrocytes, oligodendrocytes, and microglia, performs crucial and multifaceted roles in the maintenance of synaptic function and excitability. As such, aging and/or neuronal stress from disease-related misfolded proteins may involve disruption of multiple non-cell-autonomous synaptic support systems that are mediated by neighboring glia. In addition, glial cell activation induced by injury, ischemia, or neurodegeneration is thought to greatly alter the behavior of glial cells toward neuronal synapses, suggesting that neuroinflammation potentially contributes to synapse loss primarily mediated by altered glial functions.

Astrocytes in physiological aging and Alzheimer's disease

Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contributes to the aging of the brain and to neurodegenerative diseases. Changes in astroglia in aging and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter the homeostatic reserve of the brain and contribute to early cognitive deficits. At later stages of AD reactive astrocytes are associated with neurite plaques, the feature commonly found in animal models and in human diseased tissue. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at the prevention and cure of neurodegenerative disorders.

Microglia as a critical player in both developmental and late-life CNS pathologies

Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer's disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies.


Monday, July 6, 2015

Targeting antioxidants to the mitochondria inside cells has been shown to produce enough of a benefit to build therapies for a number of conditions, with better outcomes than standard antioxidant treatments. Researchers developing mitochondrially targeted antioxidants based on plastinquinones are still searching for potential clinical applications, however, and in the recent paper referenced here they demonstrate benefits in skin healing for aged mice.

Mitochondria produce reactive oxidizing molecules as a side-effect of their operation. Soaking up some of these molecules at the source has more and better effects on cellular metabolism than the introduction of non-targeted antioxidants, including in some cases extension of healthy life. The reasons for this are complex and still incompletely understood: the emitted reactive molecules are an important signal in addition to being agents that cause damage, cells react to both signals and damage, and among the interventions that slow aging in lower animals some involve greater and some involve lesser generation of reactive molecules in mitochondria. Regarding non-targeted antioxidants, the general consensus at this time is that antioxidant supplementation as a matter of course is probably mildly harmful, as it interferes with hormetic processes based on use of reactive molecules as signals such as those that mediate the beneficial effects of exercise.

The process of skin wound healing is delayed or impaired in aging animals. To investigate the possible role of mitochondrial reactive oxygen species (mtROS) in cutaneous wound healing of aged mice, we have applied the mitochondria-targeted antioxidant SkQ1. The SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. The wounds of SkQ1-treated mice contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation. This effect resembled SkQ1-induced differentiation of fibroblasts to myofibroblast, observed earlier in vitro.

The transforming growth factor beta (TGFb) produced by SkQ1-treated fibroblasts was found to stimulated motility of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. In vitro experiments showed that SkQ1 prevented decomposition of VE-cadherin containing contacts and following increase in permeability of endothelial cells monolayer, induced by pro-inflammatory cytokine TNF. Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1. Our findings point to an important role of mtROS in pathogenesis of age-related chronic wounds.

Monday, July 6, 2015

Axons extend from nerve cells, grouped in bundles to form nerves, with the longest axons running for a meter or more. When severed they tend not to regrow, a limitation that researchers are trying to work around. Here is one of a number of instances in which axon regrowth has been demonstrated in the laboratory:

Chronic spinal cord injury (SCI) is a formidable hurdle that prevents a large number of injured axons from crossing the lesion, particularly the corticospinal tract (CST). While physical therapy and rehabilitation would help the patients to cope with the aftermath, axonal regrowth potential of injured neurons was thought to be intractable. Now researchers report that the deletion of the PTEN gene would enhance compensatory sprouting of uninjured CST axons. Furthermore, the deletion up-regulated the activity of another gene, the mammalian target of rapamycin (mTOR), which promoted regeneration of CST axons.

"As one of the long descending tracts controlling voluntary movement, the corticospinal tract (CST) plays an important role for functional recovery after spinal cord injury. The regeneration of CST has been a major challenge in the field, especially after chronic injuries. Here we developed a strategy to modulate PTEN/mTOR signaling in adult corticospinal motor neurons in the post-injury paradigm. It not only promoted the sprouting of uninjured CST axons, but also enabled the regeneration of injured axons past the lesion in a mouse model of spinal cord injury, even when treatment was delayed up to 1 year after the original injury. The results considerably extend the window of opportunity for regenerating CST axons severed in spinal cord injuries. It is interesting to find that chronically injured neurons retain the ability to reform tentative synaptic connections. PTEN inhibition can be targeted on particular neurons, which means that we can apply the procedure specifically on the region of interest as we continue our research."

Tuesday, July 7, 2015

Over the last few years researchers have gathered data that suggests smooth muscle cells have a more important role in the later stages of atherosclerosis than previously suspected. This new result adds to the evidence:

Until now, doctors have believed that smooth muscle cells - the cells that help blood vessels contract and dilate - were the good guys in the body's battle against atherosclerotic plaque. They were thought to migrate from their normal location in the blood vessel wall into the developing atherosclerotic plaque, where they would attempt to wall off the accumulating fats, dying cells and other nasty components of the plaque. The dogma has been that the more smooth muscle cells in that wall -- particularly in the innermost layer referred to as the "fibrous cap" -- the more stable the plaque is and the less danger it poses.

Recent research reveals those notions are woefully incomplete at best. Scientists have grossly misjudged the number of smooth muscle cells inside the plaques, the work shows, suggesting the cells are not just involved in forming a barrier so much as contributing to the plaque itself. "We suspected there was a small number of smooth muscle cells we were failing to identify using the typical immunostaining detection methods. It wasn't a small number. It was 82 percent. Eighty-two percent of the smooth muscle cells within advanced atherosclerotic lesions cannot be identified using the typical methodology since the lesion cells down-regulate smooth muscle cell markers. As such, we have grossly underestimated how many smooth muscle cells are in the lesion."

The problem is made all the more complicated by the fact that some smooth muscle cells were being misidentified as immune cells called macrophages, while some macrophage-derived cells were masquerading as smooth muscle cells. It's very confusing and it has led to "complete ambiguity as to which cell is which within the lesion." (The research also shows other subsets of smooth muscle cells were transitioning to cells resembling stem cells and myofibroblasts.)

Researchers identified a key gene, Klf4, that appears to regulate these transitions of smooth muscle cells. Remarkably, when Klf4 was selectively knocked out in smooth muscle cells, the atherosclerotic plaques shrank dramatically and exhibited features indicating they were more stable - the ideal therapeutic goal for treating the disease in people. Of major interest, loss of Klf4 in smooth muscle cells did not reduce the number of these cells in lesions but resulted in them undergoing transitions in their functional properties that appear to be beneficial.

Tuesday, July 7, 2015

It shouldn't be too surprising to find that people with greater levels of minor brain damage are at greater risk of stroke and death, as noted by these researchers. Blood vessel integrity deteriorates with age, and as a result, many tiny areas of damage accumulate in the brain where small blood vessels suffer breakage. This destroyed tissue contributes to cognitive impairment, one small disaster at a time, all of them going individually unnoticed. The amount of this brain damage in any given individual is a reflection of the degree of deterioration that has occurred in blood vessels and other important structures, caused by underlying forms of cellular and molecular damage that accumulate throughout the body. Since aging is a global process, more damage in one location usually correlates well with more damage everywhere:

The researchers analyzed brain magnetic resonance imaging (MRI) data from nearly 1,900 individuals participating in the Atherosclerosis Risk in Communities (ARIC) Study who were 50 to 73 years of age with no prior history of stroke, tracking their health over about 15 years. Risk of stroke or stroke mortality in people with small lesions was three times greater compared with people with no lesions. People with both very small and larger lesions had seven to eight times higher risk of these poor outcomes.

"The lesions on the brain imaging were very small, less than 3 millimeters, and are typically ignored in clinical practice. This is because we have been uncertain as to their meaning; no studies have looked to see if these very small lesions are related to important clinical outcomes. Our findings suggest they are at least as important as 3 millimeter or larger lesions that are typically considered abnormal, even in absence of other lesions. We know that modifiable risk factors like hypertension and diabetes are associated with the larger structural changes in the brain, and those larger lesions are not only associated with stroke risk but with mobility impairments and cognitive impairments as well. Ongoing trials may determine whether treatment of risk factors, like high blood pressure, reduce the incidence of these lesions, stroke and associated death and disability."

Wednesday, July 8, 2015

The staff of the Buck Institute for Research on Aging, like most research centers in this field, largely work on things that won't make any meaningful difference to human longevity, such as calorie restriction mimetic drugs and other forms of metabolic manipulation that can only slightly slow the aging process. In among that there are a few useful projects that might form the basis for therapies capable of rejuvenation, repairing and reversing the course of aging, such as efforts to clear senescent cells, but they are a tiny minority of initiatives. Turning the aging research community around to primarily focus on things that actually matter, like senescent cell clearance, is still very much a work in progress, and this isn't helped by the funding situation for all lines of work related to aging:

In April, Novato-based Buck Institute for Research on Aging, with a 32.5 million budget and nearly 300 employees, launched a new partnership with Google-funded Calico Life Sciences, a San Francisco-based startup dedicated to research on aging. Calico's Arthur Levinson strolled the campus of Buck Institute and met with its CEO Brian Kennedy and other top researchers as he explored the emerging partnership. Calico plans to put some of its employees on the Buck site.

Over the past 15 years, government funding has not increased for research on aging such as that done at the Buck Institute, Kennedy said. "We are trying to figure out how to keep the lights on rather than growing. This is ridiculous." Research universities have similar funding struggles, he said. "When I go and argue for more funding I can't say we are going to do science for science's sake. You get put in an insane asylum if you say that. But precisely that spirit of pure inquiry is what drove huge technology advances. People explore and find interesting things. It's a sad indictment in the wealthiest country in the world - you can't make that case anymore. The anti-­intellectual movement in this country is very dangerous. When I go to China, I hear people's imaginations at work. When I talk to scientists in the U.S., I hear, how do I write my grant?"

Their talent for science is diverted to the task of drumming up money and keeping the flow going. "It makes you risk-averse," Kennedy said, yet the most exciting science happens in a risk-embracing environment. "I worry about the long-term state of this culture. We're not investing" even small amounts to drive discovery forward. "We should have a government that isn't afraid to be a little progressive."

About half of Buck Institute's 32.5 million budget comes from the National Institutes of Health. A few years ago, a much larger percentage of NIH funding went to research on aging, Kennedy said. He would like to have 50 investigators exploring the science of aging. He seeks investors in the science or philanthropists to expand the institute. "We need someone to make a 50 million bet" that the research will pay off, he said, a billionaire "to believe in this mission" as a vision, a legacy. "Aging research is an adventure in something completely different," he said. "We know it's going to work. It's time to implement it. We have this huge paradox. The promise of this field is great - the next medical revolution. There's no money. It's a big challenge. Meanwhile we are spending 19 percent of our (federal) budget on health care. It's not even effective." The cost of prevention can be a twentieth of the cost of treatment, he said.

Wednesday, July 8, 2015

Women have a longer life expectancy than men, but why is this? There is no definitive answer to that question, but many competing theories exist. It is a good illustration of the point that the biochemistry of aging is, in detail, enormously complex and still poorly understood as a process with definitive causes and consequences at each stage and in each tissue type. There is a mountain of data, but many more mountains to be cataloged yet, and linking together what is known into a coherent picture is another massive task still in the comparatively early stages. In the research noted here, the authors advance a novel theory on the gender longevity gap, painting the comparative longevity of women as a modern phenomenon driven by a combination of improved medical technology and cardiovascular disease rates.

With regards to the complexity of aging, it is fortunately the case that we don't need a full understanding of the progression of aging if researchers just focused on repairing what we know to be the root cause cell and tissue damage. The situation is akin to that of rust in an ornate metal structure: there is a big difference in effort between (a) just rust-proofing the thing and (b) building a complete module of how rust works and interacts at the molecular level and how exactly, in detail, that causes various structural failure modes over decades of exposure to the elements. In aging research, there is a lot more work on (b) than on (a), which is fine from the pure science perspective where the only goal is complete understanding, but not so good from the point of view of producing therapies for aging in time for you and I to benefit.

Across the entire world, women can expect to live longer than men. But why does this occur and was this always the case? According to a new study, significant differences in life expectancies between the sexes first emerged as recently as the turn of the 20th century. As infectious disease prevention, improved diets and other positive health behaviors were adopted by people born during the 1800s and early 1900s, death rates plummeted, but women began reaping the longevity benefits at a much faster rate. In the wake of this massive but uneven decrease in mortality, a review of global data points to heart disease as the culprit behind most of the excess deaths documented in adult men. "We were surprised at how the divergence in mortality between men and women, which originated as early as 1870, was concentrated in the 50-to-70 age range and faded out sharply after age 80."

Focusing on mortality in adults over the age of 40, the team found that in individuals born after 1880, female death rates decreased 70 percent faster than those of males. Even when the researchers controlled for smoking-related illnesses, cardiovascular disease appeared to still be the cause of the vast majority of excess deaths in adult men over 40 for the same time period. Surprisingly, smoking accounted for only 30 percent of the difference in mortality between the sexes after 1890. The uneven impact of cardiovascular illness-related deaths on men, especially during middle and early older age, raises the question of whether men and women face different heart disease risks due to inherent biological risks and/or protective factors at different points in their lives.

Thursday, July 9, 2015

Among the sea urchins can be found some of the few species to exhibit negligible senescence, an apparent lack of the obvious features of degenerative aging. By studying negligibly senescent species and the differences in their biochemistry, researchers hope to learn more about the mechanisms that drive aging. As this review notes, the data uncovered to date in sea urchins looks quite similar to the situation for long-lived and negligibly senescent clam species such as Arctica islandica:

Aging in humans and other animals is a well-defined process characterized by a progressive functional decline and increasing mortality over time. However, there are a number of different animals that show negligible senescence, with no increase in mortality rate or decrease in fertility, physiological function, or disease resistance with age. Studying these animals may suggest effective defenses against the degenerative process of aging, and sea urchins provide an ideal model to investigate mechanisms of longevity and negligible senescence.

Different species of sea urchins exhibit very different natural lifespans, and some have extreme longevity and negligible senescence. For example, the red sea urchin Strongylocentrotus franciscanus is one of the earth's longest living animals, living in excess of 100 years with no age-related increase in mortality rate or decline in reproductive capacity. In contrast, Lytechinus variegatus has an estimated lifespan of only 4 years, while the most widely studied species of sea urchin, S. purpuratus, has an estimated maximum lifespan of more than 50 years. Comparisons between long-, intermediate-, and short-lived species may provide insight into mechanisms involved in lifespan determination and negligible senescence. Thus, sea urchins represent an interesting alternative model for aging research.

Studies to date have demonstrated maintenance of telomeres, maintenance of antioxidant and proteasome enzyme activities, and little accumulation of oxidative cellular damage with age in tissues of sea urchin species with different lifespans. Gene expression studies indicate that key cellular pathways involved in energy metabolism, protein homeostasis, and tissue regeneration are maintained with age. Taken together, these studies suggest that long-term maintenance of mechanisms that sustain tissue homeostasis and regenerative capacity is essential for indeterminate growth and negligible senescence, and a better understanding of these processes may suggest effective strategies to mitigate the degenerative decline in human tissues with age.

Thursday, July 9, 2015

Here the Buck Institute blog explains a recent paper on links between mTOR, a focus for research into modestly slowing aging by altering the operation of metabolism, and the bad behavior of senescent cells. Ever more cells become senescent with advancing age, and this contributes to degenerative aging because these cells act in ways that damage surrounding tissue. From where I stand, the best approach is to remove them, however, not modulate their activity. There is a lot left to understand in order to safely change the behavior of senescent cells for the better, while clearing them is a near-term prospect, for example by adapting targeted cell killing technologies developed by the cancer research community.

We showed that the mTOR inhibitor rapamycin blocks the senescence-associated secretory phenotype (SASP) by inhibiting translation of IL-1α, which prevents senescent fibroblasts from promoting cancer tumor growth. What we found is that after chemotherapy or radiotherapy, cancer cells and the cells surrounding them become senescent. That means that the cells surrounding the cancer cells are no longer performing their normal function and they begin to secrete cytokines and growth factors that stimulate cancer growth. We found that a small molecule called rapamycin can prevent this from happening.

So if we extend the findings of that story, this drug may be useful following chemotherapy as an adjuvant. By giving the patient rapamycin after chemotherapy, we might slow down the relapse of the tumor. The next step obvious step is to run a clinical trial with rapamycin or a rapalog. Rapamycin is already FDA approved, so this is exciting for clinical trials, but trials aren't really something that basic scientists are equipped to do. Our paper is showing is that rapamycin would work well as an adjuvant therapy. So after you have received chemotherapy, senescent cells have been induced, and rapamycin can be used to block those otherwise harmful senescent cells. So rapamycin treatment should, in theory, delay relapse.

Half of the people at the Buck Institute work in one way or another with mTOR. So everyone has some connection to translation or mTOR because of how important mTOR is in aging. We have various people working on different aspects of aging. Some are focusing on age-related pathologies, and others are working on aging in general using model organisms. We know that senescent cells accumulate at sites of age-related pathologies and in some pathologies that aren't age related. We are still finding these things out. What is being taught currently is that the deleterious effect that senescent cells have is due to a proinflammatory profile. It is possible that rapamycin extends lifespan because it reduces the low level of chronic inflammation. So if you can think that this is true for aging in general, this could also be true for various age-related pathologies. It will be interesting to see the follow up on rapamycin and modulation of the proinflammatory profile of senescent cells.

Friday, July 10, 2015

Researchers here demonstrate restoration of immune function in mice via transplant of tissue engineered thymus-like organoids, one of a number of lines of research that aims to restore thymic function to boost the aging immune system. A sizable part of the age-related decline of the adaptive immune system arises from a problem of supply: there are no longer enough naive T cells to mount an effective response to new threats.

Some potential approaches to solving this problem involve dealing with issues that reduce the naive T cell population, while others focus on increasing the supply of new T cells. The thymus plays a vital role in the generation of new T cells, and is very active in early life, but withers away upon reaching adulthood in a process known as thymic involution, reducing the supply of immune cells to a trickle. Thus placing new thymic tissue with youthful characteristics into old individuals should be a way to generate more T cells - a straightforward transplant works, for example:

One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering.

Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells.

Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine.

Friday, July 10, 2015

Exercise improves health, but why? Many researchers are digging into the biochemical details, such as the authors of the paper referenced here, who focus on tendon integrity and its deterioration in aging, a degenerative process that is slowed by exercise. Overall regular moderate exercise is comprehensively demonstrated to improve long-term health and raise median life span in animal studies, and is robustly associated with better health, lower medical expenditures, and increased life expectancy in human epidemiological studies.

In recent years, a few studies have been performed to better understand the cellular and molecular mechanisms responsible for the effects of aging on tendons. In general, aging slowly lowers the functional competence of the human body, largely due to the damages in DNA, changes in the cellular microenvironments of the body and epigenetic regulation. In tendons, aging increases the nucleus to cytoplasm ratio and lipid deposition, but decreases vascularization and tendon matrix integrity, and alters tendon cell's response to cellular stimuli. In addition, aging also reduces the number of tendon cells and decreases their activity thereby depleting the resources required to repair injured tendons. Consequently, there is a steady decline in the ability of tendons to repair its injuries over time. Through these changes aging reduces the mechanical strength of tendons and makes them susceptible to injuries, thus lowering the quality of life of the aging population and increasing the healthcare cost.

While aging generally causes detrimental effects on tendons, exercise is known to exert beneficial effects on tendons. Traditionally, tendons were considered to contain only one cell type, the tenocytes, which are resident fibroblast-like cells that maintain tendon integrity, remodeling and repair. However, a new tendon cell type, termed tendon stem/progenitor cells (TSCs), has been identified in recent years in humans, rabbits, mice, and rats. However, the role of TSCs in aging- and exercise-induced changes in tendons is not well understood. Therefore, to explore the TSC-based mechanisms responsible for the beneficial effects of exercise on aging tendons, we tested two hypotheses in this study: i) aging impairs TSC function in tendons, and ii) moderate exercise revives impaired TSC function and thereby exerts beneficial effects on aging tendons.

TSCs derived from aging mice (9 and 24 months) proliferated significantly slower than TSCs obtained from young mice (2.5 and 5 months). In addition, expression of the stem cell markers Oct-4, nucleostemin (NS), Sca-1 and SSEA-1 in TSCs decreased in an age-dependent manner. Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression. In the in vivo study, moderate treadmill running of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons. These findings indicate that while aging impairs the proliferative ability of TSCs and reduces their stemness, moderate exercise can mitigate the deleterious effects of aging on TSCs and therefore may be responsible for decreased aging-induced tendon degeneration.


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