Fight Aging! Newsletter, August 1st 2016

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

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  • Towards a Greater Knowledge of Mitochondrial DNA Damage in Aging
  • A Few of the More Interesting of Recent Alzheimer's Research Results
  • Exercise and TERRA in Telomere Biology
  • The Effects of Retirement are Complex
  • A Review of Telomerase as a Therapeutic Target
  • Latest Headlines from Fight Aging!
    • Use of Stem Cells in Bypass Therapy Reduces Scarring and Mortality
    • Further Investigation of P21 and SDF-1 Shows that Cxcr4 Inhibitors can Promote Scarless Healing in Mammals
    • Nanog May Improve Function of Old Stem Cells
    • Progress in the Use of Bioscaffolds for Muscle Regeneration
    • Stem Cell Therapy as a Potential Glaucoma Treatment
    • More Details on SENS Research Foundation's ALT Cancer Program
    • GPR17 as a Target to Reduce Measures of Aging in the Brain
    • A Smad7 Gene Therapy to Inhibit Age-Related Muscle Loss is in Development
    • How Extracellular Matrix Scaffolds Influence Cell Behavior in Therapies
    • Building a Tau Immunotherapy that does not Increase Inflammation

Towards a Greater Knowledge of Mitochondrial DNA Damage in Aging

Today I'll point out a very readable scientific commentary on mutations in mitochondrial DNA (mtDNA) and the importance of understanding how these mutations spread within cells. This is a topic of some interest within the field of aging research, as mitochondrial damage and loss of function is very clearly important in the aging process. Mitochondria are, among many other things, the power plants of the cell. They are the evolved descendants of symbiotic bacteria, now fully integrated into our biology, and their primary function is to produce chemical energy store molecules, adenosine triphosphate (ATP), that are used to power cellular operations. Hundreds of mitochondria swarm in every cell, destroyed by quality control processes when damaged, and dividing to make up the numbers. They also tend to promiscuously swap component parts among one another, and sometimes fuse together.

Being the descendants of bacteria, mitochondria have their own DNA, distinct from the nuclear DNA that resides in the cell nucleus. This is a tiny remnant of the original, but a very important remnant, as it encodes a number of proteins that are necessary for the correct operation of the primary method of generating ATP. DNA in cells is constantly damaged by haphazard chemical reactions, and equally it is constantly repaired by a range of very efficient mechanisms. Unfortunately mitochondrial DNA isn't as robustly defended as nuclear DNA. Equally unfortunately, some forms of mutation, such as deletions, seem able to rapidly spread throughout the mitochondrial population of a single cell, even as they make mitochondria malfunction. This means that over time a growing number of cells become overtaken by malfunctioning mitochondria and fall into a state of dysfunction in which they pollute surrounding tissues with reactive molecules. This can, for example, increase the level of oxidized lipids present in the bloodstream, which speeds up the development of atherosclerosis, a leading cause of death at the present time.

The question of how exactly some specific mutations overtake a mitochondrial population so rapidly is still an open one. There is no shortage of sensible theories, for example that it allows mitochondria to replicate more rapidly, or gives them some greater resistance to the processes of quality control that normally cull older, damaged mitochondria. The definitive proof for any one theory has yet to be established, however. In one sense it doesn't actually matter all that much: there are ways to address this problem through medical technology that don't require any understanding of how the damage spreads. The SENS Research Foundation, for example, advocates the path of copying mitochondrial genes into the cell nucleus, a gene therapy known as allotopic expression. For so long as the backup genes are generating proteins, and those proteins make it back to the mitochondria, the state of the DNA inside mitochondria doesn't matter all that much. Everything should still work, and the present contribution of mitochondrial DNA damage to aging and age-related disease would be eliminated. At the present time there are thirteen genes to copy, a couple of which are in commercial development for therapies unrelated to aging, another couple were just this year demonstrated in the lab, and the rest are yet to be done.

Still, the commentary linked below is most interesting if you'd like to know more about the questions surrounding the issue of mitochondrial DNA damage and how it spreads. This is, as noted, a core issue in the aging process. The authors report on recent research on deletion mutations that might sway the debate on how these mutations overtake mitochondrial populations so effectively.

Expanding Our Understanding of mtDNA Deletions

A challenge of mtDNA genetics is the multi-copy nature of the mitochondrial genome in individual cells, such that both normal and mutant mtDNA molecules, including selfish genomes with no advantage for cellular fitness, coexist in a state known as "heteroplasmy." mtDNA deletions are functionally recessive; high levels of heteroplasmy (more than 60%) are required before a biochemical phenotype appears. In human tissues, we also see a mosaic of cells with respiratory chain deficiency related to different levels of mtDNA deletion. Interestingly, cells with high levels of mtDNA deletions in muscle biopsies show evidence of mitochondrial proliferation, a compensatory mechanism likely triggered by mitochondrial dysfunction. In such circumstances, deleted mtDNA molecules in a given cell will have originated clonally from a single mutant genome. This process is therefore termed "clonal expansion."

The accumulation of high levels of mtDNA deletions is challenging to explain, especially given that mitophagy should provide quality control to eliminate dysfunctional mitochondria. Studies in human tissues do not allow experimental manipulation, but large-scale mtDNA deletion models in C. elegans have proved to be helpful, showing some conserved characteristics that match the situation in humans, as well as some divergences. Researchers have used a C. elegans strain with a heteroplasmic mtDNA deletion to demonstrate the importance of the mitochondrial unfolded protein response (UPRmt) in allowing clonal expansion of mutant mtDNAs to high heteroplasmy levels. They demonstrate that wild-type mtDNA copy number is tightly regulated, and that the mutant mtDNA molecules hijack endogenous pathways to drive their own replication.

The data suggests that the expansion of mtDNA deletions involves nuclear signaling to upregulate the UPRmt and increase total mtDNA copy number. The nature of the mito-nuclear signal in this C. elegans model may have been the transcription factor ATFS-1 (activating transcription factor associated with stress-1), which fails to be imported by depolarized mitochondria, mediates UPRmt activation by mtDNA deletions. A long-standing hypothesis proposes that deleted mtDNA molecules clonally expand because they replicate more rapidly due to their smaller size. To address this question, researchers examined the behavior of a second, much smaller mtDNA deletion molecule. They found no evidence for a replicative advantage of the smaller genome, and clonal expansion to similar levels as the larger deletion. In human skeletal muscle, mtDNA deletions of different sizes also undergo clonal expansion to the same degree. Furthermore, point mutations that do not change the size of the total mtDNA molecule also successfully expand to deleterious levels, indicating that clonal expansion is not driven by genome size. Thus, similar mechanisms may be operating across organisms. In the worm, this involves mito-nuclear signaling and activation of the UPRmt.

There is some debate over interpretation of results. One paper indicates that UPRmt allows the mutant mtDNA molecules to accumulate by reducing mitophagy. Another demonstrates that the UPRmt induces mitochondrial biogenesis and promotes organelle dynamics (fission and fusion). Both papers show that by downregulating the UPRmt response, mtDNA deletion levels fall, which may allow a therapeutic approach in humans. Could there be a similar mechanism in humans, especially since some features detected in C. elegans are also present in human tissues, including the increase in mitochondrial biogenesis and the lack of relationship between mitochondrial genome size and expansion? It is likely that there will be a similar mechanism to preserve deletions since, as in the worm, deletions persist and accumulate in human tissues, despite an active autophagic quality-control process. Although the UPRmt has not been characterized in humans as it has in the worm, and no equivalent protein to ATFS-1 has been identified in mammals, proteins such as CHOP, HSP-60, ClpP, and mtHSP70 appear to serve similar functions in mammals as those in C. elegans and suggest that a similar mechanism may be present.

A Few of the More Interesting of Recent Alzheimer's Research Results

A large fraction of the public funding devoted to aging research goes towards Alzheimer's disease, a very broad set of initiatives that dovetail with other large investments in mapping and understanding the biochemistry of the brain. This is a diverse area of study, since it involves figuring out how a fair-sized slice of the brain actually works at the detail level in order to understand how it becomes broken in this particular case. This means that a great many papers and research results flow past on a weekly basis. Not all of them are useful; institutions of public funding always turn into jobs programs over time, and that inevitably means a lot of people working on things that are neither useful nor interesting. Further, these sorts of institutions are so risk averse that they essential stop funding true fundamental research, the high-risk search for new knowledge. To have a good shot at winning a grant from the National Institute on Aging you really have to be working on something that is already fairly well known and characterized - grant awarding bodies want to see little risk, and want to pay for an expected outcome. Which is the antithesis of actual research. This is why most of the important work at any given time, the real cutting edge in medical research, is funded by some combination of philanthropy and creative accounting by lab managers.

The nature of government programs is a big problem for any group that seeks to use the public funding mainstream as a guide to what they should be doing to help things move faster in the field. If you simply follow that lead, you wind up like the Ellison Medical Foundation, spending a lot of money on fundamental research to no good end, with very little in the way of practical outcomes to show for it at the end of the day. The National Institute on Aging playbook includes a large amount of waste and make-work, and all too little in the way of earnestly pushing the bounds of the possible. In this day and age, an era of rapid progress in biotechnology and medicine, both pushing the bounds of the possible and practical outcomes should be high on the priority list for aging research, meaning radically better and more effective ways to treat aging and age-related disease. Still, there is a lot of Alzheimer's research underway, and some of it is interesting, potentially useful, or at the very least not make-work. A few recent examples can be found below.

Scientists discover how proteins in the brain build-up rapidly in Alzheimer's

Fibrils, known as amyloids, become intertwined and entangled with each other, causing the so-called 'plaques' that are found in the brains of Alzheimer's patients. Spontaneous formation of the first amyloid fibrils is very slow, and typically takes several decades, which could explain why Alzheimer's is usually a disease that affects people in their old age. However, once the first fibrils are formed, they begin to replicate and spread much more rapidly by themselves, making the disease extremely challenging to control.

Despite its importance, the fundamental mechanism of how protein fibrils can self-replicate without any additional machinery is not well understood. Researchers found that the seemingly complicated process of fibril self-replication is actually governed by a simple physical mechanism: the build-up of healthy proteins on the surface of existing fibrils. The researchers used a molecule known as amyloid-beta, which forms the main component of the amyloid plaques found in the brains of Alzheimer's patients. They found a relationship between the amount of healthy proteins that are deposited onto the existing fibrils, and the rate of the fibril self-replication. In other words, the greater the build-up of proteins on the fibril, the faster it self-replicates. They also showed, as a proof of principle, that by changing how the healthy proteins interact with the surface of fibrils, it is possible to control the fibril self-replication. "This discovery suggests that if we're able to control the build-up of healthy proteins on the fibrils, we might be able to limit the aggregation and spread of plaques."

Antibiotic treatment weakens progression of Alzheimer's disease through changes in the gut microbiome

Two of the key features of Alzheimer's disease are the development of amyloidosis, accumulation of amyloid-ß (Aß) peptides in the brain, and inflammation of the microglia, brain cells that perform immune system functions in the central nervous system. Buildup of Aß into plaques plays a central role in the onset of Alzheimer's, while the severity of neuro-inflammation is believed to influence the rate of cognitive decline from the disease. For this study, researchers administered high doses of broad-spectrum antibiotics to mice over five to six months. At the end of this period, genetic analysis of gut bacteria from the antibiotic-treated mice showed that while the total mass of microbes present was roughly the same as in controls, the diversity of the community changed dramatically. The antibiotic-treated mice also showed more than a two-fold decrease in Aß plaques compared to controls, and a significant elevation in the inflammatory state of microglia in the brain. Levels of important signaling chemicals circulating in the blood were also elevated in the treated mice.

While the mechanisms linking these changes is unclear, the study points to the potential in further research on the gut microbiome's influence on the brain and nervous system. "We don't propose that a long-term course of antibiotics is going to be a treatment - that's just absurd for a whole number of reasons. But what this study does is allow us to explore further, now that we're clearly changing the gut microbial population and have new bugs that are more prevalent in mice with altered amyloid deposition after antibiotics."

Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease

Clinically, Alzheimer's disease (AD) is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the proto-oncogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice.

We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than controls. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2% reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38%. Mechanistically, these changes were linked to a significant increase in proteasome activity. These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors.

Brain cell death in Alzheimer's linked to structural flaw

Studying cells from postmortem brains of people who had Alzheimer's disease, researchers previously found that areas of DNA that are typically tightly wound in the cell's nucleus are instead relaxed and unwound in brain cells from Alzheimer's patients. When DNA is unwound it can switch on genes that should be turned off. In the new study, the researchers took a closer look at the nuclei of Alzheimer's patients' brain cells to find out how the DNA becomes unwound. When the researchers used a very high-resolution microscopy technique that let them observe the entire nucleus, they were surprised to see tunnels running through the nucleus of brain cells from people with Alzheimer's disease that were not seen in normal brain cells. "We wanted to find out if these tunnels were actually causing neurons to die or whether they were a side effect of the disease. Using the fly model of Alzheimer's disease we genetically blocked the process of tunnel formation and found that indeed less brain cells died and the flies lived longer. We are now performing lab experiments to see if we can also block the process using drugs."

After identifying this first potential new drug target, the researchers continued their experiments to further elucidate this biological pathway. The cell nucleus is surrounded by what is known as the lamin nucleoskeleton, a structural scaffold made of the protein lamin. They found that when the lamin nucleoskeleton is disrupted and tunnels form, the DNA inside can no longer anchor to the nucleoskeleton and becomes unraveled. In other words, the interaction between tightly wound DNA and the nucleoskeleton is required to maintain the overall 3D architecture of the DNA. They also discovered that the tau that aggregates in the brains of people with Alzheimer's disease disrupts the lamin nucleoskeleton by overstabilizing the actin cytoskeleton found outside of the nucleus, in the cell's cytoplasm. This interrupts the normal coupling between the actin cytoskeleton and the lamin nucleoskeleton, which, in turn, causes the tightly wound DNA to relax. This causes genes to turn on that are not supposed to and, consequently, brain cells die.

Exercise and TERRA in Telomere Biology

Occasionally I'll post research that is only tenuously relevant to aging, but nonetheless fascinating. That is the case for this article and open access paper on a fairly new and still poorly understood area of telomere biology. The researchers link exercise to the generation of TERRA, or telomeric repeat-containing RNA, which might lead to all sorts of speculation among long-time readers here. Exercise, telomere length, and aging are all in the same general bucket of items with many established links. Speculation is all that can be done by onlookers at the present time, however, given that the research community has yet to establish firm connections leading from TERRA to any of the behaviors of telomeres and, separately, exercise that are known to be relevant in aging. Still, reading through gives a good sense of just how complex the situation is under the hood. There are no simple relationships in biochemistry.

Telomeres are repeating DNA sequences that cap the ends of chromosomes. Every time a cell divides a little of the telomere is lost as the cell's DNA is replicated. When the remaining telomeres become too short the cell self-destructs or becomes senescent. This is a part of the Hayflick limit, which has evolved to ensure that most cells can only replicate so many times. Every tissue consisting of such limited cells is supported by a much smaller population of stem cells, which use telomerase to lengthen their telomeres and thus consistently produce an ongoing supply of new cells with long telomeres to replace those that reach their limits. The situation in which only some cells are privileged to divide indefinitely exists because it keeps cancer rates low enough for complex long-lived species to exist and evolve. These days telomere length and telomerase are hot topics in aging research, though not all of it is entirely justified to my eyes. Telomerase gene therapies have been shown to extend life in mice, which may be a result that works along the same lines as stem cell therapies, by increasing the activity of cells and maintenance of tissues. Average telomere length declines with age, but this is a statistical relationship across populations, of limited use for individual diagnosis. Telomere length seems very much like a marker and not a cause of aging.

Telomeres are DNA, and DNA encodes blueprints for proteins. A part of the process of gene expression by which proteins are created is transcription, wherein DNA is used as the pattern to produce RNA molecules. Are telomeres transcribed just like the rest of the nuclear DNA? Yes, as it turns out. Telomeric DNA is transcribed to produce TERRA molecules. What does TERRA do? That is an interesting question with few firm answers at the present time, but a lot of leads and maybes. Telomeres are not just passively sitting there: they encode for RNA, and that RNA does things. By linking TERRA to exercise, known to improve health via a variety of mechanisms, there is the thought that perhaps there are more direct connections than previously thought between changing telomere length and the various options like exercise and calorie restriction known to slow the progression of aging. It is particular interesting, for example, that TERRA may regulate the activity of telomerase, though as for much of the other results relating to TERRA this is fairly tentative and subject to revision. Is this all really relevant to the future of our lives, however? Probably not, as exercise, calorie restriction, and similar ways to modestly slow aging are not the gateways to human rejuvenation. They do too little to address the forms of damage that cause aging, and only repair of that damage, rather than merely slowing it down, can greatly extend life. But that said, this is a most interesting space in the study of cellular biology.

Exercise Boosts Telomere Transcription

When healthy individuals perform a cardiovascular workout, their muscles increase transcription of telomeres. A novel transcription factor appears to promote telomere transcription and provides the first direct evidence that telomere transcription is linked to exercise and metabolism in people. Telomeres were thought to be transcriptionally silent until several years ago when researchers found that mammalian telomeres, including human ones, are readily transcribed into telomeric repeat-containing RNA (TERRA). These RNA molecules have been shown to associate with telomeres but whether and how TERRA can protect telomeres - the repetitive sequences at the ends of linear chromosomes that form a sort of aglet to protect the structures - or promote the lengthening of the ends of chromosomes is not yet fully understood.

Researchers first analyzed human telomeric sequences for potential transcription factor binding sites. The researchers identified a potential binding site for the transcription factor nuclear respiratory factor 1 (NRF1), then confirmed its ability to bind the ends of chromosomes in human cancer cell lines. Because NRF1 is activated when stores of ATP are depleted, as during exercise, the team next enlisted 10 young and healthy volunteers to a low- or high-intensity workout on a stationary bicycle for 45 minutes. The researchers took muscle biopsies and blood samples prior to, right after, and 2.5 hours after the exercise. TERRA levels were increased 2.5 hours after both the low and high intensity workouts and were highest after the high intensity exercise. This is the first evidence that telomeres are transcribed in non-dividing human tissue. Exercise produces reactive oxidative species (ROS) that may damage telomeres. The researchers are now addressing the hypothesis that the TERRA molecules produced from NRF1-dependent telomere transcription may act as scavenger molecules that react with the ROS, protecting the telomere itself from oxidation. "As it is not yet established what role TERRA plays at mammalian telomeres, it is premature to speculate on the effect of NRF1 and TERRA upregulation in exercise on telomere biology or aging."

Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription

DNA breaks activate the DNA damage response and, if left unrepaired, trigger cellular senescence. Telomeres are specialized nucleoprotein structures that protect chromosome ends from persistent DNA damage response activation. Whether protection can be enhanced to counteract the age-dependent decline in telomere integrity is a challenging question. Telomeric repeat-containing RNA (TERRA), which is transcribed from telomeres, emerged as important player in telomere integrity. However, how human telomere transcription is regulated is still largely unknown.

We identify nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α as regulators of human telomere transcription. In agreement with an upstream regulation of these factors by adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), pharmacological activation of AMPK in cancer cell lines or in normal nonproliferating myotubes up-regulated TERRA, thereby linking metabolism to telomere fitness. Cycling endurance exercise, which is associated with AMPK activation, increased TERRA levels in skeletal muscle biopsies obtained from 10 healthy young volunteers. The data support the idea that exercise may protect against aging.

The Effects of Retirement are Complex

Whenever looking at correlations between behavior and lifespan, or behavior and health, one should always ask whether calorie intake or physical activity level could be involved. Both animal and human studies tell us that the effects of both of these items are large in comparison to almost all other commonly varying factors, with smoking being one of the few exceptions to that rule. In recent years, the growing use of accelerometers rather than self-reporting in studies of exercise have revealed that even quite modest physical activity correlates with a sizable difference in outcomes in later life. Animal studies tell us that exercise does in fact cause improvements in health and at least healthy life span if not maximum life span. It is very hard to pull out causation from human statistics, but it is reasonable to arrange one's life on the basis that causation in other mammals matches up with causation in humans in this matter.

Retirement as an institution has interesting correlations with life span, especially in those countries where it is voluntary, and people are not forced into it, pushed out of their own lives by uncaring bureaucrats. More than one set of research results indicates that retirement is bad for health, and there is the suggestion that this might be because of declining physical activity. Certainly it is easy enough to point to correlations between ill health and retirement - people who age more rapidly or become ill and frail will certainly retire at much higher rates. Much of this research goes beyond the event of retirement itself to look at what happens later, however, and that is where suggested causation emerges from the data.

The open access paper I'll point out today might be taken to indicate that most earlier studies of this nature are perhaps overly simplistic. There are many life paths to consider: an obese individual who retires due to ill health is in a very different bracket of influences and outcomes from a thin individual who transitions from a desk job to actively gardening during the day. Some groups of people do actually undertake more physical activity following retirement. The paper itself splits out retirees into a fair number of categories, and it is worth looking through to find the tables and charts. What we might take away from this is a reminder that rejuvenation therapies are on the horizon, some already in early clinical development, and for many of us a few years here or a few years there may wind up being the difference between living to benefit or dying just at the verge of the new era of treatments for the causes of aging.

Does retirement mean more physical activity? A longitudinal study

Participation in physical activity declines with age concurrent to an increasing risk of preventable health conditions like type 2 diabetes. Yet physical activity is widely recognized as crucial for strengthening and maintaining physical and mental health during aging. Some transitions out of the labor market, such as retirement and semi-retirement, may free up time that could be used to (re) engage in physical activity. Retirement can be seen, therefore, as a potentially sensitive period in the lifecourse to target interventions for promoting healthy ageing. Evidence on physical activity during retirement from cross-sectional studies is mixed and limited by the spectre of reverse causality. Some longitudinal studies have the potential to approximate the transition to retirement, so should be regarded as higher quality evidence. Of the longitudinal studies, some have attempted to isolate the impact of retirement on leisure-time physical activity specifically. Others have investigated whether trajectories in physical activity across retirement vary by indicators of socioeconomic circumstances. Findings remain equivocal, however, providing no firm answer on how retirement affects participation in physical activity.

Accordingly, the purpose of this longitudinal study was to examine participation in different intensities of physical activity among people transitioning out of full-time employment to different forms of retirement, while also accounting for transitions to unemployment, part-time work, or disability status. Data was obtained for 5,754 people in full-time employment aged 50-75 from the US Health and Retirement Survey. Logistic regression was used to examine trajectories in twice-weekly participation in light, moderate and vigorous physical activity among those transitioning to part-time work, semi-retirement, full retirement, or economic inactivity due to disability, in comparison to those remaining in full-time employment.

Twice weekly participation in vigorous and light physical activity changed little for those who remained in full-time employment, while moderate physical activity decreased between baseline and follow-up. Differences in physical activity according to transitional categories at follow-up were evident. Baseline differences in physical activity across all intensities were greatest among participants transitioning from full-time to part-time employment compared to those who remained in full-time employment throughout the study period. Those transitioning to unemployment were already among the least physically active at baseline, irrespective of intensity. Those transitioning to full-time retirement were also among the least active. Declines in physical activity were reported for those transitioning to economic inactivity due to a disability. Physical activity increased regardless of intensity among participants transitioning to semi-retirement and full retirement. Light physical activity increased for those transitioning to unemployment, though less change was evident in moderate or vigorous physical activity.

Insufficient physical activity is suggested to cause 6% of coronary heart disease, 7% of type 2 diabetes, 10% of breast cancer, 10% of colon cancer, and 9% of premature mortality. Although finding opportunities to promote the initiation and maintenance of physically active lifestyles is needed across the lifecourse, this study supports previous evidence that indicates the process of retirement as one such time period. Inevitably, the findings raise questions and hypotheses requiring analyses that are beyond the remit of the paper and, in some cases, also the data available. For example, is the rise in physical activity regardless of intensity among people moving into semi-retirement due to less time spent in employment? Why are people who move into part-time work already more physically active than their counterparts who remained in full-time work? Is the rise in light physical activity among people who become unemployed sustained among those who re-enter some level of employment? What factors buffer the potential impact of disability on the substantial decreases in physical activity? What types of activities do people become more or less engaged in and are there differences between transitional groups? To what extent do changes in physical activity coinciding with the transition out of full-time employment reflect personal choices versus any number of possible competing demands upon time, including informal caring and volunteering? This is not an exhaustive list and it is clear that much remains unknown. Yet, the need to promote physical activity in ageing populations remains a pressing concern and these hypotheses warrant investigation in order to target future interventions accordingly.

A Review of Telomerase as a Therapeutic Target

Telomerase provides the primary mechanism by which cells lengthen their telomeres. In our species only stem cells and cancer cells do this, while in mice more types of cell use more telomerase. Telomere length determines the limit to cell divisions, a little of the length being lost each time a cell divides. Cells that can lengthen their telomeres can continue dividing indefinitely, and that is how stem cells can continually deliver a useful supply of daughter cells to support surrounding tissues. It is also how cancer grows. Cancer and regeneration are the two sides of the same coin of growth and regeneration, one controlled, the other uncontrolled. Thus, broadly speaking, there are two things that can be done with telomerase in medicine, and both projects, while in the comparatively early stages, have a fair number of research groups involved.

Firstly, blocking the ability of telomerase to lengthen telomeres is the larger part of the basis for a universal cancer therapy. Some 90% of cancers abuse telomerase in order to grow and spread. If that can be shut down, then the cancer will be halted in its tracks - any cancer. The challenge of cancer research is not that it is hard and expensive, but rather that most approaches to treating cancer are highly specific to just a few types out of the hundreds of forms of cancerous tissue. This is a poor strategy. Meaningful progress towards defeating cancer will require the development of therapies that can instead be applied to many, or for preference all cancers. Thus blocking telomere lengthening has the potential to completely change the economics of the field, making it feasible to bring an end to cancer within our lifetimes and within the present budget allocated to that goal.

Secondly, taking the opposite approach to increase the activity of telomerase may prove to be a way to enhance regeneration and tissue maintenance, and therefore compensate for the onset of aging and age-related degeneration. In animal studies the outcome of additional telomerase is somewhat analogous to the effects of stem cell therapies, in that cellular activity increases to produce greater healing than normally take place. This is of particular interest in the old, who suffer in part because stem cell activity declines with age, and frailty and organ failure encroaches as a result. Telomerase gene therapies have been used to extend life in mice, and have the secondary effect in that species of reducing cancer rates. This second item is a very interesting outcome, given the role of telomerase in cancer, and we might speculate that it occurs because of improved immune function - enough of a benefit there to counteract any increased cancer risk as old and damaged cells are given the opportunity to do more and divide more often. There is uncertainty as to whether the outcomes in mice reflect the balance of effects that would occur in humans, since mice have a very different balance of telomerase activity. Investigations are ongoing, and great deal remains to be explained.

Therapeutic Targeting of Telomerase

Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer.

Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies.

Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches.

Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a 'mild' integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

It is important to note that therapies like telomerase enhancement or stem cell transplants do little to nothing to address a range of other issues that cause age-related disease. Age-related changes such as mitochondrial DNA damage, persistent cross-links, and the accumulation of other metabolic waste such as lipofuscin are not going to be meaningfully affected. Each of those individually probably causes enough harm to kill people. So while adjusting stem cells and regeneration can be beneficial, it does not repair these forms of underlying damage, and thus is limited in the degree to which it can turn back the clock. A good way to look at this is in terms of the stem cell therapies now becoming more widely available that address joint paint and dysfunction. They help many patients to a greater degree than any other form of therapy presently available. They do not and cannot remove liver spots or undo macular degeneration, or turn back stiffening of arteries and loss of elasticity of skin, all items driven by the forms of damage noted above. Rejuvenation will in the end require a complete toolkit.

Latest Headlines from Fight Aging!

Use of Stem Cells in Bypass Therapy Reduces Scarring and Mortality

The press here reports on the positive results of a recent small trial of the introduction of stem cells during bypass surgery for heart attack survivors. Stem cell therapies have over the past decade demonstrated highly variable outcomes in patients, and the methodology of delivery has been shown to be very important. A fair amount of the work accomplished in this field over the past fifteen years has involved trying to determine why seemingly similar approaches to the use of stem cells in regenerative medicine can produce both very successful and marginal outcomes. This therapy, for example, isn't all that different from others that have failed to move the needle in heart regeneration.

People suffering from heart disease have been offered hope by a new study that suggests damaged tissue could be regenerated through a stem cell treatment injected into the heart during surgery. The small-scale study followed 11 patients who during bypass surgery had stem cells injected into their hearts near the site of tissue scars caused by heart attacks. One of the trial's most dramatic results was a 40% reduction in the size of scarred tissue. Such scarring occurs during a cardiac event such as a heart attack, and can increase the chances of further heart failure. The scarring was previously thought to be permanent and irreversible.

At the time of treatment, the patients were suffering heart failure and had a very high (70%) annual mortality rate. But 36 months after receiving the stem cell treatment all are still alive, and none have suffered a further cardiac event such as a heart attack or stroke, or had any readmissions for cardiac-related reasons. Twenty-four months after participants were injected with the stem cell treatment there was a 30% improvement in heart function, 40% reduction in scar size, and 70% improvement in quality of life, as judged by the Minnesota living with heart failure (MLHF) score. "It's an early study and it's difficult to make large-scale predictions based on small studies. But even in a small study you don't expect to see results this dramatic. These are 11 patients who were in advanced heart failure, they had had a heart attack in the past, multiple heart attacks in many cases. The life expectancy for these patients is less than two years, we're excited and honoured that these patients are still alive." The next study will include a control group who undergo bypass but do not receive stem cell treatment, to measure exactly what impact the treatment has.

Further Investigation of P21 and SDF-1 Shows that Cxcr4 Inhibitors can Promote Scarless Healing in Mammals

Mice lacking p21 can regenerate small wounds without scarring, something that is not normally possible in adult mammals. Separately, SDF-1 has been identified as a signal to recruit and activate stem cells, and efforts are underway build regenerative therapies on this basis. Here, scientists dig further into the intersection of these two lines of research to find - as in other studies - that immune system involvement seems to be key to the process. They show that an existing class of drug can induce healing of minor injuries without scars in mice by blocking some of the immune cell activities that normally take place in mammalian wound healing. Ultimately, the goal in this and a range of similar research is to establish whether or not our biochemistry is capable of salamander-like regeneration of limbs and organs, and if so which of the numerous differences between highly regenerative and less regenerative species are blocking this ability.

The ability to regenerate lost organs following trauma is one of the great unsolved mysteries in medical research, and understanding the basis of mammalian regenerative biology is relevant to human regenerative medicine. In mammals, traumatic injuries typically heal with a fibroblast- and collagen-rich response, producing a fibrous scar rather than full reconstitution of cellular subtypes and functional tissue architecture. A central focus of regenerative and developmental biology is to restore normal tissue structure and function after injury. Astonishing examples of tissue and organ regeneration following injury include appendage and eye regeneration in amphibians and teleosts. Limited examples of tissue regeneration also exist in mammals, suggesting that mechanisms governing tissue regeneration may be evolutionarily conserved. Here, we investigated mouse ear regeneration to identify cellular, genetic, and signaling mechanisms driving mammalian appendage regeneration.

Mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration.

The hypothesis that wound epidermis initiates or regulates tissue regeneration has been suggested in other species. In salamanders, the absence of the wound epidermis prevents limb regeneration. Deer antlers regenerate annually, but antlerogenesis is lost if the skin overlying the antler bone pedicle is removed and replaced with a full-thickness skin graft. These findings suggest a two-way interaction between the overlying skin and underlying skeletal tissues and cell types to coordinate tissue regeneration. Our identification of p21-dependent Sdf1 production by keratinocytes at the wounded edge is consistent with this possibility. Further localization of this effect may benefit from studies of mice with conditional p21 knockout alleles, when available. How multiple tissue-specific precursor cells expand and collaborate to restore integrated tissue architecture and function also remains to be defined.

While immune cell recruitment is required to initiate early wound-healing responses, previous studies have demonstrated that some forms of immunosuppression can accelerate subsequent regeneration. In humans, fetal skin regenerates after injury without scarring (unlike adult wound healing), a phenomenon accompanied by reduced immune cell infiltration and decreased inflammation. In our studies, we found that decreased Sdf1 expression and diminished recruitment of Cxcr4+ leukocytes promote tissue regeneration. The balance between inflammatory responses and tissue regeneration is likely to be complex and multiphasic. Further studies are needed to investigate the subsets of wound Cxcr4+ leukocytes recruited by Sdf1 and understand how these cells normally promote wound healing, fibrosis, and scar formation.

Using AMD3100, an established antagonist of Cxcr4 signaling, we induced appendage regeneration in wild-type animals. In the past, AMD3100, either by itself or in combination with platelet-derived growth factor or tacrolimus, improved wound healing and scar formation in diabetic mice and mice receiving thermal burns. Here we show that AMD3100 treatment promotes tissue regeneration and restores normal tissue structure and function after injury in a scarless manner. Currently, short courses of AMD3100 are used to mobilize bone marrow stem cells for transplantation in humans, and a common side effect of AMD3100 is peripheral blood leukocytosis. We speculate that the peripheral blood leukocytosis seen in patients may also result from disruption of Sdf1-mediated leukocyte trafficking, and future studies are needed to understand this mechanism more precisely. Collectively, our observations suggest that the clinical uses of AMD3100 may be expanded to include treatment of traumatic appendage wounds or chronic nonhealing wounds in skin. These are common problems that lack effective treatments and represent an important unmet need in current clinical practice.

Nanog May Improve Function of Old Stem Cells

In this research, the scientists involved investigate a potential role for the gene nanog in the aging of stem cells, a prospect that has been studied for a few years now. Nanog is involved in pluripotency, the ability of embryonic stem cells to generate any cell type, but, as is the case for most cellular biology, not in a straightforward way. In recent years, with the development of induced pluripotent stem cells, a great deal of attention has been directed towards the molecular biology of genes such as nanog.

To battle aging, the human body holds a reservoir of nonspecialized cells that can regenerate organs. These cells are called adult stem cells, and they are located in every tissue of the body and respond rapidly when there is a need. But as people age, fewer adult stem cells perform their job well, a scenario which leads to age-related disorders. Reversing the effects of aging on adult stem cells, essentially rebooting them, can help overcome this problem.

In the new study, researchers introduced Nanog into aged smooth muscle stem cells and found that Nanog opens two key cellular pathways: Rho-associated protein kinase (ROCK) and Transforming growth factor beta (TGF-β). In turn, this jumpstarts dormant proteins (actin) into building cytoskeletons that adult stem cells need to form muscle cells that contract. Force generated by these cells ultimately helps restore the regenerative properties that adult stem cells lose due to aging.

Additionally, the researchers showed that Nanog activated the central regulator of muscle formation, serum response factor (SRF), suggesting that the same results may be applicable for skeletal, cardiac and other muscle types. The researchers are now focusing on identifying drugs that can replace or mimic the effects of NANOG. This will allow them to study whether aspects of aging inside the body can also be reversed. This could have implications in an array of illnesses, everything from atherosclerosis and osteoporosis to Alzheimer's disease.

Progress in the Use of Bioscaffolds for Muscle Regeneration

Researchers have demonstrated some restoration of strength in patients with severe muscle injuries, using scaffold materials derived from the extracellular matrix (ECM) of pig tissues. This is an incremental step forward towards the end goal of complete regeneration, but shows the potential utility of suitable guide materials to spur reconstruction of missing tissues. This has some relevance to the issue of age-related loss of muscle mass and strength; many of the approaches used to regenerate severe muscle injuries may see adaptation to restoration of muscle in the elderly, though for preference not those involving surgical procedures.

For the Muscle Tendon Tissue Unit Repair and Reinforcement Reconstructive Surgery Research Study, 11 men and two women who had lost at least 25 percent of leg or arm muscle volume and function first underwent a customized regimen of physical therapy for four to 16 weeks. Researchers then surgically implanted a "quilt" of compressed ECM sheets designed to fill in their injury sites. Within 48 hours of the operation, the participants resumed physical therapy for up to 24 additional weeks. By six months after implantation, patients showed an average improvement of 37.3 percent in strength and 27.1 percent in range of motion tasks compared with pre-operative performance numbers. CT or MRI imaging also showed an increase in post-operative soft tissue formation in all 13 patients.

The new data builds upon a 2014 study that showed damaged leg muscles grew stronger and showed signs of regeneration in three out of five men whose old injuries were surgically implanted with ECM derived from pig bladder. Those patients also underwent similar pre- and post-operative physical therapy. The recent results included more patients with varying limb injuries; used three different types of pig tissues for ECM bioscaffolds; investigated neurogenic cells as a component of the functional remodeling process; and included CT and MRI imaging to evaluate the remodeled muscle tissue. "The three different types of matrix materials used all worked the same, which is significant because it means this is a generic property of these materials and gives the surgeons a choice for using whichever tissue they like."

Stem Cell Therapy as a Potential Glaucoma Treatment

Researchers here provide evidence in mice to suggest that stem cell treatments could be used to address some forms of glaucoma, usually caused by an increase in pressure in the eye that can damage the optic nerve and other structures. The types of glaucoma of interest here are those in which the drainage channels for aqueous humour deteriorate, as those channels might be induced to regenerate via the transplantation of stem cells produced from the patient's own tissues:

Researchers injected stem cells into the eyes of mice with glaucoma. The influx of cells regenerated the tiny, delicate patch of tissue known as the trabecular meshwork, which serves as a drain for the eyes to avoid fluid buildup. When fluid accumulates in the eye, the increase in pressure could lead to glaucoma. The disease damages the optic nerve and can result in blindness. "We believe that replacement of damaged or lost trabecular meshwork cells with healthy cells can lead to functional restoration following transplantation into glaucoma eyes."

One potential advantage of the approach is that the type of stem cells used - called induced pluripotent stem cells - could be created from cells harvested from a patient's own skin. That gets around the ethical quandary of using fetal stem cells, and it also lessens the chance of the patient's body rejecting the transplanted cells. The researchers were able to get the stem cells to grow into cells like those of the trabecular meshwork by culturing them in a solution that had previously been "conditioned" by actual human trabecular meshwork cells. The researchers were encouraged to see that the stem cell injection led to a proliferation of new endogenous cells within the trabecular meshwork. In other words, it appears the stem cells not only survived on their own, but coaxed the body into making more of its own cells within the eye, thus multiplying the therapeutic effect. The team measured the effects in the mice nine weeks after the transplant. Lab mice generally live only two or three years, and nine weeks is roughly equal to about five or six years for humans.

The researchers say they are confident that their findings hold promise for the most common form of glaucoma, known as primary open angle glaucoma. They aren't sure yet if their mouse model is as relevant for other forms of the disease. Another possible limitation of the research: It could be that new trabecular meshwork cells generated from the stem cell infusion eventually succumb to the same disease process that caused the breakdown in the first place. This would require retreatment. It's unclear, though, whether an approach requiring multiple treatments over time would be viable. The researchers plan to continue studying the approach.

More Details on SENS Research Foundation's ALT Cancer Program

The SENS Research Foundation is currently raising funds for the next step in its cancer research program: building one of the necessary foundations for a universal cancer therapy, one form of treatment that can in principle halt all types of cancer. This requires putting a stop to the lengthening of telomeres in cancer cells, as without that ability cancer tissue cannot grow and spread. This is the one actionable common mechanism shared by all cancers. Cancer cells can use telomerase or alternative lengthening of telomeres (ALT) to extend telomere length, and while some research groups are working on telomerase inhibition, it is unfortunately the case that very few people are working on ALT. Since it has been demonstrated in mice that telomerase cancers can become ALT cancers, both approaches are needed to build a truly universal cancer treatment. Thus the SENS team has stepped in to fill the gap, and needs our help to raise the funds to make this happen.

The Major Mouse Testing Program staff writers took the opportunity to catch up with SENS Research Foundation's Dr. Haroldo Silva who is leading the OncoSENS campaign seeking cures for ALT Cancer.

I saw the article "Control ALT, Delete Cancer" about this project that you co-wrote in April, 2015. Why are you only now starting the crowdfunding effort?

Because we are now at the point where our hard work paid off and we were able to overcome most of the technical hurdles associated with making our novel ALT-specific assay compatible with robotic/automation methods. This is essential to performing high-throughput and large-scale screening studies. We will be measuring a particular biomarker that has only been observed in ALT cancers, namely C-circles, which are circular pieces of DNA containing a repetitive sequence only found at the ends of chromosomes (i.e., telomeres). The more ALT activity is present in a given cancer, the higher the levels of C-circles present in them. Therefore, once we exposed the ALT cancer cells to different compounds we will measure C-circle content quickly to assess if any of the compounds was able to inhibit the ALT pathway.

If your screening does find a promising compound, what do you plan to do with it? Will you patent its anti-ALT properties?

After exhaustive validation of the initial positive screening results, the next step will depend on the nature of the particular compound. If it is currently used in patients for cancer or any other indications we could approach the company that commercializes it to start a joint development program focused on ALT cancer therapy. Otherwise we will explore alternative ways of moving the development of these potential therapies into the private sector. We will absolute aim to patent any compounds that we find helpful in the fight against cancer whenever possible. It takes an average of 12 years for a compound to go from discovery to clinical use in the US. Now, it is possible to reduce that time significantly in case the promising compound we find in our screening is either already approved for clinical use or has been through extensive clinical trials. We will be testing such compounds as part of our screening as explained above. Alternatively, we could target initially ALT cancers that affect less than 200,000 patients in the US in order to obtain orphan drug designation, which can significantly expedite the approval process. This would pave the way for bringing therapies to more common ALT cancers.

How many other groups have also looked at ways to inhibit ALT?

There are very few research groups performing ALT-related cancer research worldwide, especially when you compare it to the amount of scientific output from telomerase-based cancer research efforts. Even within the research groups dedicating a lot of resources to ALT research, none of them to the best of our knowledge have the technical capability to perform such a large small molecule screening in the way we are planning to do it. Our technological achievement with the C-circle assay puts our group in a unique position to perform the largest screening study ever attempted in the field of ALT cancer research.

GPR17 as a Target to Reduce Measures of Aging in the Brain

Researchers here note that leukotriene receptor antagonists appear to reduce inflammation and increase plasticity in the brains of rats. They pin down the receptor GPR17 as a protein of interest in this effect. While not directly addressing underlying damage and change that causes inflammation and loss of neural plasticity, it is possible that this type of approach may produce sufficient benefits in humans to merit development. The same arguments apply here as for other classes of therapy that improve tissue maintenance without doing much to reduce the molecular damage that drives aging, such as stem cell transplants. There are clearly meaningful benefits in that case, and so long as this sort of research and development doesn't result in the abandonment of attempts to repair damage and thus halt and reverse aging, it is worth pursuing.

Counteracting some, or ideally all, of such age-related changes might rejuvenate the brain and lead to preservation or even improvement of cognitive function in the elderly. The feasibility of such an approach was recently demonstrated by experiments exposing the aged brain to a young systemic environment, that is, young blood, through heterochronic parabiosis. The aged brain responded to young blood by reduced microglia activation, enhanced neurogenesis, and importantly, by improved cognition. Vice versa, old blood caused premature ageing of the young brain and led to impaired cognition. A proteomic approach identified eotaxin, a chemokine involved in asthma pathology, as one of the molecules that is elevated in ageing and that contributes to neuroinflammation, reduced neurogenesis and to impaired cognition. This triggered us to hypothesize that, aside from eotaxin, additional mechanisms that are originally related to peripheral inflammatory conditions such as asthma might act or even be present in the central nervous system (CNS), where they potentially modulate degenerative and regenerative events.

Leukotriene signalling is well studied in the field of asthma. Leukotrienes mediate inflammatory reactions associated with increased vascular permeability, and leukotriene receptor antagonists such as the drug montelukast have been successfully developed to treat asthmatic patients. The role of leukotrienes in the brain, in particular their contribution to degeneration and regeneration, is less clear and sometimes even controversial. Nevertheless, elevated levels of leukotrienes were reported in acute as well as chronic CNS lesions, and also in the aged brain, where they might mediate neuroinflammatory responses including microglia activation. Here, we demonstrate that montelukast reduces neuroinflammation, restores blood-brain barrier integrity and increases neurogenesis specifically in the brain of old rats, the latter being mediated through inhibition of the GPR17 receptor. Most importantly, montelukast treatment restores cognitive function in the old animals, paving the way for future clinical translation for the treatment of dementias.

The effect on neurogenesis was, like the anti-inflammatory activity, specific to old rats. Thus, montelukast might stimulate neural progenitor proliferation only in situations in which neurogenesis is compromised. Montelukast might liberate progenitors from age-associated inhibitory mechanisms, which most likely include elevated levels of leukotrienes. Obviously, the extrapolation of these results from normal ageing to neurodegenerative diseases is intriguing, and some of the beneficial effects of montelukast in animal models of neurodegeneration might well be attributed to enhanced neurogenesis. In general, a clear dissection between neurogenesis- and neuroinflammation-mediated effects on cognition is not straightforward as neurogenesis and neuroinflammation strongly influence each other. For example neural progenitors induce microglia proliferation and activation, and vice versa, microglia regulate adult hippocampal neurogenesis.

A Smad7 Gene Therapy to Inhibit Age-Related Muscle Loss is in Development

There are always many ways to influence any specific process in cells and tissues. When it comes to enhanced muscle growth, the most popular approaches so far are myostatin inhibition, such as via gene knockout or the use of antibodies, or increased levels of the myostatin inhibitor follistatin. Both of these have been shown to greatly increase muscle mass in a number of species, and are thus potential treatments to compensate for the loss of muscle mass and strength that occurs over the course of aging. Physical weakness is a large component of age-related frailty, and even partially removing that part of the aging process is a worthy goal. The research group noted here has taken a different approach to this area of biochemistry, targeting smad7 to inhibit processes that break down muscle tissue:

"Chronic disease affects more than half of the world's population. It occurs with chronic infection, muscular dystrophy, malnutrition and old age. About half the people who die from cancer are actually dying from muscle wasting. What kills a lot of people isn't the loss of skeletal muscle but heart muscle. The heart literally shrinks, causing heart failure." In cachexia, tumors secrete hormones that cause muscle deterioration; in effect, the body eats its own muscles, causing weakness, frailty and fatigue. Researchers have long sought to stop this process, but failed to find a safe way. That's because the hormones that cause wasting - in particular, a naturally occurring hormone called myostatin - play important roles elsewhere in the body.

So researchers needed a way to stop myostatin, but only in muscles. Their solution: an adeno-associated virus - a benign virus that specifically targets heart and skeletal muscle. The virus delivers a small piece of DNA - a signaling protein called Smad7 - into muscle cells. Smad7 then blocks two signaling proteins called Smad2 and Smad3, which are activated by myostatin and other muscle-wasting hormones. By blocking those signals, Smad7 stops the breakdown of muscles. "Smad7 is the body's natural break and, by inhibiting the inhibitor, you build muscle." In 2015, the researchers launched AAVogen, a company that will develop this discovery into a commercial drug, AVGN7.

How Extracellular Matrix Scaffolds Influence Cell Behavior in Therapies

One approach to regenerative medicine is to use donor extracellular matrix as a scaffolding material. The extracellular matrix is the support structure created by cells that determines the structural properties of a tissue. Its presence in a regenerative therapy can guide cells to rebuild lost tissue to some degree, but a better understanding of how this actually works under the hood could be used to improve the quality of the outcome, as well as to hopefully allow the development of a viable artificial replacement for natural donor matrix materials.

Researchers have identified a mechanism by which bioscaffolds used in regenerative medicine influence cellular behavior, a question that has remained unanswered since the technology was first developed several decades ago. Bioscaffolds composed of extracellular matrix (ECM) derived from pig tissue promote tissue repair and reconstruction. Currently, these bioscaffolds are used to treat a wide variety of illnesses such hernias and esophageal cancer, as well as to regrow muscle tissue lost in battlefield wounds and other serious injuries.

Researchers know that ECM is able to instruct the human body to replace injured or missing tissue, but exactly how the ECM material influences cells to cause functional tissue regrowth has remained a fundamental unanswered question in the field of regenerative medicine. In the new study, the team showed that cellular communication occurs using nanovesicles, extremely tiny fluid-filled sacs that bud off from a cell's outer surface and allow cells to communicate by transferring proteins, DNA and other "cargo" from one cell to another. Exosomes are present in biological fluids such as blood, saliva and urine, where they influence a variety of cellular behaviors, but researchers had yet to identify them in solid body tissues. "We always thought exosomes are free floating, but recently wondered if they are also present in the solid ECM and might facilitate the cellular communication that is critical to regenerative processes."

To explore this possibility, researchers used specialized proteins to break up the ECM, similar to the process that occurs when a bioscaffold becomes incorporated into the recipient's tissue. The research team then exposed two different cell types - immune cells and neuronal stem cells - to isolated matrix bound vesicles, finding that they caused both cell types to mimic their normal regrowth behaviors. "Sure enough, we found that vesicles are embedded within the ECM. In fact, these bioscaffolds are loaded with these vesicles. This study showed us that the matrix bound vesicles are clearly active, can influence cellular behavior and are possibly the primary mechanism by which bioscaffolds cause tissue regrowth in the body."

Building a Tau Immunotherapy that does not Increase Inflammation

Alzheimer's disease is associated with the aggregation of misfolded amyloid-β and tau proteins. The consensus position is that these aggregates are the primary cause of pathology, though the biochemistry involved is exceedingly complex and still being mapped. A sizable faction in the research community is working on immunotherapies to clear out misfolded amyoid, tau, or both, though so far this has proven to be more challenging than hoped. One of the potential issues is the risk of such a therapy generating greater inflammation in a patient whose condition is already inflammatory. This article gives an overview of one line of research into tau immunotherapies, and notes a recent step forward towards solving the inflammation problem:

The tangled buildup of tau protein in brain cells is a hallmark of the cognitive decline linked with Alzheimer's disease. Antibodies have been shown to block tau's spread, but some scientists worry it could also fuel inflammation. Now, researchers have found that an antibody's ability to recruit immune cells - known as its effector function - is not necessary for stopping tau's spread. Alzheimer's disease causes a characteristic constellation of pathologies: accumulation of amyloid-β plaques outside neurons, neurofibrillary tangles of tau inside brain cells, and chronic inflammation. Clinical research has mostly focused on targeting amyloid-β with antibody therapies, and several treatments based on this approach are currently in clinical trials. But recent efforts have zeroed in on tau as a new potential target.

Antibodies are known to spur the brain's defense system, microglia, to absorb and degrade tau, but their recruitment of immune cells may also worsen inflammation. Researchers wondered whether effector function was necessary for stopping tau's spread. To find out, the researchers raised transgenic mice that develop a tau pathology similar to that seen in Alzheimer's disease. The team treated the animals with antibodies that had either strong effector function or none at all. The animals that received antibodies with no effector function were able to clear tau as effectively as those that received full-effector function antibodies. "Low and behold, we don't need effector function in order to achieve a halting of accumulation of tau pathology." The findings suggest the antibodies could have an indirect effect on microglial activation, and may be unnecessary for therapeutic effect. The findings are likely to reignite an ongoing debate in the field over whether antibodies target tau inside or outside brain cells.


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