Fight Aging!

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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Contents

• Forever Healthy Foundation Provides a 150,000 Challenge Fund to Match SENS Rejuvenation Research Donations
• From Nuclear DNA Damage to Inflammatory Immune Aging via Cellular Senescence
• Suddenly Everyone is Casting their Views of Aging in Terms of Cellular Senescence
• BAG3 as a Target to Reduce Reperfusion Injury in Heart Tissues
• A Selection of Recent Regenerative Research
• Latest Headlines from Fight Aging!
  • Measuring the Effects of Prevention on Heart Disease
  • Age-Related Decline in Thymic Activity Correlates with Life Span in Dog Breeds
  • Hypertension Causes Neural Damage in Part via Altered Macrophage Behavior
  • Progression of Retinitis Pigmentosa Slowed by Sirt6 Inhibition in Mouse Model
  • Young Human Blood Plasma Produces Benefits in Old Mice
  • An Update on Reversing Heart Scarring via Gata4, Mef2c, and Tbx5
  • A Study Suggesting Tau Produces Rapid Impairment of Memory Mechanisms
  • GABA Linked to Working Memory Capacity
  • Considering Low Level Radiation Exposure and Alzheimer's Disease
  • Working to Turn Back the Loss of Skin Healing Capacity in Aging

Forever Healthy Foundation Provides a 150,000 Challenge Fund to Match SENS Rejuvenation Research Donations
https://www.fightaging.org/archives/2016/11/forever-healthy-foundation-provides-a-150000-challenge-fund-to-match-sens-rejuvenation-research-donations/

Good news! Thanks to the generous pledges of new SENS Patrons, signing up for monthly donations to the SENS Research Foundation over the past two weeks since the fundraiser started, the 24,000 matching fund put up by Josh Triplett and Fight Aging! is nearly met. Just a little more left to reach the target: if you are the next person to sign up, the next year of your donations to the SENS Research Foundation will be matched. But if you miss out on that, donations made before the end of the year can still be matched. The Forever Healthy Foundation's Michael Greve, who earlier this year pledged 10 million to SENS rejuvenation research and startup companies building rejuvenation therapies, has put up a further 150,000 challenge fund. He will match all donations to the SENS Research Foundation made before the end of 2016, and there is still a way to go in order to meet that target. So help us get this done!

Why support the SENS Research Foundation, and their ally the Methuselah Foundation? Because these organizations have proven capable of using your charitable donations more effectively than any other in order to make significant progress towards an end to aging and age-related disease. For fifteen years now, the principals and their network of advocates and scientists have nudged, debated, and funded researchers to ensure that the broader research community builds the basis for human rejuvenation. Aging is an accumulation of molecular damage, and if that damage is repaired sufficiently well, a goal that modern medicine is only just starting to grapple with despite decades of evidence, then the result will be a halt to the processes of degenerative aging. An end to the disease, dysfunction, and suffering of aging. When you look at near any area where the academic laboratories or biotechnology companies are making good progress towards this end, you'll find the SENS Research Foundation and Methuselah Foundation in the background and the history of that development.

The current brace of senescent cell clearance startup companies, working to bring this treatment to the clinic, after it has been shown to improve health and longevity in mice? SENS Research Foundation funding has for years helped that research progress at the Campisi lab, one of the groups that joined forces to create UNITY Biotechnology, recently funded for 116 million. SENS Research Foundation and Methuselah Foundation provided seed funding for Oisin Biotechnology, where the principals are building a better approach to senescent cell clearance than that fielded by UNITY Biotechnology. Or how about work on allotopic expression of mitochondrial genes, a way to prevent mitochondrial damage from contributing to aging by placing copies of mitochondrial genes in the cell nucleus? The SENS Research Foundation and Methuselah Foundation before it helped to fund the research programs that led to Gensight Biologics, a company now deploying tens of millions in venture funding to build a platform to back up mitochondrial genes. Or how about progress towards treatments capable of clearing out the glucosepane cross-links that produce tissue stiffening, such as the loss of elasticity in blood vessels that produces hypertension and tissue damage? The SENS Research Foundation has funded the few interested researchers for years, enabling them to build the toolkit needed to work with glucosepane, and now researchers are at the stage of hunting for the first drug candidate.

I could go on: the advocacy and conferences bringing together academia and industry to build a new development community; the support for thymic rejuvenation and other means of immune system repair; the work on a universal cancer treatment based on blockade of telomere lengthening; the mining of bacterial enzymes to find those capable of removing damaging metabolic waste products that our biology cannot handle. The point is that the SENS Research Foundation and Methuselah Foundation deliver. They take our donations and use them to make a real difference, creating step by step progress towards the therapies that will enable us to live far longer in good health, and effectively treat and prevent age-related disease. If the damage that causes aging can be periodically repaired, even poorly at first, then ultimately aging will be brought under control. As the therapies become better and more comprehensive, no-one will need to suffer. The hundreds of millions with age-related frailty and disease and the more than 100,000 who die from aging every day might be saved. This is the greatest and most important altruistic goal: if we get the job done soon enough, we all win together.

Our community is making this happen: our actions, our donations, our advocacy. We are changing the world, and now that the wheel is beginning to turn, that is no time to slacken in our support. Donate to the SENS Research Foundation in this current fundraiser, and your donations will be matched. The more we raise, the faster that research progresses, and the sooner that real, working rejuvenation therapies will arrive at the clinic.

From Nuclear DNA Damage to Inflammatory Immune Aging via Cellular Senescence
https://www.fightaging.org/archives/2016/11/from-nuclear-dna-damage-to-inflammatory-immune-aging-via-cellular-senescence/

Today I'll point out an open access paper in which the authors discuss some aspects of DNA damage with a particular focus on age-related inflammation and immune system dysfunction. Cells are fluid, dynamic landscapes of molecular machinery, near every component constantly damaged by inappropriate chemical reactions, but also constantly repaired and replaced. Little is static or lasting. The greatest, most intricate, and effective repair mechanisms are those that attend nuclear DNA, the blueprints for proteins and cellular operations that reside in the cell nucleus. One of the characteristics of aging is that despite the panoply of repair efforts, cells accumulate random nuclear DNA damage. Since the research community can't yet stop this from happening, there is considerable difficulty in separating out and quantifying this one particular contribution to the broader aging process. Certainly we can talk about cancer risk, and we can talk about rising numbers of cells becoming senescent in response to DNA damage, and researchers can disable DNA repair to observe the shortened life spans that result from such a fundamental breakage in cellular operation, but beyond that it becomes increasingly challenging to quantify effects within the scope of normal degenerative aging. If nuclear DNA damage was removed, such as via the somewhat distant molecular nanomachinery of chromallocytes, programmable nanorobots moving from cell to cell to fix each breakage, then aside from the elimination of cancer, would it have any other measurable effect on health and longevity? This is an unanswerable question at the present time.

Still, it will not remain unanswerable, and even today convincing and well-anchored arguments can be made either way, for and against the significance of nuclear DNA damage in aging. Interestingly, many of those on the side of nuclear DNA damage as being important in aging beyond cancer risk tend to pull senescent cells into the picture they paint. Senescent cells in turn produce inflammation, and chronic inflammation and related aspects of immune system decline are a big part of the broader progression of aging. This may well be more a sign of the times, a measure of the increasing interest in the research community directed towards the role of cellular senescence in aging, rather than something that arises organically. Certainly, much more funding is moving into efforts to treat aging by removal of senescent cells these days than was the case even a decade ago. The lines can be drawn, however, the connections made, but again it is hard to put numbers to these things without a way to remove nuclear DNA damage in isolation, carried out without influencing any other process relevant to degenerative aging.

From a long-term perspective, nuclear DNA damage is a thorny problem. It will be one of the hardest forms of damage to repair via rejuvenation biotechnology; the only one that springs to mind as likely being even more difficult is the matter of damaged nuclear pore proteins in long-lived cells, single molecules that might be as old as you are, doing the same job for an entire human life span. The only plausible methods of repairing stochastic nuclear DNA damage look to be the aforementioned advanced molecular nanotechnology, something that lies some decades in the future, or major advances in gene therapy, to the point at which it could be cost-effective and safe to scan and conditionally alter the majority of genes in the majority of cells all at once. When you stop to think about what would be required, it isn't clear that there is in fact much difference between the two items I mentioned there. Given this, it seems very plausible that in the decades ahead there will be many partially rejuvenated, active, healthy people at advanced ages walking around, all bearing very high levels of nuclear DNA damage, but protected from the consequent cancer incidence by highly effective next generation therapies. We shall see how it goes, but it certainly beats the present alternative of certain frailty and death.

DNA Damage: From Chronic Inflammation to Age-Related Deterioration

To withstand the hazards of existence, multicellular organisms need to preserve their bodily functions for long periods of time and protect themselves against pathogens. Taking the cell as a point of reference, the maintenance is directed inwards to counteract macromolecular damage. This often involves restoring injured nucleic acids back to their native form or replenishing proteins and lipids once damaged by harmful byproducts of metabolism. Further, cellular defense mechanisms, such as the innate immune responses are mainly directed outwards to protect the organism against irritants, pathogens, or injured cells. Since the problem of damage or the invasion of cells by pathogens has existed nearly ab initio, maintenance and defense must have arisen early during evolution. Indeed, even simple unicellular organisms such as bacteria possess multiple caretaking systems.

Remarkably, some prokaryotes employ a structurally distinct family of nucleases with a dual function e.g., in DNA repair and antiviral immunity. Similar to bacteria, mammals provide ample evidence that mechanisms of DNA repair and immunity have evolved together. For example, non-homologous end-joining is involved in the development of lymphocytes in resolving recombination intermediates i.e., DNA strand breaks (DSBs) that occur during V(D)J recombination. Likewise, "programmed" DNA lesions followed by error-prone DNA repair dramatically increase antibody diversity by triggering somatic hypermutation of immunoglobulin variable genes. Nonetheless, the evolutionary transition from one-celled microbes to more complex living systems has pushed for drastic changes in maintenance and defense strategies. In mammals, a single fertilized egg rapidly divides into several trillions of cells grouped into specialized tissues with marked differences in terms of developmental origin, regenerative capacity and ability to cope with damage. Moreover, tissues, organs and organ systems team up to perform specific tasks such as the body's first line of defense against bacteria or viruses. This inherent complexity arising from manifold levels of organization within multicellular life forms requires that genome maintenance, the DNA damage response (DDR) and defense strategies are tightly linked and highly coordinated processes.

Recent evidence points to reciprocal interactions between DNA repair, DNA damage responses and aspects of immunity; both self-maintenance and defense responses share a battery of common players and signaling pathways aimed at safeguarding our bodily functions over time. In the short-term, this functional interplay would allow injured cells to restore damaged DNA templates or communicate their compromised state to the microenvironment. In the long-term, however, it may result in the (premature) onset of age-related degeneration, including cancer. Until recently, there would have been few examples to link DNA damage and inflammation to health and disease. However, recent findings allow us to consider several instances where innate immune responses driven by intrinsic genome instability or chronic exposure to exogenous genotoxins is causal to age-related degeneration, metabolic abnormalities and cancer. Indeed, chronic inflammation is thought to generate an excess of reactive oxygen and nitrogen species (ROS, RNS) triggering DNA damage and malignancy. In support, chronic inflammation in the colon or the gastric cardia of mice is functionally linked to the formation of DNA lesions and the induction of the DDR, as well as with cancer induction.

Cellular senescence is a term used to describe cells that cease to divide in culture and has been one of the first paradigms to link DNA damage and immunity to disease. Cellular senescence is often fueled by nuclear DNA damage followed by chronic DDR activation; telomere shortening, mitogenic oncogenes, or intrinsic DNA damage can lead to different types of senescence limiting the replicative lifespan of cells. Persistent DNA damage and DDR signaling triggers senescent cells to secrete immunomodulatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). SASP factors range from inflammatory and immune-modulatory cytokines to chemokines as well as growth factors, shed cell surface molecules, survival factors and extracellular matrix remodeling enzymes. Together, they impinge on cell-fate decisions in neighboring cells or the tissue microenvironment. As DNA damage accumulates with age, persistent DDR-mediated release of SASP factors could be associated with degenerative changes that manifest with old age; in support, several SASP factors are considered amongst the most reliable biomarkers for age-related diseases.

Nevertheless, any direct evidence linking DNA damage to chronic inflammation stems from recent findings in progeroid (accelerated aging) syndromes and accompanying mouse models that carry inborn DNA repair defects. Patients with Werner syndrome (WS, associated with mutations in the RecQ DNA helicase) manifest with features of systemic chronic inflammation. Eventually, a universal theme arises from these recent findings; it is neither DNA damage nor senescence or cancer per se but persistent DDR that triggers the repertoire of innate immune responses. Thus, any events that could potentially activate DDR could trigger the activation of innate immune responses in the absence of DNA damage; similarly suppressing DDR signaling in the presence of tolerable DNA damage levels could alleviate some of the pathological features associated with DNA damage-driven inflammation.

DNA damage-driven inflammation can be both beneficial and detrimental for organismal survival. To understand this controversy, it may be helpful to consider that such responses have been selected for by having their early benefits outweigh their late costs during evolution. Early in life, priorities in mammals are shifted toward development, growth, and reproductive fitness. As cells divide, gain volume or differentiate, tissues rely on maintenance and defense mechanisms to efficiently detect and remove damaged cells. In doing so, specific cell types may activate immune responses to fine tune cell-fate decisions at the organismal level; for instance, DNA damage in germ cells induces an innate immune response in worms that promotes endurance of somatic tissues to allow delay of progeny production when germ cells are hit by DNA damage. Once reproductive maturity has been reached, the competitive advantage to signal the presence of damaged cells (in youth) is gradually deteriorating. Despite the efficiency of DNA repair mechanisms, some DNA damage is left unrepaired leading to the gradual accumulation of DNA lesions in cells. In turn, the slow but steady buildup of damaged cells within tissues is expected to intensify DDR responses over time. Likewise, the DDR-mediated pro-inflammatory signals may further alarm the neighboring cells and tissues for the presence of cells with compromised genome integrity. The latter triggers a vicious cycle of persistent DDR and pro-inflammatory signals leading to chronic inflammation, tissue malfunction and degeneration with old age; in DNA repair-deficient patients, the rapid accumulation of DNA damage (in view of the DNA repair defect) would trigger the untimely activation of DDR signaling leading to the early manifestation of age-related pathology that is associated with chronic inflammation.

Suddenly Everyone is Casting their Views of Aging in Terms of Cellular Senescence
https://www.fightaging.org/archives/2016/11/suddenly-everyone-is-casting-their-views-of-aging-in-terms-of-cellular-senescence/

I exaggerate in the title of this post, of course, but there is some truth in it. Certainly, a lot more attention is focused on the phenomenon of cellular senescence now that mouse life spans have been extended and aspects of aging have been reversed via clearance of senescent cells. The existence of several startup biotechnology companies aiming to bring senescent cell clearance treatments to the clinic is shining even more of a spotlight on this area. It has been something of a transformation. Five years ago, one of the few groups of researchers interested in this field struggled greatly to raise the funding for the pivotal study to prove that selectively removing senescent cells had a significant impact on health. Five years from now, every major research center will have a cellular senescence arm in the same way that they have a cancer arm today. It is that important to that many aspects of aging and age-related disease.

Cells become senescent when they reach the end of their replicative life span, or in response to damage, or a toxic environment. They cease to divide, and largely destroy themselves or are destroyed by the immune system. It is an evolutionary adaptation that serves, at least initially, to suppress cancer by removing those cells most at risk of uncontrolled replication. Unfortunately not all are destroyed. Some remain, and their numbers grow over the years, secreting a disruptive mix of signal molecules that causes chronic inflammation, corrodes surrounding tissue structures, changes the behavior of healthy cells for the worse, and no doubt more that is yet to be cataloged. Recently researchers have shown that senescent cells contribute directly to the progression of atherosclerosis, as well as declining lung function and loss of tissue elasticity in that organ. The inflammation angle on its own is enough to link greater numbers of senescent cell to an increased risk of most age-related diseases, and a worse prognosis for long-term health. Then, of course, there is the life span study showing extended life in mice as a result of senescent cell clearance.

Senescent cell accumulation is only one of the processes that cause degenerative aging. Fixing it via periodic selective destruction of these cells is only a narrow, partial rejuvenation. There is still everything else in the SENS rejuvenation research agenda to work through. Nonetheless, it is a great improvement over the present state of medicine to have senescence cell clearance therapies on the horizon. Given that senescent cells can be linked to near every age-related condition via at least inflammatory mechanisms, and given the greatly increased awareness of cellular senescence in far-flung parts of the research community that probably weren't paying all that much attention in the past, we are now seeing the first of what will no doubt prove to be a wide selection of efforts to link preexisting theories, data, and viewpoints on aging and age-related disease to what is known of the biochemistry of cellular senescence. I offer the open access paper quoted below as one example of the type, though I wouldn't take everything the authors have to say about oxidative stress in aging at face value. They mention the supporting evidence, but omit the equally numerous counterexamples that demonstrate the relationship between oxidative damage and aging to be far from simple.

A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1-/- mice is correlated to increased cellular senescence

The Free Radical or Oxidative Stress Theory of Aging postulates that reactive oxygen species (ROS) formed exogenously or endogenously from normal metabolic processes play a role in the aging process. The imbalance of pro-oxidants and antioxidants leads to an age-related accumulation of oxidative damage in macromolecules, resulting in a progressive loss in function and aging. Over the past three decades, the Oxidative Stress Theory of Aging has become one of the most popular theories to explain the biological/molecular mechanism underlying aging because several lines of evidence support the theory. First, the levels of oxidative damage to lipid, DNA, and protein have been reported to increase with age in a wide variety of tissues and animal models. Second, studies with animal models showing increased longevity are consistent with the Oxidative Stress Theory of Aging. Longer-lived animals show reduced oxidative damage and/or increased resistance to oxidative stress, e.g., dietary restriction in rodents and genetic manipulations that increase lifespan in invertebrates (C. elegans and Drosophila) and in mice. Thus, the observations that experimental manipulations that increase lifespan in invertebrates and rodents were correlated to increased resistance to oxidative stress or reduced oxidative damage provided strong support for the Oxidative Stress Theory of Aging. However, all of the experimental manipulations that increase lifespan also alter processes other than oxidative stress/damage; therefore, the increase in longevity in these animal models could arise through another mechanism.

Over the past two decades, our group has directly tested the role of oxidative damage/stress in aging by genetically manipulating the antioxidant status of a wide variety of antioxidant genes to increase or reduce the level of oxidative stress/damage and determine what affect these manipulations had on lifespan. Our research with 18 different genetic manipulations in the antioxidant defense system shows that only the mouse model null for Cu/Zn-superoxide dismutase (Sod1) had an effect on lifespan (in this case a decrease in lifespan) as predicted by the Oxidative Stress Theory of Aging. Because it has been reported that more than 70% of Sod1-/- mice developed liver hyperplasia and hepatocellular carcinoma later in life, it was initially believed that the 30% decrease in the lifespan of Sod1-/- mice was not due to accelerated aging but was the result of a dramatic increase in hepatocellular carcinoma, which is rare in C57BL/6 mice. In a more recent study, we found a similar 30% decrease in lifespan of the Sod1-/- mice; however, in our study, only about 30% of Sod1-/- mice developed hepatocellular carcinoma later in life. In addition, we showed that dietary restriction, which is a manipulation that retards aging in rodents, increased the lifespan of the Sod1-/- mice to that of normal, wild type (WT) mice. These data combined with studies showing that Sod1-/- mice exhibited various accelerated aging phenotypes (e.g., muscle atrophy and loss of fat mass, hearing loss, cataracts, skin thinning and delayed wound healing) lead us to conclude that the Sod1-/- mice exhibit accelerated aging. This then raised the question of why we observed a significant decrease in lifespan and accelerated aging in only the Sod1-/- mice and not in other mouse models with compromised antioxidant defense systems that showed changes in oxidative stress/damage.

Sod1-/- mice show a much higher level DNA oxidation (i.e., 8-oxo-dG levels) in tissues than any of the mouse models we have studied, which all have deficiencies in one or more of the antioxidant genes. In addition, DNA mutations have been reported to increase significantly in several tissues in Sod1-/- mice. Because the DNA damage response has been shown to play a central role in the generation of senescent cells and because it has been shown that clearance of senescent cells delays aging-associated disorders and increases lifespan in a progeroid mouse model as well as in normal, wild type (WT) mice, we hypothesized that the increased oxidative damage to DNA in tissues of Sod1-/- mice could activate the DNA damage response and drive cells into becoming senescent. To test our hypothesis, we measured various markers of cellular senescence in kidney tissue, a tissue that shows a significant increase in senescent cells with age. We compared kidney from young-adult and old WT mice and young-adult Sod1-/- mice fed ad libitum or a dietary restriction diet. Our data clearly demonstrate that the level of senescent cells is dramatically increased in the kidney of young-adult Sod1-/- mice compared to young-adult WT mice and are at a level comparable to old WT mice. In addition, we observed that the increase in cellular senescence observed in the Sod1-/- mice was attenuated by dietary restriction. Interestingly, the increase in cellular senescence in the Sod1-/- mice was correlated to increased circulating cytokines. Thus, our data suggest that increased cellular senescence could play a role in the accelerated aging phenotype we have observed in the Sod1-/- mice.

BAG3 as a Target to Reduce Reperfusion Injury in Heart Tissues
https://www.fightaging.org/archives/2016/11/bag3-as-a-target-to-reduce-reperfusion-injury-in-heart-tissues/

There have been a number of life science discoveries of late that might lead to therapies capable of reducing the level of tissue damage caused by structural failures in important blood vessels, the basis for a range of age-related conditions. News of another possible approach arrived recently, and you will find links to the publicity materials and open access paper below. Blood vessel failures cause an interruption of oxygenated blood flow to tissues, and depending on the location in the body and size of the failed vessel, can produce the dramatic symptoms of stroke, heart attack, and so forth. While methods of prevention are far preferable to methods the produce greater than normal resilience, if the resilience is on offer it would be foolish to turn it down.

In ischemic injuries where blood flow is lost for a period of time, the real damage is done not after blood supply ceases, but after it is restored. With renewed oxygenation, cells fall into a self-sabotaging state of intense activity and die in large numbers. Of course if blood supply is never restored, the same end result occurs and the tissue dies, but reperfusion injury is perhaps the biggest threat in stroke, heart attack, and the like. Thus there is great interest in the research community in finding ways to reduce this damage, and many different methodologies have been tried, sadly to little success. Now that researchers are getting a better handle on the cellular biochemistry of ischemia and reperfusion, however, targets are emerging. For example, suppressing the oxygen sensor PHD1 greatly reduces reperfusion damage, as fewer cells react inappropriately to the return of oxygenated blood. Similarly, temporary sabotage of the cell death process might achieve a similar outcome, while letting the cells otherwise react normally, and MIF is one target there. Another possible approach is to spur greater growth of alternative vasculature via Rabep2, so as to reduce the impact of any one path for blood failing. As you can see, there are many possible points at which to intervene.

Still, prevention seems a whole lot better. When the problem is failing aged blood vessels, the solution has to be something like the SENS approach to rejuvenation research. Taking the proximate causes of blood vessel failure, that include hypertension, loss of elasticity in blood vessels, and atherosclerosis, for example, we can the look at the root causes of these issues. These include cross-linking in the extracellular matrix of blood vessel walls, rising numbers of senescent cells, and the oxidized lipids produced as a result of cells taken over by malfunctioning mitochondria. Each of these root cause classes of cell and tissue damage has an associated path to therapies that will repair or work around this type of damage to remove its effects. The programs are as clearly mapped out as anything can be in the world of research and development. If we want to see an end to strokes and heart attacks, a world in which older people have great cardiovascular health with little to no decline beyond their earlier years, then this is the type of research we need to support.

BAG3 Protein Plays Critical Role in Protecting Heart From Reperfusion Injury, Temple Researchers Show

The inability of cells to eliminate damaged proteins and organelles following the blockage of a coronary artery and its subsequent re-opening with angioplasty or medications - a sequence known as ischemia/reperfusion - often results in irreparable damage to the heart muscle. To date, attempts to prevent this damage in humans have been unsuccessful. According to a new study, however, it may be possible to substantially limit reperfusion injury by increasing the expression of a protein known as Bcl-2-associated athanogene 3 (BAG3).

Ischemia impairs the function of cellular organelles including mitochondria, the cell's energy-producers, resulting in harmful effects that set the stage for a sudden burst in the generation of toxic oxidizing substances when oxygenated blood reenters the heart. The toxins lead to fundamental changes in the biology of the heart. Notably, they activate cell death pathways and decrease autophagy - the process by which cells remove malfunctioning proteins and organelles. Autophagy plays a critical role in removing damaged myocardial cells (the muscular tissue of the heart) and misfolded heart muscle fibers. The new work shows that BAG3 expression both inactivates cell death pathways, helping prevent the loss of heart cells triggered by ischemia, and activates autophagy, thereby enabling cells to clear out impaired components of the heart cell before they inflict extensive damage.

In initial work, the research group found that BAG3 promotes autophagy and inhibits programmed cell death (apoptosis) in cultured cardiac myocytes. Subsequently, they found that when heart cells were exposed to the stress of hypoxia/reoxygenation or when living mice were stressed with ischemia/reperfusion, they suffered dramatic reductions in BAG3 expression. Those paradoxical changes in BAG3 levels turned out to be directly associated with increases in biomarkers of autophagy and with decreases in biomarkers of apoptosis. By artificially knocking down BAG3 in mouse heart cells, the researchers were able to produce an apoptosis-autophagy biomarker phenotype nearly identical to that produced by hypoxia/reoxygenation. By contrast, BAG3 overexpression normalized apoptosis and autophagy. In a key experiment, the team further showed that tissue damage sustained following ischemia/reperfusion could be substantially reduced by treating mice with BAG3 prior to vessel re-opening. BAG3 overexpression before the onset of ischemia/reperfusion also resulted in normalization in apoptosis and autophagy biomarkers.

Bcl-2-associated athanogene 3 protects the heart from ischemia/reperfusion injury

BAG3 has come to the attention of investigators focused on the heart due to the observation that mutations in BAG3 lead to familial dilated cardiomyopathy, the finding that BAG3 modulates excitation-contraction coupling in the heart, and our recent observation that BAG3 promoted mitochondrial degradation through the autophagy-lysosome pathway and through direct interactions with mitochondria. Because disruption of the normal removal of damaged and dysfunctional mitochondria plays a pivotal role in reperfusion injury following ischemia, we hypothesized that alterations in the expression or function of BAG3 might play a role in reperfusion injury.

The role of autophagy and apoptosis in the development of cardiovascular disease and in particular in the development of heart failure has been well recognized. In fact, modest overexpression of active caspase leads to the development of heart failure. However, a pivotal role for BAG3 in regulating cardiac protection and its associated effects on autophagy and apoptosis have not been previously recognized. Importantly, while restitution of diminished levels of BAG3 after hypoxia/reoxygenation or ischemia/reperfusion lead to salutary effects in cells or tissues that have been stressed, BAG3 appears to have no untoward effects on either autophagy or apoptosis when BAG3 levels are increased in cells or hearts that have not been exposed to stress, suggesting that attempts to increase BAG3 levels could provide a unique and important therapeutic approach to cardiac protection.

Despite successful efforts to limit the time between the onset of coronary obstruction and coronary intervention in patients with an acute myocardial infarction, myocardial damage due to reperfusion injury remains a major clinical problem that has failed to be influenced by multiple pharmacologic approaches. The findings that BAG3 levels are reduced during the stress of hypoxia/reoxygenation in vitro or ischemia/reperfusion in vivo and that overexpression of BAG3 reduces infarct size and improves left ventricle function after ischemia/reperfusion in mice suggest that BAG3 could provide a therapeutic target for cardiac protection. We recognize that biological differences exist between mice and humans, and it will be important to demonstrate that similar salutary benefits of enhancing BAG3 levels can be seen in a large animal model of ischemia/reperfusion injury. Nonetheless, our results suggest that moving from evaluations in mice to studies in large animals with ischemia and reperfusion, the next step in translational science paradigm, would be warranted.

A Selection of Recent Regenerative Research
https://www.fightaging.org/archives/2016/11/a-selection-of-recent-regenerative-research/

Here I'll point out a varied collection of recent papers and research results linked by the theme of regeneration. I found them interesting enough to note in passing for one reason or another, but a great deal of similar research is passing by these days, far too much for any one individual to read in detail. Regenerative medicine is much more than just the production of effective stem cell treatments. In its broadest definition it also encompasses the sort of rejuvenation therapies outlined in the materials and scientific programs of the SENS Research Foundation. It is a matter of finding the breakage, the abnormality, the injury, and then taking the path of augmenting, altering, or steering cellular activity in order to induce regeneration sufficient to restore normal function. There are countless ways to achieve that goal: tissue engineering for transplantation; cell therapies and small molecule therapies that aim to adjust the behavior of local tissues; augmentations such as gene therapies that introduce entirely new capabilities to cells. Aging is a collection of breakages and damage at the level of cells and proteins that leads to lost functionality. Repairing that damage in order to allow the normal operation of organs and tissues is exactly a facet of regeneration.

Transplantation with induced neural stem cells improves stroke recovery in mice

In a study to determine whether induced neural stem cells (iNSCs), a type of somatic cell directly differentiated into neural stem cells, could exert therapeutic effects when transplanted into mice modeled with ischemic stroke, researchers found that the cells promoted survival and functional recovery. Additionally, they discovered that when administered during the acute phase of stroke, iNSCs protected the brain from ischemia-related damage. In contrast to other studies that have induced somatic cells to become pluripotent stem cells (iPSCs), which can then be differentiated into neural cells, this study directly converted somatic cells into neural stem cells. Researchers concluded that in addition to iNSC transplantation improving survival rate, results also demonstrated reduced infarct volume in the brain and enhanced sensorimotor function in the mice modeled with stroke. "The iNSCs did not produce any adverse responses in the animals, including tumor formation, which may suggest they are safer than regular iPSCs. Further studies are needed to confirm this cell type as a candidate for cell replacement therapy for stroke."

Loss of niche-satellite cell interactions in syndecan-3 null mice alters muscle progenitor cell homeostasis improving muscle regeneration

The skeletal muscle stem cell niche provides an environment that maintains quiescent satellite cells, required for skeletal muscle homeostasis and regeneration. Syndecan-3, a transmembrane proteoglycan expressed in satellite cells, supports communication with the niche, providing cell interactions and signals to maintain quiescent satellite cells. Syndecan-3 ablation unexpectedly improves regeneration in repeatedly injured muscle and in dystrophic mice, accompanied by the persistence of sublaminar and interstitial, proliferating myoblasts. Additionally, muscle aging is improved in syndecan-3 null mice. Since syndecan-3 null myofiber-associated satellite cells downregulate Pax7 and migrate away from the niche more readily than wild type cells, syxndecan-3 appears to regulate satellite cell homeostasis and satellite cell homing to the niche. Manipulating syndecan-3 provides a promising target for development of therapies to enhance muscle regeneration in muscular dystrophies and in aged muscle.

Bursting the unfolded protein response accelerates axonal regeneration

The endoplasmic reticulum (ER) is a dynamic interconnected network involved in quality control processes that maintain a functional proteome in the cell. Accumulating evidence indicates that central nervous system and peripheral nervous system injury alters ER proteostasis engaging a stress reaction in neurons and glial cells. ER stress activates an adaptive mechanism to cope with protein folding alterations, known as the unfolded protein response (UPR). We recently investigated the impact of the UPR to peripheral nerve regeneration. Using genetic manipulation, we studied the consequences of targeting XBP1 to assess the impact of the UPR to Wallerian degeneration after sciatic nerve damage. Deletion of Xbp1 in the nervous system led to decreased myelin clearance, axonal regeneration and macrophage infiltration after mechanical damage. Importantly, locomotor recovery in Xbp1 deficient mice was significantly delayed. Furthermore, overexpression of XBP1s in neurons using a transgenic mice increased axonal regeneration and locomotor recovery after injury. We moved forward and developed a therapeutic strategy to artificially engage XBP1-dependent gene expression programs to enhance axonal repair. We validated a gene transfer approach to deliver XBP1s into sensory axons using adeno-associated viruses (AAVs). AAV-XBP1s transduced neurons showed an enhancement in the axonal regeneration process. Altogether, these results demonstrated a differential contribution of the IRE1α/XBP1 signaling branch of the UPR in the injured peripheral nervous system.

We speculate that the local activation of UPR stress sensors in the axonal compartment after damage may trigger the retrograde transport of active XBP1s to engage transcriptional programs that contribute to alleviate proteostasis alterations. The next step in the field is to determine if the UPR has therapeutic potential. Overall, modulation of axonal regeneration programs by the UPR incorporates novel players in the process of nerve repair after mechanical damage. Since several small molecules and gene therapy strategies are available to target the UPR, manipulation of the ER proteostasis network might emerge as a new avenue to develop interventions that improve axonal regeneration in different degenerative conditions of the nervous system.

Rejuvenating Muscle Stem Cell Function: Restoring Quiescence and Overcoming Senescence

Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle satellite (or stem) cells (SMSCs) and progenitor cells. Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a presenescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion. Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the presenescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the presenescent state results from loss of autophagy, leading to increased reactive oxygen species and epigenetic modification at the CDKN2A locus, upregulating cell senescence biomarker p16ink4a. However, the presenescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells. Other work suggests that in humans, loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus downregulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to presenescence in the very old.

Researchers amplify regeneration of spinal nerve cells

Researchers successfully boosted the regeneration of mature nerve cells in the spinal cords of adult mammals - an achievement that could one day translate into improved therapies for patients with spinal cord injuries. "This research lays the groundwork for regenerative medicine for spinal cord injuries. We have uncovered critical molecular and cellular checkpoints in a pathway involved in the regeneration process that may be manipulated to boost nerve cell regeneration after a spinal injury." The researchers focused on glial cells, the most abundant non-neuronal type of cells in the central nervous system. Glial cells support nerve cells in the spinal cord and form scar tissue in response to injury. In 2013 and 2014, researchers created new nerve cells in the brains and spinal cords of mice by introducing transcription factors that promoted the transition of adult glial cells into more primitive, stem cell-like states, and then coaxed them to mature into adult nerve cells. The number of new spinal nerve cells generated by this process was low, however, leading researchers to focus on ways to amplify adult neuron production.

In a two-step process, researchers first silenced parts of the p53-p21 protein pathway that acts as a roadblock to the reprogramming of glial cells into the more primitive, stem-like types of cells with potential to become nerve cells. Although the blockade was successfully lifted, many cells failed to advance past the stem cell-like stage. In the second step, mice were screened for factors that could boost the number of stem-like cells that matured into adult neurons. They identified two growth factors - BDNF and Noggin - that accomplished this goal. Using this approach, researchers increased the number of newly matured neurons by tenfold. "Our ability to successfully produce a large population of long-lived and diverse subtypes of new neurons in the adult spinal cord provides a cellular basis for regeneration-based therapy for spinal cord injuries. If borne out by future studies, this strategy would pave the way for using a patient's own glial cells, thereby avoiding transplants and the need for immunosuppressive therapy."

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

The average population age is increasing and the incidence of age-related vascular complications is rising in parallel. Impaired wound healing and disordered ischemia-mediated angiogenesis are key contributors to age-impaired vascular complications that can lead to amputation. High-density lipoproteins (HDL) have vasculo-protective properties and augment ischemia-driven angiogenesis in young animals. We aimed to determine the effect of reconstituted HDL (rHDL) on aged mice in a murine wound healing model and the hindlimb ischemia (HLI) model.

Daily topical application of rHDL increased the rate of wound closure by Day 7 post-wounding (25%). Wound blood perfusion, a marker of angiogenesis, was elevated in rHDL treated wounds (Days 4-10 by 22-25%). In addition, rHDL increased wound capillary density by 52.6%. In the HLI model, rHDL infusions augmented blood flow recovery in ischemic limbs (Day 18 by 50% and Day 21 by 88%) and prevented tissue necrosis and toe loss. Assessment of capillary density in ischemic hindlimb sections found a 90% increase in rHDL infused animals. In vitro studies in fibroblasts isolated from aged mice found that incubation with rHDL was able to significantly increase the key pro-angiogenic mediator vascular endothelial growth factor (VEGF) protein (25%). In conclusion, rHDL can promote wound healing and wound angiogenesis, and blood flow recovery in response to ischemia in aged mice. Mechanistically, this is likely to be via an increase in VEGF. This highlights a potential role for HDL in the therapeutic modulation of age-impaired vascular complications.

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Measuring the Effects of Prevention on Heart Disease
https://www.fightaging.org/archives/2016/11/measuring-the-effects-of-prevention-on-heart-disease/

Despite the rising proportion of the older population who choose to be overweight or obese, risk of heart disease has declined somewhat in past few decades. This outcome can be attributed to prevention in the sense of at least some people taking better care of their health by specifically targeting measures such as blood pressure and blood lipid levels, coupled with prevention in the sense of treatments such as statins that also reliably influence these measures. Increased blood pressure with age, or hypertension, directly impacts risk of cardiovascular disease and other conditions by putting additional stress on tissue structures and causing the heart to remodel itself detrimentally. Higher blood lipid levels on the other hand contribute to the progression of atherosclerosis, attacking blood vessel walls to form fatty deposits that can later break to cause blockages or ruptures of blood vessels. These are all things best avoided if possible, but until the advent of rejuvenation therapies after the SENS model the best that can be done is to slow down the damage.

Diagnosis and control of coronary heart disease (CHD) risk factors have received particular emphasis in guidelines issued since 1977 (blood pressure) and 1985 (lipids). Yet on a population level, little is known about how these efforts have altered CHD incidence and its association with modifiable risk factors. Researchers pooled individual patient-level data from 5 observational cohort studies available in the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center. Two analytic data sets were created: 1 set with baseline data collected from 1983 through 1990 (early era) with follow-up from 1996 through 2001, and l set with baseline data collected from 1996 through 2002 (late era) with follow-up from 2007 through 2011. The study included characteristics of 14,009 pairs of participants in the 2 groups. Participants ages 40 to 79 years who were free of cardiovascular disease were selected from each era and matched on age, race, and sex. Each group was followed for up to 12 years for new-onset CHD (i.e., heart attack, coronary death, angina, coronary insufficiency).

"Examination of adults from 5 large observational cohort studies led to several findings. First, the incidence of CHD declined almost 20 percent over time from 1983 to 2011. Second, although the prevalence of diabetes increased, the fraction of CHD attributable to diabetes decreased over time, due to attenuation of the association between diabetes and CHD. This may have resulted from changing definitions and awareness of diabetes, improvements in diabetes treatment and control, and/or better primary prevention. Third, there was no evidence that the strength of the association between smoking, systolic blood pressure, or dyslipidemia and CHD changed between eras, nor was there evidence that the proportion of CHD due to these factors changed. This underscores the importance of continued prevention efforts targeting these risk factors."

Age-Related Decline in Thymic Activity Correlates with Life Span in Dog Breeds
https://www.fightaging.org/archives/2016/11/age-related-decline-in-thymic-activity-correlates-with-life-span-in-dog-breeds/

Researchers here report on thymic activity in dog breeds of varying longevity. The thymus plays an important role in the creation of new T cells, but its activity declines with age, most notably in early adulthood via the process of thymic involution, but then further in later life. A lower supply of new immune cells contributes to the age-related decline of the immune system, which is in part a structural problem of too many memory T cells dedicated to specific pathogens and too few naive T cells capable of dealing with new threats. Those threats are not just invading microorganisms, but also harmful senescent and cancerous cells. The progressive failure of the immune system is one of the reasons why cancer is an age-related condition and the number of senescent cells increase with age. It isn't just a matter of increasing frailty due to vulnerability to infection, as immune decline also influences many other aspects of aging. Given all of this, there is some interest in rejuvenation of the thymus, restoring it to youthful levels of activity. Possible approaches here include engineering of thymus tissue for transplantation, or manipulation with signal molecules that direct thymic growth and function.

With increasing age, there is a gradual deterioration in immune function, leading to a reduced response to infectious agents and vaccination, alongside an increase in prevalence of autoimmune and neoplastic diseases. A similar age-related decline in health is seen comparing humans and companion animals. Intimately linked with the decline in immune function is the age-associated regression of the thymus. Since thymic involution is seen in all mammalian species, this has led to the suggestion that immunosenescence, associated with a decline in thymic output, is an evolutionary conserved event. Thus, identifying the features of immunosenescence in companion animals represents an opportunity for comparative and translational research into how immune function declines with age.

Thymic involution is associated with a progressive decline in T cell output to the peripheral lymphocyte pool and as a consequence, expansion of existing memory T cell populations can take place. However, this might lead to reduced diversity in the T cell repertoire and impairment of immune responses to novel antigens, for example during infection or vaccination. Preservation of immunity is a major contributory factor for maintaining health into old age and although there is evidence for an association between thymic output and longevity, many of these experiments have been performed in inbred or genetically-modified laboratory rodents, which might not reflect the situation in humans. Whilst thymic size may be an indicator of immunocompetence/immunosenescence in mammals it is not easily measured clinically. Evaluation of thymic output in terms of the presence of recent thymic emigrants (RTE) in peripheral blood might be an acceptable surrogate marker.

During T cell development in the thymus, the T cell receptor δ gene segments are excised and form a signal joint T cell receptor excision circle (sj-TREC). Since its formation occurs specifically in the thymus and this DNA does not replicate, sj-TREC has been used as a marker for RTEs in peripheral blood samples. In humans and mice, real-time qPCR has been employed, showing an age-associated decline in sj-TREC values in blood, suggesting a reduction in the number of RTEs with increasing age. However, sj-TRECs are still detectable, even in some very elderly humans, suggesting that thymic output can be maintained into old age in some individuals. A recent study has demonstrated that sj-TRECs can be measured in companion animals. Studies in pedigree dogs have demonstrated that there are breed-related differences in longevity, the rate of aging, and susceptibility to diseases associated with aging. Such differences in longevity suggest that there are likely to be breed effects/genetic factors influencing the aging process that might impact on the onset of immunosenescence. The aim of the present study was to develop a real-time qPCR assay to measure sj-TRECs in canine blood samples and to examine how age and breed influence sj-TREC values in dogs.

When sj-TREC values were assessed in Labrador retriever dogs, normalized against either lymphocyte counts or albumin expression, an age-associated decline was identified in both instances. The greatest decline occurred between the ages of 1 and 5 years, which suggests the largest reduction in thymic output occurs between reaching sexual maturity and early middle age in the canine species. A similar trend is seen in humans, where thymic output remains relatively high until the teenage years, when it begins to decline rapidly, with the greatest decline in sj-TRECs having occurred by middle age, between 40 and 50 years old. After reaching 5 years of age, canine sj-TREC values were found to stabilise, with a mean value approximately 20% of that seen in dogs younger than 1 year old, before declining further at around 9 years of age. In older humans, sj-TREC values show a slow decline between the 6th and 9th decades of life before decreasing significantly in the 10th decade. sj-TRECs were undetectable in many mature and geriatric dogs, suggesting that thymic output in these dogs is very low or that production of naïve T-cells has ceased. However, this was not the case in all dogs of a similar age, suggesting that some individuals can maintain thymic output into old age, which is similar to that reported in human studies.

Breed influences on sj-TREC were investigated by studying two groups that represent the extremes of the canine lifespan spectrum; small breed dogs with a relatively long life expectancy and large breed dogs with a relatively short life expectancy. Studies in humans have proposed an association between maintenance of thymic function and lifespan and have suggested that sj-TREC analysis might be of use as a biomarker for determining longevity. Both groups demonstrated a similar age-related decline in sj-TREC, with the greatest reduction occurring between young adulthood and middle age. However, the onset of the decline in sj-TRECs was found to occur at an earlier age in the short-lived breeds compared with the long-lived breeds, suggesting that thymic involution might occur prematurely in the former. Furthermore, some individuals of short-lived breeds were identified that had undetectable sj-TREC as young as 2 years of age, compared with the other breeds assessed, where this did not occur until around 4-5 years of age. Therefore, if thymic involution is occurring at an earlier biological time point in some dog breeds, this might have an impact on their subsequent lifespan/healthspan. This is consistent with a recent study in which there was a strong relationship between lifespan, body size and rate of aging, with the largest breeds also having evidence of an earlier onset of the aging process.

Hypertension Causes Neural Damage in Part via Altered Macrophage Behavior
https://www.fightaging.org/archives/2016/11/hypertension-causes-neural-damage-in-part-via-altered-macrophage-behavior/

The increased blood pressure of age-related hypertension is driven by the stiffening of blood vessels. It harms fragile tissues, such as those of the kidney, directly through the physical processes of greater pressure. It also increases the rate at which small blood vessels suffer structural failure, and in the brain that means an ongoing series of minuscule strokes, each unnoticed, but over time adding up to contribute to cognitive decline. Researchers here outline another mechanism by which hypertension causes harm, in this case via alteration of the behavior of a population of macrophages in the brain, leading to greater levels of oxidative stress and vascular dysfunction. The researchers also show that selectively depleting these macrophages can improve the situation, and thus perhaps form the basis for a therapy:

Hypertension afflicts up to one-third of the world population and is a leading risk factor for morbidity and mortality worldwide. The brain is a major target organ of the damaging effects of hypertension. Well recognized as the most important risk factor for stroke and vascular cognitive impairment, hypertension has also been linked to Alzheimer disease, the leading cause of dementia in the elderly. The health of the cerebrovascular system is vital for the brain's functional and structural integrity. The brain has no energy reserves and requires a continuous supply of blood well matched to its dynamic and regionally diverse metabolic needs. Neurons, glia, and vascular cells, key components of the so-called neurovascular unit (NVU), work in concert to assure that the brain is always adequately perfused. Thus, brain activation increases cerebral blood flow (CBF) to support the increased energy demands and remove potentially harmful by-products of cerebral metabolism, a process known as neurovascular coupling. At the same time, endothelial cells, the site of the blood-brain barrier (BBB), regulate the trafficking of molecules and cells between blood and brain, and coordinate microvascular flow by releasing vasoactive agents. Hypertension leads to profound cerebrovascular alterations. In addition to structural changes (hypertrophy, remodeling, stiffening, lipohyalinosis, etc.), hypertension induces alterations in cerebrovascular regulation that promote vascular insufficiency. Thus, in humans as in animal models, hypertension disrupts all the major factors regulating the cerebral circulation, including neurovascular coupling and endothelial vasomotor function. As a result, the brain becomes more susceptible to neuronal dysfunction and damage, which underlies vascular cognitive impairment

The factors responsible for these functional alterations of the NVU are poorly understood, and their exploration is essential to develop preventative or therapeutic approaches to mitigate the impact of hypertension on brain health. Perivascular macrophages (PVMs) and meningeal and choroid plexus macrophages represent the bulk of resident brain macrophages, and are distinct from macrophages infiltrating the wall of large vessels in inflammatory conditions, such as atherosclerosis. Residing in the intracerebral perivascular space, delimited by the glia limitans and the vascular basement membrane, PVMs are closely apposed to the outer vessel wall and originate from hematopoietic precursors. As the vessels penetrate deeper into the substance of the brain, the glial and vascular basement membranes fuse together and the perivascular space disappears. In this study we investigated the contribution of PVMs to the neurovascular and cognitive dysfunction induced by hypertension.

We found that depletion of PVMs in models of chronic hypertension suppresses vascular oxidative stress and ameliorates the attendant impairment in neurovascular coupling and endothelium-dependent responses. Brain PVMs are thought to be beneficial in models of Alzheimer disease by removing amyloid-β peptides from the perivascular space and preventing amyloid accumulation in cerebral blood vessels. On the other hand, hypothalamic neurohumoral signaling by PVMs across the BBB may be deleterious by promoting inflammation and sympathetic activation in models of fever or myocardial infarction, respectively, and may contribute to hypertensive cerebrovascular remodeling. In the present study we discovered that PVMs play a key role in the cerebrovascular dysfunction of hypertension. Our data suggest that PVMs, while serving vital homeostatic functions in the normal state, become the target of neurovascular inflammatory signaling leading to reactive oxygen species production, vascular dysfunction, and cognitive deficits. However, the molecular interactions of PVMs with cells of the NVU and their role in the neurovascular dysfunction and BBB alteration remain to be defined.

Progression of Retinitis Pigmentosa Slowed by Sirt6 Inhibition in Mouse Model
https://www.fightaging.org/archives/2016/11/progression-of-retinitis-pigmentosa-slowed-by-sirt6-inhibition-in-mouse-model/

Retinitis pigmentosa is one of a number of forms of retinal degeneration that produce progressive blindness, though in this case it is primarily an inherited condition. Researchers here find a genetic manipulation that slows the progression of this effect. Interestingly, they are inhibiting sirt6 in a mouse model of the condition in order to obtain this outcome. In the broader context, increased levels of sirt6 have been shown to modestly extend the life of male mice. This is perhaps a helpful reminder that things are never simple when it comes to biochemistry and the manipulation of cellular metabolism. It would nonetheless be interesting to see how this approach does in forms of age-related blindness that involve retinal cell death, but since it fails to address underlying forms of molecular damage directly I'm not optimistic. Age-related retinal degeneration is strongly connected to, for example, accumulation of hardy forms of metabolic waste that form lipofuscin and disrupt cellular recycling processes. That may or may not be impacted in any way via altered sirt6 levels, but certainly targeted clearance of lipofuscin - such as the work undertaken by Ichor Therapeutics - should be a much more effective approach than tinkering with metabolism to slow down its accumulation.

Researchers have demonstrated that vision loss associated with a form of retinitis pigmentosa (RP) can be slowed dramatically by reprogramming the metabolism of photoreceptors, or light sensors, in the retina. "Although gene therapy has shown promise in RP, it is complicated by the fact that defects in 67 genes have been linked to the disorder, and each genetic defect would require a different therapy. Our study shows that precision metabolic reprogramming can improve the survival and function of affected rods and cones in at least one type of RP. Since many, if not most, forms of the disorder have the same metabolic error, precision reprogramming could conceivably be applied to a wide range of RP patients."

RP, an inherited form of vision loss, is caused by genetic defects that lead to the breakdown and loss of rods, the photoreceptors in the retina that enable peripheral and night vision. Over time, the deterioration of rods compromises the function of cones, the color-sensing photoreceptors. Rods are among the most metabolically active cells in the body. They are particularly active during periods of darkness, when they burn glucose to release energy. Researchers theorized that rods deteriorate in RP, in part, because they lose the daytime's ability to use glucose to rebuild the rods' outer segment (the light-absorbing portion of the photoreceptor). "We hypothesized that diseased rods could be rescued by reprogramming sugar metabolism."

Researchers tested this hypothesis in mice with a mutation in the Pde6 gene that disrupts rod metabolism, leading to an RP-like disorder. The mice were treated so that their rods could not express Sirt6, a gene that inhibits sugar metabolism. Examination of photoreceptors with electroretinography showed that the mice had significantly greater measures of rod and cone health than untreated controls. While the treatment significantly prolonged survival of the diseased rods and cones, it did not prevent their eventual death. "Our next challenge is to figure out how to extend the therapeutic effect of Sirt6 inhibition. Although the treatment that was used in the mice cannot be applied directly to humans, several known Sirt6 inhibitors could be evaluated for clinical use. Further studies are needed to explore the exciting possibility that precision metabolic reprogramming may be used to treat other forms of RP and retinal degeneration."

Young Human Blood Plasma Produces Benefits in Old Mice
https://www.fightaging.org/archives/2016/11/young-human-blood-plasma-produces-benefits-in-old-mice/

There is a fair amount of interest in finding out whether the observations derived from heterochronic parabiosis, where the circulatory systems of an old and a young mouse are linked, can be reproduced by transferring whole blood or blood plasma from a young individual to an old individual. In theory the introduction of young signals into an old environment may adjust cellular behavior for the better, analogous to the effects produced by some forms of stem cell transplant. So far the results are mixed, however, with some studies showing no benefit - it is quite possible that transfer doesn't recreate all of the effects of a fully joined circulation for one reason or another. That said, researchers with Alkahest, involved in trials of plasma transfer as a human therapy, are now presenting initial results from introducing young human blood plasma into old mice, in which benefits were observed:

Blood plasma from young people has been found to rejuvenate old mice, improving their memory, cognition, and physical activity. The method has the potential to be developed into a treatment for people. Previous research has found that stitching old and young mice together has an interesting effect. While sharing a blood system works out well for the older mouse, the younger one isn't so lucky. The young animals started to show signs of brain ageing, while the brains of the older mice started to look younger. The key to youth appears to be in the blood plasma - the liquid part of blood. Several studies have found that injecting plasma from young mice into old mice can help rejuvenate the brain and other organs, including the liver, heart, and muscle.

Could blood plasma from young people have the same benefits? To find out, researchers took blood samples from 18-year-olds, and injected them into 12-month-old mice. At this age, the equivalent of around age 50 for people, the mice start to show signs of ageing - they move more slowly, and perform badly on memory tests. The mice were given twice-weekly injections of the human plasma. After three weeks of injections, they were submitted to a range of tests. The treated mice's performance was compared to young, 3-month-old mice, as well as old mice who had not received injections. Treated mice ran around an open space like young mice. Their memories also seemed to improve, and they were much better at remembering their way around a maze than untreated mice.

The team then examined the brains of the treated and untreated mice. They looked for clues on the birth of new neurons in the hippocampus - a process called neurogenesis, which is thought to be important for memory and learning. Sure enough, the treated mice appeared to have created more new cells in their brain. The researchers have identified some factors in young blood that might be responsible for these benefits, but that won't reveal what they are yet. Some of them seem to be crossing into the brain, while others may be acting remotely, elsewhere in the body.

An Update on Reversing Heart Scarring via Gata4, Mef2c, and Tbx5
https://www.fightaging.org/archives/2016/11/an-update-on-reversing-heart-scarring-via-gata4-mef2c-and-tbx5/

Four years ago, researchers reported that they could use gene therapy to increase levels of Gata4, Mef2c, and Tbx5 in order to provoke the conversion of a fraction of scar tissue into healthy muscle tissue in damaged hearts. This seems a promising approach, but like many fields of research it is proceeding only slowly. Here is a recent update, in which the researchers report on efforts to make the conversion process more efficient and thus practical as the basis for a therapy:

Scientists are exploring cellular reprogramming - turning one type of adult cell into another - in the heart as a way to regenerate muscle cells in the hopes of treating, and ultimately curing, heart failure. It takes only three transcription factors - proteins that turn genes on or off in a cell - to reprogram connective tissue cells into heart muscle cells in a mouse. After a heart attack, connective tissue forms scar tissue at the site of the injury, contributing to heart failure. The three factors, Gata4, Mef2c, and Tbx5 (collectively known as GMT), work together to turn heart genes on in these cells and turn other genes off, effectively regenerating a damaged heart with its own cells. But the method is not foolproof - typically, only ten percent of cells fully convert from scar tissue to muscle.

In the new study, scientists tested 5500 chemicals to try to improve this process. They identified two chemicals that increased the number of heart cells created by eightfold. Moreover, the chemicals sped up the process of cell conversion, achieving in one week what used to take six to eight weeks. "While our original process for direct cardiac reprogramming with GMT has been promising, it could be more efficient. With our screen, we discovered that chemically inhibiting two biological pathways active in embryonic formation improves the speed, quantity, and quality of the heart cells produced from our original process."

The first chemical inhibits a growth factor that helps cells grow and divide and is important for repairing tissue after injury. The second chemical inhibits an important pathway that regulates heart development. By combining the two chemicals with GMT, the researchers successfully regenerated heart muscle and greatly improved heart function in mice that had suffered a heart attack. The scientists also used the chemicals to improve direct cardiac reprogramming of human cells, which is a more complicated process that requires additional factors. The two chemicals enabled the researchers to simplify the process bringing them one step closer to better treatments for heart failure.

A Study Suggesting Tau Produces Rapid Impairment of Memory Mechanisms
https://www.fightaging.org/archives/2016/11/a-study-suggesting-tau-produces-rapid-impairment-of-memory-mechanisms/

One of the big questions in Alzheimer's research is the degree to which the pathology of dementia results from aggregates of amyloid-β or the neurofibrillary tangles composed of altered forms of tau protein. That question will probably be best and finally answered via the development of therapies that can effectively remove one or the other, but here researchers offer an interesting study carried out in human tissue samples and mice to suggest that the influence of tau is significant:

Amyloid-β (Aβ) was the focus of most of the studies on Alzheimer's disease (AD) in the last 20 years. However, Aβ is not the only pathological agent involved in AD. Microtubule Associated Protein Tau (MAPT) is also likely to play a major role in the disease. While Aβ species derive from APP processing, six tau isoforms are derived from alternative splicing of the MAPT gene transcript in the adult brain. Aβ forms extracellular amyloid plaques, whereas tau forms intracellular insoluble filaments and neurofibrillary tangles (NFTs). In addition, both Aβ and tau form intracellular and extracellular oligomeric species that are soluble pre-fibrillar aggregates, suggesting that the two proteins might share common mechanisms in AD etiopathogenesis.

The prevailing hypothesis in the AD field is that deleterious effects on synaptic function underlying memory loss caused by tau are initiated by Aβ. As AD progresses, tau pathology spreads from the entorhinal cortex in a contiguous, highly selective and highly reproducible fashion, suggesting that extracellular soluble forms of tau transmit pathology from neuron to neighboring neuron. Moreover, once Aβ triggers tau pathology, the disease would progress independent of Aβ. Therefore, therapies targeting Aβ may not be effective once tau pathology is triggered. Nevertheless, tau toxicity does not involve Aβ pathology in tauopathies, suggesting that Aβ is not necessary for tau pathology to occur, and pointing at the need to better clarify the relationship between tau and Aβ.

Here, we investigated whether and how extracellular oligomeric forms of tau (oTau) affect memory and its cellular correlate, long-term potentiation (LTP), either by themselves or in combination with Aβ. We show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment.

GABA Linked to Working Memory Capacity
https://www.fightaging.org/archives/2016/11/gaba-linked-to-working-memory-capacity/

Increased levels of the neurotransmitter GABA have in the past been shown to produce greater neural plasticity. Here researchers link higher GABA levels in one part of the brain with a greater capacity of working memory. This preliminary finding is a very long way from being the basis for some form of therapy for age-related loss of memory function or enhancement technology to improve memory at all ages, but that is where investigations of the biochemistry of memory will eventually lead.

Working memory is the brain function that lets you carry on a phone conversation while adding three numbers in your head and remembering that you need to steer the car onto the freeway exit in about two minutes - all this time not forgetting who you're talking to. Working memory serves as a buffer where information, derived from the senses or retrieved from long-term memory, can be temporarily placed so the conscious brain can process it. It's tied to assessments of cognitive capacity such as IQ, and to real-world outcomes such as academic performance. As most people eventually find out, working memory declines with age.

A new study teases apart three key components of working memory and shows that one component, but not the other two, is tied to the amount of a chemical called GABA in a brain area known as the dorsolateral prefrontal cortex, or DLPFC. This component, referred to as load, is a measure of the number of separate bits of information a person's working memory can store at the same time. A second component, maintenance, denotes how long information can be stored in working memory before it's lost. A third, distraction resistance, gauges how well an individual's working memory holds onto information in the face of interfering stimuli. The DLPFC, a broad swath of neural tissue on the forebrain surface, has been shown in animal studies and in observations of brain-damaged patients to be integral to high-level executive functions in the brain, such as planning, prioritizing and avoiding distractions. It has likewise been strongly implicated in working memory. The DLPFC orchestrates activity in numerous distant centers throughout the brain, including the visual cortex, which is located near the brain's surface but in the hindbrain.

In the study, 23 healthy participants ages 19-32 were subjected to batteries of tests of working memory. The researchers reasoned that different components of working memory would involve different neurotransmitter inputs. They devised working-memory tests that separated the measurement of load, maintenance and distraction resistance. Participants repeated several related tasks. In the simplest, they were shown a drawing of a face and then, after a two-second delay, shown a second face and asked whether it was the same as or different from the first one. Variations of this task - initially presenting two faces instead of just one; lengthening the intervening delay; or displaying a different, irrelevant face between the initial and final displays - tested load, maintenance and distraction resistance, respectively. The investigators compared individuals' error rates on the simple version of the task with outcomes on tasks taxing one or another working-memory component more heavily. The smaller the deterioration in performance on a test of a particular working-memory component, the greater the individual's capacity regarding that component was judged to be.

Using an advanced imaging method, the scientists measured GABA levels in the DLPFC and, for comparison, in the visual cortex. GABA, secreted by nerve cells, is an inhibitory neurotransmitter: Its uptake by other nerve cells inhibits their firing. The researchers also measured levels of an excitatory neurotransmitter, glutamate. By far the two most abundant neurotransmitters in the brain, GABA and glutamate are considered to be that organ's stop and go signals. Individuals with higher levels of GABA in their DLPFC performed better on tests of their load capacity - the ability to juggle more bits of information - the researchers found. In contrast, no significant association emerged linking GABA levels in the DLPFC to maintenance or to distraction resistance, or tying participants' load capacity to GABA levels in the visual cortex. Nor did imaging reveal any connection between performance on tests of load capacity and levels of glutamate in the DLPFC.

Considering Low Level Radiation Exposure and Alzheimer's Disease
https://www.fightaging.org/archives/2016/11/considering-low-level-radiation-exposure-and-alzheimers-disease/

To me at least, it seems that links between low-level radiation exposure and Alzheimer's disease are tenuous at best. You can look at the painkiller theory of Alzheimer's for an example of finding correlations with rising levels of dementia that are unlikely to involve causation, but where one can dig up biochemistry that looks somewhat supportive to the idea. Yet in comparison to the standard view, that has very little weight of evidence. Suggestions that greater exposure to low levels of ionizing radiation, via medical scanning procedures and air travel, contributes meaningfully to dementia seems like another example of the type. If anything, the weight of evidence on low-level radiation exposure indicates that it produces beneficial hormetic effects that should modestly slow the progression of aging. But again, it is possible to produce results that look somewhat supportive of the thesis, as here. I am skeptical on the whole, and would want to see a lot more evidence before abandoning the more mainstream view that rising Alzheimer's incidence is a consequence of demographic aging and rising rates of obesity in the population at large.

Alzheimer's disease is the leading cause for dementia in the elderly, and its global prevalence is supposed to increase dramatically in the following decade - up to 80 million patients by 2040. In a new study, researchers show that low doses of ionising radiation induce molecular changes in the brain that resemble the pathologies of Alzheimer's. Large numbers of people of all age groups are increasingly exposed to ionizing radiation from various sources. Many receive chronic occupational exposure from nuclear technologies or airline travel. The use of medical diagnostics and therapeutic radiology has increased rapidly - for example more than 62 million CT scans per year are currently carried out in USA. Approximately one third of all diagnostic CT examinations are scans of the head region. "All these kinds of exposures are low dose and as long as we talk about one or a few exposures in a lifetime I do not see cause for concern. What concerns me is that modern people may be exposed several times in their lifetime and that we don't know enough about the consequences of accumulated doses."

Recent data suggest that even relatively low radiation doses, similar to those received from a few CT scans, could trigger molecular changes associated with cognitive dysfunction. In their new study, the researchers have elucidated molecular alterations in the hippocampus of mice. The hippocampus is an important brain region responsible for learning and memory formation and it is known to be negatively affected in Alzheimer´s. The authors induced changes in the hippocampus by two kinds of chronic low-dose-rate ionizing radiation treatments. The mice were exposed to cumulative doses of 0.3 Gy or 6.0 Gy given at low dose rates of 1 mGy over 24 hours or 20 mGy over 24 hours for 300 days. "Both dose rates are capable of inducing molecular features that are reminiscent of those found in the Alzheimer's disease neuropathology. When you compare these figures you will find that we exposed the mice to a more than 1000 times smaller cumulative dose than what a patient gets from a single CT scan in the same time interval. And even then we could see changes in the synapses within the hippocampus that resemble Alzheimer´s pathology." According to the researchers, the data indicate that chronic low-dose-rate radiation targets the integration of newborn neurons in existing synaptic wires.

Working to Turn Back the Loss of Skin Healing Capacity in Aging
https://www.fightaging.org/archives/2016/11/working-to-turn-back-the-loss-of-skin-healing-capacity-in-aging/

Researchers have been making progress in understanding exactly why skin healing falters with age. Changes in the behavior of sweat glands and surrounding structures built out of keratinocyte cells appear to be important, for example. Skin normally heals through construction of keratinocytes spreading outwards from the sweat glands, but that becomes disrupted in later life. Researchers here fill in more details in the signaling changes involved in that disruption, as well as the role of the immune system, and suggest that it should be possible to nudge the balance of signals back in the right direction. That wouldn't address the root causes of these changes, of course, such as the presence of senescent cells and cross-links in skin tissue, and the age-related decline of the immune system, but might produce enough of a benefit in wound healing to be worth the effort.

Older bodies need longer to mend. Yet until now, researchers have not been able to tease out what age-related changes hinder the body's ability to repair itself. Recent experiments explored this physiological puzzle by examining molecular changes in aging mouse skin. The results delineate a new aspect of how the body heals wounds. "Within days of an injury, skin cells migrate in and close the wound, a process that requires coordination with nearby immune cells. Our experiments have shown that, with aging, disruptions to communication between skin cells and their immune cells slow down this step. Wound healing is one of the most complex processes to occur in the human body. Numerous types of cells, molecular pathways, and signaling systems go to work over timescales that vary from seconds to months. Changes related to aging have been observed in every step of this process."

Both skin cells and immune cells contribute to this elaborate process, which begins with the formation of a scab. New skin cells known as keratinocytes later travel in as a sheet to fill in the wound under the scab. The team focused on this latter step in healing in two-month-old versus 24-month-old mice - roughly equivalent to 20- and 70-year-old humans. They found that among the older mice, keratinocytes were much slower to migrate into the skin gap under the scab, and, as a result, wounds often took days longer to close. Wound healing is known to require specialized immune cells that reside in the skin. The researchers' new experiments showed that following an injury, the keratinocytes at the wound edge talk to these immune cells by producing proteins known as Skints that appear to tell the immune cells to stay around and assist in filling the gap. In older mice, the keratinocytes failed to produce these immune signals.

To see if they could enhance Skint signaling in older skin, the researchers turned to the protein IL-6 that resident immune cells normally release after injury, activating STAT3. When they applied this protein to young and old mouse skin tissue in a petri dish, they saw an increase in keratinocyte migration, which was most pronounced in the older skin. In effect, the old keratinocytes behaved more youthfully. The scientists hope the same principle could be applied to developing treatments for age-related delays in healing. "Our work suggests it may be possible to develop drugs to activate pathways that help aging skin cells to communicate better with their immune cell neighbors, and so boost the signals that normally decline with age."