Fight Aging! Newsletter, March 13th 2017

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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  • Searching for Similarities in the Biochemistry of Long-Lived Mammals
  • Another Example of Work on Markers of Cellular Senescence and Disruption of Signaling by Senescent Cells
  • Old Stem Cells are Most Likely Still Useful Stem Cells
  • Choosing to Lead an Inactive Life Means Paying the Price for that Choice
  • Researchers Report on More New Senolytic Drug Candidates
  • Latest Headlines from Fight Aging!
    • Age-Related Failure of Autophagy Contributes to Stem Cell Decline
    • Modest Life Extension in Yeast by Reducing Intentional DNA Damage
    • A Popular Science Article on Treating Aging as a Medical Condition
    • A Demonstration in Mice of Whole Mitochondria Delivered as a Therapy
    • Quantifying the Effects of Exercise on Mitochondria and Other Cellular Structures
    • A Mechanism by Which Inflammation Spreads in the Brain
    • Investigating Retrotransposons in Alzheimer's Disease
    • Infection and Inflammation in Neurodegenerative Conditions
    • GABA and Retinal Regeneration in Zebrafish
    • A Recent Example of Progress in the Quality of Bone Tissue Engineering

Searching for Similarities in the Biochemistry of Long-Lived Mammals

Portions of the aging research community study various long-lived mammals, such as naked mole-rats, bowhead whales, elephants, and Brandt's bats. In most cases research projects compare a long-lived species with another species that is similar but short lived; consider the many papers examining the differences between naked mole-rats and mice or rats, for example. Naked mole rats and mice are about the same size, but the naked mole-rats live an order of magnitude longer. The hope is that such large differences in life span should help to illuminate those areas of cellular biochemistry most important in determining the pace of aging.

At this stage in the growth of the comparative biology of aging it is still a question mark as to just how much can be done with this knowledge, once obtained. Will it be practical to port over aspects of the biology of long-lived mammals to humans any time soon? Given the lengthy, expensive, and so far largely fruitless struggles to find ways to make human biochemistry undergo the beneficial calorie restriction response without actual calorie restriction, a mere change of state in one species, I have to think that we shouldn't be holding our breath waiting for medicine based on the biochemistry of other species. Controlling the operation of metabolism to this degree has been demonstrated to be a substantial challenge given present capabilities. Progress will occur, but for now there are far more effective paths forward, such as the SENS approach of repairing our existing metabolism rather than making attempts to change its operation.

In the research linked below, researchers take the approach of looking at the genetics and biochemistry of a few different long-lived mammal species, searching for similarities between them. In theory these species are long-lived for broadly similar evolutionary reasons despite their differences, or at least the hope is that evolutionary pressures converge at similar mechanisms for longevity assurance in species in the same portion of the tree of life. This may or may not be the case, of course, but it seems sensible to try an investigation along these lines if the goal is to better understand exactly how mammalian biochemistry gives rise to such large variations in life span between species.

Adaptive sequence convergence of the tumor suppressor ADAMTS9 between small-bodied mammals displaying exceptional longevity

For several decades, it has been well recognized that there is strong correlation between lifespan and body mass, with larger species typically living longer than smaller species. There are, however, several species that violate this general rule, living much longer than expected given their small size and high metabolic rates. Of particular interest are the microbats, several species of which demonstrate longer maximum lifespans than any other mammals when controlling for body size. In addition to their exceptional longevity, microbats appear to be resistant to neoplasia and remain healthy and reproductively capable throughout the majority of their lives. Much like the microbats, the naked mole-rat lives approximately three times longer than expected given its small size, is remarkably resistant to neoplasia and displays no symptoms of aging well into its second decade.

Although once thought to be rare, there have been numerous recent studies demonstrating adaptive sequence convergence between a variety of species displaying convergent traits. These studies have highlighted genes that have been repeatedly targeted during the evolution of a given trait. For example, the evolution of echolocation in bats and toothed whales appears to be driven, in part, by common mutations. This and other evidence demonstrates that common selective pressures can drive common mutations in relevant genes.

The evolution of extreme longevity in microbats and the naked mole-rat is likely attributable to a lack of extrinsic sources of mortality in these species. Bats, being nocturnal and capable of flight, generally contend with few predators. Likewise, the naked mole-rat lives in subterranean burrows where the risk of predation is low. Several theories of aging suggest that a lack of extrinsic sources of mortality will result in selection for longer lifespan. For example, according to the antagonistic pleiotropy (AP) theory of aging, a mutation can be beneficial during development, but have late-onset deleterious effects. AP is expected to be more prevalent in species with high levels of extrinsic mortality since most individuals are unlikely to survive long after reaching sexual maturity, therefore there will be little pressure to select against the deleterious effects that manifest later in life. Also, the disposability theory of aging suggests that there exists a trade-off between growth/development and repair/maintenance. In species that contend with many predators, it should be beneficial to allocate resources to grow and develop as quickly as possible rather than to invest in repair and maintenance since longevity is already unlikely.

According to both theories, for species that contend with numerous extrinsic sources of mortality, the decline in fitness due to aging is minimal, so selection is inefficient at promoting mutations that increase longevity. However, for species that exist in relatively safe niches, like microbats and the naked mole-rat, the strength of selection to delay senescence will be much stronger, as individuals that live longer will have higher lifetime reproductive fitness. We hypothesize that the pressure to delay senescence shared by microbats and naked mole-rat may have led to convergent sequence evolution in key longevity promoting genes. The identification of genes that have undergone convergent evolution in these long-lived species would provide a better understanding of the genetics of longevity and could potentially identify therapeutic targets for cancer and other age-related illnesses. Here we tested for adaptive convergent sequence evolution between microbats and the naked mole-rat in almost 5,000 genes conserved across a wide-range of mammals. We found that A disintegrin-like and metalloprotease with thrombospondin type 1 motifs 9 (ADAMTS9) displays numerous convergent substitutions between the long-lived species that were likely driven by positive selection.

ADAMTS9 is the most widely conserved member of the ADAMTS family and has recently been reported to be a novel tumor suppressor that is downregulated in several varieties of human cancer. Intriguingly, ADAMTS9 inhibits tumor growth by blocking the mTOR pathway, which has long been known to be associated with aging. In addition to its role in tumor suppression, ADAMTS9 has also been implicated in several age-related conditions including arthritis, type 2 diabetes, macular degeneration, and menopause. Furthermore, in C. elegans the loss of GON-1, the roundworm homolog of ADAMTS9, alters lifespan and promotes dauer formation. These effects are likely due to modified insulin and insulin-like ortholog secretion and altered insulin/IGF-1 signaling, which is also known to contribute to aging.

Although it may be possible that the observed convergent changes shared by microbats and the naked mole-rat may be the product of some non-adaptive force rather than selection for increased longevity, several lines of evidence suggest otherwise. First, the convergent substitutions are distributed along the length of the coding sequence, eliminating gene conversion or alternate exon usage as possible causes. Second, the convergent topology was strongly favored when only sites with evidence of positive selection occurring on the long-lived microbat branch were considered, suggesting that the convergence was indeed driven by selection. Finally, ADAMTS9 has previously been implicated in several aging processes and age-related diseases, supporting the hypothesis that modulation of ADAMTS9 function alters lifespan. Together, this evidence suggests that ADAMTS9 has been repeatedly targeted by selection for increased longevity in microbats and the naked mole-rat.

Another Example of Work on Markers of Cellular Senescence and Disruption of Signaling by Senescent Cells

A great deal of research into the phenomenon of cellular senescence is taking place these days; an explosion of effort and funding in comparison to the start of the decade, a time at which it was next to impossible to make any progress in this part of the field. The turning point was philanthropy, a gift of the necessary funds to run the first animal study that provided direct evidence for targeted removal of senescent cells to slow the aging process. For decades prior to this point, compelling indirect evidence existed for senescent cells to be a contributing cause of degenerative aging, but despite the growing advocacy of groups like Methuselah Foundation and SENS Research Foundation, it was still very hard to find that money. Now the tipping point has passed, all sorts of findings are being made, however: direct links between cellular senescence and age-related disease, findings that could have been made ten or twenty years ago were there the will and the funding at that time, albeit at greater cost and effort. This is something we should all bear in mind as we look at other areas of the SENS rejuvenation research agenda and ask why it is not progressing as rapidly as we'd like. All it takes is that one study and suddenly everyone in the research community, all the people who wouldn't give you the time of day last year, agree that you were right all along - and then forget your name in the rush to append their own to the newly growing field. Such is the way the world works. It isn't fair, it isn't efficient, but it is what it is, and we do our best to change it.

The open access paper linked below is one of many examples to illustrate two trends in the more energetic recent research of cellular senescence: firstly, to find more and better biomarkers that distinguish senescent cells from their peers, and secondly to find ways to minimize the harms done by senescent cells without destroying them. The first sounds like a great idea, as the presently established state of the art in senescent cell assays and markers is more or less the same as it was fifteen years ago - good enough for laboratory research after the old model, but not a sound basis for the clinical therapies and more discriminating research of the years ahead. It seems evident that something better is possible in this age of accelerating growth in the capabilities of biotechnology. The second course of action, on the other hand, strikes me as a tough road in comparison to the more direct approach of destroying senescent cells. That destruction seems unambiguously beneficial in mice, even when all such cells are constantly removed throughout life, via genetic engineering approaches. In human therapies, at least at the outset, removal would only occur every so often, during a treatment. The transient roles for senescent cells would continue as they were, such as in wound healing and suppression of potentially cancerous cells.

So the argument made in this paper, and elsewhere, that we should be cautious and leave senescent cells in place, doesn't seem like one with a lot of support given the evidence to date. Those researchers making it are asking for the community to give up the short path to effective therapies in exchange for a long path to worse therapies. Removal of senescent cells could be carried out quite infrequently, perhaps every few years or every decade. Suppression of senescent cells on the other hand would mean constant medication, and the struggle to safely adjust very complex cellular behavior that is still incompletely cataloged. Each form of damage and misbehavior created by the senescence-associated secretory phenotype (SASP) would have to be mapped and then drugs designed to impact it; it could take decades, even under optimistic estimates of future capabilities of the industry. Destruction of these cells, on the other hand, can be done now in the lab, and is only a few years away from the clinic. Time matters in the treatment of aging, as we don't have an infinite amount of it.

Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway

Cellular senescence is characterized by a proliferative arrest induced to prevent the propagation of damaged cells in a tissue. This arrest is mainly driven by the activation of two important pathways, p53/p21CIP and RB/p16INK4A. The senescence program can be triggered by a number of stressors, like the activation of oncogenes, drug treatment, or deregulation of Polycomb Repressive Complex 1 (PRC1) proteins, including the polycomb protein chromobox 7 (CBX7). Although arrested, senescent cells are metabolically and transcriptionally functional, and they actively communicate with their surroundings. In fact, senescent cells secrete an array of inflammatory proteins, growth factors, and metalloproteases that collectively constitute the SASP (senescence-associated secretory phenotype). The SASP recruits the immune system in order to eliminate senescent cells and induces changes in the extracellular matrix (ECM), thus facilitating tissue homeostasis and regeneration. The presence of senescent cells has been found in vivo in preneoplastic lesions, in wound healing, during embryonic development, and in different tissues throughout aging. Interestingly, a recent study has demonstrated that p16INK4A-positive cells accumulate during aging and contribute to age-related dysfunctions in different tissues. Thus, the elimination of senescent cells reverses the aging phenotype and stimulates tissue regeneration, demonstrating that the activation of senescence is a direct cause of aging and opening avenues for targeting senescent cells as a therapy to extend healthy lifespan.

Intercellular communication is an important feature to maintain tissue homeostasis, where the activation of cellular senescence plays a crucial role. In fact, previous reports have found ECM remodeling to regulate fibrosis by activating the senescence program. Apart from inflammation and ECM remodeling, cells can communicate via the secretion of extracellular vesicles, cell-cell contact, or intercellular protein transfer. Here, we provide evidence that the integrin β3 subunit plays a role in senescence through activation of the TGF-β pathway. A great deal of information exists regarding the biological function of integrins and their regulation of the microenvironment, but relatively little is known about the transcriptional regulation of integrins themselves. We show that β3 subunit expression accelerates the onset of senescence in human primary fibroblasts, which is dependent on the activation of the p21CIP/p53 pathways. Our results also show a robust expression of β3 upon senescence activation induced by a variety of stimuli, while interference with its expression levels disrupts the senescence phenotype. Furthermore, mice lacking β3 accelerate wound-healing closure, which could be by restricting the induction of senescence.

Cellular adhesion is a key feature of senescence. In agreement with our results, several reports have found differential expression of integrins during cellular senescence activation. Analysis of published datasets show that the "cellular adhesion" pathway and integrins are differentially expressed during senescence activation. Likewise, a number of studies have found that TGF-β ligands are part of the SASP and play an important role in senescence through p21CIP regulation, in agreement with our data. The TGF-β superfamily controls numerous cellular and biological processes, such as development, regeneration, fibrosis, and cancer. Accumulating evidence indicates that a cross-talk between integrins and TGF-β exists, in particular to regulate fibrosis, wound healing, and cancer. However, even if senescence is known to regulate all these biological processes, none of these studies have reported the existence of a cross-talk between integrins and TGF-β in senescence or aging. Our data show that β3 regulates senescence by activating TGF-β via cell-autonomous and non-cell-autonomous mechanisms. The use of small molecule inhibitors, RNAi technology, and the analysis of the expression levels of various members of the TGF-β pathway authenticate a role for TGF-β during senescence induced by β3 expression.

Our data show an increase in the expression levels of β3 mRNA concomitant with an increase in different markers of senescence in tissue from old mice. Upregulation of β3 and senescence/aging markers, including TGF-β members, was further observed in fibroblasts from old human donors. This is in accordance with previous reports, which have found that p16INK4A levels correlate with chronological age in most tissues analyzed, both in mice and in humans. Interestingly, knockdown of β3 mRNA partially reversed the aging phenotype of fibroblasts derived from old human donors. However, the αvβ3 antagonist, cilengitide, could not reverse aging, suggesting that the role for β3 in this cellular system is independent of its ligand-binding activity. Our data show that cilengitide has a diverse effect on the SASP and on the senescence growth arrest. As senescent cells accumulate during aging, causing chronic inflammation, cilengitide could be a potential therapeutic route to block inflammation without affecting proliferation in aging. In summary, here, we provide evidence for the β3 subunit being a marker and regulator of senescence, and identify integrins as potential therapeutic targets to promote healthy aging.

Old Stem Cells are Most Likely Still Useful Stem Cells

There is an intriguing amount of evidence to suggest that the stem cells remaining in the tissues of old people are still quite capable. If removed from the old cellular environments, many aspects of their behavior become similar to those of the same type of stem cell taken from a younger individual, at least in some reports. There is a greater level of accumulated cellular damage in old stem cells, but much of the evidence suggests that this does not provide as great a contribution to degenerative aging as do diminished numbers and diminished activity. Stem cell activity in the old is much declined from youthful levels, as I'm sure regular readers know. This activity is necessary for the support of tissues, supplying replacement somatic cells and generating signals that adjust cell behavior. The loss of regenerative capacity and consequent slow failure of tissue function an important part of the processes of aging.

As to whether the principal problem is loss of stem cells or that the stem cells are present but become perpetually quiescent, the evidence is varied. The situation is probably different for different stem cell populations, and to muddy the waters further, these are most likely overlapping issues. The stem cell populations react to the aging of tissues, meaning the rising level of damage and the changing signal environment that results from that damage. This reaction may be to self-renew less readily, decreasing the size of the stem cell population, or to remain quiescent and inactive for ever longer periods, decreasing the number of active stem cells at any point in time. Or both. The consensus theory on this process is that it is a part of the evolved balance between aging and cancer. As damage grows, so too does cancer risk, and stem cell decline can serve to reduce cancer risk at the cost of a slower decline into frailty and death.

Whether old stem cells are inherently dysfunctional is a question of considerable relevance to the practical development of stem cell therapies. The present direction in therapies is to use a patient's own cells, to take existing stem cells to generate more of the same for transplant, or to use those stem cells to create differentiated cells and tissues, again for transplantation. If aged stem cells are inherently dysfunctional, that would greatly limit the ability to use this class of therapies for older people, those who most need such treatments. But if, as seems to be the case, old stem cells are still capable in and of themselves, then this approach to regenerative medicine for age-related disease has a brighter future. Of course, the influence of the aged tissue environment still means that a challenging problem must be to solve to build effective regenerative therapies for the old: how to ensure that the fate of transplanted cells isn't just a repeat of what has already happened to the native cell populations? The regenerative medicine industry has to grapple with the causes and mechanisms of aging in one way or another, given that the vast majority of patients are in fact old, and the state of their aged tissues impacts cell therapy effectiveness.

Regenerative capacity of autologous stem cell transplantation in elderly: a report of biomedical outcomes

Stem cells are found not only in embryonic or fetal tissues but also in all adult tissues in relatively high numbers. These cells are committed to tissue repair throughout adult life. Although the number of cells and their capabilities decrease over time, rich stem cell niches remain such as bone marrow and adipose tissue. The observation that stem cells differentiate into several cell lineages reveals their potential for use in regenerative medicine. More importantly, stem cells harvested from adult tissue can be used for autologous transplantation and can also avoid immunological rejection. However, whether stem cells from elderly people have similar capabilities as those found in younger people is yet unknown. Some studies suggest that elderly people have fewer stem cells and that they have lost their capacity for growth and differentiation in vitro. Other evidence indicates that sufficient numbers of stem cells remain throughout adult life, providing an alternative for use in cell therapy.

Self-renewal in vitro is one of the main stem cell characteristics that occur after harvest. Healthy adult stem cells grown in vitro have a high proliferation capacity. However, stem cells from elderly subjects show less proliferation potential. Several studies have reported a decrease in the number of colony forming units in mesenchymal stem cell (MSC) cultures from donors aged ≥40 years. In vitro doubling times are longer in cells taken from elderly patients than those from younger donors and show a substantial decrease in proliferation rate. Similar observations have been reported for lipoaspirate samples obtained from adipose tissue. In vitro doubling times differ depending on donor age and are longer in those collected from older donors. The relationship between the decrease in number and functionality of stem cells could be a consequence of the loss of proper environmental signals. In addition, decreased telomere length and an increased rate of apoptosis and its signals have been reported in MSCs harvested from elderly donors. In addition, the definition of MSCs requires the presence of specific cell membrane antigens, as well as human leukocyte antigen class II. Until now, flow cytometry has been performed on MSCs from younger and elderly patients to confirm the presence or absence of these specific stem cell markers. The overall conclusions from these reports are that MSCs from elderly donors have less capability to grow.

Differential expression of stemness genes on MSCs from elderly donors may be ultimately responsible for the decline of the stem cell proliferation rate. Stemness genes characterized in bone marrow-derived stem cells from patients with amyotrophic lateral sclerosis (ALS) show decreased expression of two genes related with pluripotential for the transcription factors OCT4 and NANOG. In addition, decreased expression of trophic factors have been reported. Similar observations have been reported for adipose-derived stem cells (ADSCs) from healthy patients aged from 50 to 60 years. However, others have reported no difference in the expression of NANOG or OCT4 between MSCs isolated from the bone marrow of children and those obtained from adults. Despite these controversial reports, the general consensus supports that the expression of stemness genes is lower, but their activity is sufficient for growth and self-renewal.

Several studies have shown that healthy adult stem cells grown under specific culture conditions will differentiate into various cell lineages in vitro. The bone-forming capacity is similar in cells obtained from younger and older donors. One hypothesis proposes that the senescence-associated decrease in bone formation is due to a defect in the bone microenvironment. Chondrogenic differentiation is also controversial, as some studies have shown independent age-related responses or reduced capacity with age. Other stem cell sources, such as muscle-derived stem cells obtained from young (age 9 years) and old (age ≥60 years) humans, replicated 20- to 30-times in vitro and differentiated into different tissue lineages. These cells (satellite cells) are found in aged human skeletal muscle and are capable of regeneration. Stem cells from elderly donors do not have as much pluripotential as cells from younger donors. Nevertheless, these cells are capable of self-renewal and differentiation into osteoblasts, chondroblasts, adipocytes and other cell lineages.

Samples of pluripotent stem cells for autologous transplantation have been obtained from several tissues of differently aged donors. The most abundant and relatively accessible sources for adult stem cells are bone marrow, peripheral blood and adipose tissue. Samples from elderly people have been obtained, applied to autologous transplantation and have improved some degenerative diseases. The beneficial effects of autologous cell transplantation have been reported in patients with neurodegenerative diseases, including those performed on elderly patients. The stem cell subpopulations selected for treatment may have improved the outcomes. Several clinical trials have been performed on cardiomyopathies in patients greater than 50 years old. The most promising among those trials included infusion bone marrow-derived stem cells or MSCs from peripheral blood in patients suffering a myocardial infarction, in whom a moderate but significant improvement in left ventricular ejection volume was observed. There is no consensus about the best MSC subtype to treat ischemic heart disease. Nevertheless, all studies in this area have reported improved cardiac function after autologous MSC transplantation.

In summary, stem cells obtained from elderly patients retain pivotal membrane cell markers and have in vitro self-renewal and differentiation capabilities in adipocytes, osteoblasts and chondroblasts. In addition, stem cells from elderly patients express the transcription factors responsible for cell proliferation, such as SOX2, NANOG and OCT4. Some reports have indicated that these genes are expressed at lower levels in elderly subjects than stem cells obtained from younger donors. Nevertheless, the cells respond to induced differentiation as well as those obtained from younger donors. Several trials are currently being performed using autologous MSCs in elderly patients. Until more data are gathered indicating some beneficial effects, there is no consensus on the utility of stem cells as a gold standard treatment, but stem cells from elderly donors have similarly capabilities to growth and differentiation as younger donors.

Choosing to Lead an Inactive Life Means Paying the Price for that Choice

It is no great secret that, all other things being equal, people who are some combination of less fit, less active, and more overweight suffer from a greater incidence of age-related health issues and have a shorter life expectancy. They also pay a higher lifetime cost for medical treatment despite that shorter life expectancy. A century of medical studies on this topic demonstrate these points quite comprehensively. Much as some sedentary or overweight people like to hear that their choices do not have serious consequences, this is not the case - they do have serious consequences. Yes, it is harder to stay thin and active in this age of ease of transport and more calories than any individual can possibly work their way through. Yes, it is easier to postpone exercise indefinitely and eat whatever you feel like eating. Nonetheless, this is all still a matter of choice. Those thinner people you see walking around out there? Those physiques didn't happen by accident. Choose to swing the odds towards a healthier, longer future, or choose to swing the odds towards a less healthy, shorter future: it is up to you.

If this was an age of stasis, in which medicine was not advancing at a very rapid pace, one might make the nihilist's argument that we'll all end up in the same place in the end, and that it is a person's free choice to consume for pleasure now at the cost of suffering later. Kicking the can down the line is a human specialty, after all. But we do live in an age of rapid progress in biotechnology, in which practical, working rejuvenation therapies will emerge over the decades ahead. In this environment, a few years here and a few years there do matter. Postponing the decline of old age to the best reasonable extent possible with the limited but freely available and reliable tools of today, meaning exercise and calorie restriction, might make a very large difference in the end - the difference between living to benefit significantly from rejuvenation treatments, or missing out on that era. Consider the odds. Perhaps science will advance enough to rescue you from any additional harms you do to yourself above and beyond those inflicted by aging, but why roll the dice if you don't have to?

For today's glance at the scientific world, look below to see a brace of references to recent studies on activity levels and age-related disease. They recapitulate thin slices of what is already well known about exercise, fat tissue, and health, but there seems to be an endless font of funding for the increasingly details quantification of exercise and its effects. Why this must be the case, whilst researchers working on genuinely new medical science find it ever a struggle to obtain grants, is a question with no satisfactory answer. If we lived in a better world, there would be a great deal more funding for the new and the experimental aimed at cures, when considered in comparison to the work of finely cataloging the present state of health and operation of the human machine absent those cures.

Physical inactivity and sedentary behaviors are associated with cardiometabolic risk factors

Previous studies of healthy adults and persons with diabetes have demonstrated that physical activity - particularly activities with moderate-high intensity - and daily sedentary behaviors, such as watching television, have a significant effect on cardiometabolic health. Nevertheless, these observations have never been explored in older adults at high cardiovascular risk, a typically sedentary and physically inactive population that has a high risk of developing chronic diseases. Consequently, researchers implemented the PREDIMED-PLUS trial and thus address this question by evaluating different types of physical activities and sedentary behaviors in a population of 5,576 men and women with high cardiovascular risk. They have also studied the effect of replacing the time spent watching television with the same time engaging physical activities with different intensities.

The most striking results from this investigation show that increasing the time spent on physical activities with moderate-high intensity (brisk walking, climbing stairs, working in the garden or performing sports) by one hour a day was associated with a 3%-6% increase in protection against obesity, diabetes, abdominal obesity and low HDL-cholesterol. In contrast, increasing the time spent watching television by one hour a day was associated with an increased presence of these cardiometabolic risk factors. Moreover, when one hour a day of watching television was replaced by one hour a day of physical activity with moderate-high intensity, the protection against these cardiometabiloc risk factors was even greater (3%-9%) than the protection observed when each activity was evaluated separately.

Overweight, obese people risk heart disease at younger ages

In a new study, overweight and obese people tended to have slightly shorter or similar lifespans compared to people with normal body weight, whether or not they had cardiovascular diseases. But compared to people with normal BMI, lifetime risks for developing cardiovascular disease were higher in overweight and obese adults. For example, overweight middle-aged women were 32 percent more likely to develop cardiovascular disease in their lifetime compared to those of normal weight. Average years lived without cardiovascular disease were longest for people with normal BMI, while years lived with cardiovascular disease were longest for overweight and obese people.

Overweight or obese people also experienced cardiovascular disease at an earlier age than those with normal BMI. For example, among overweight middle-aged women, cardiovascular disease began 1.8 years earlier than normal weight women, and 4.3 years earlier for those who were obese. For the study, the researchers looked at cardiovascular disease data of 72,490 people, focusing on patients in middle-age, who were 55-years-old on average. Participants were healthy and free of cardiovascular disease when they enrolled in the study. The average BMI was 27.4 for men and 27.1 for women. "Our findings suggest that healthcare providers need to continue to be aware of the increased risk of earlier cardiovascular disease faced by overweight and obese people. Healthcare providers should emphasize the importance of maintaining healthy weight throughout their lives to live longer, healthier lives."

Prolonged sedentary time and physical fitness among Canadian men and women aged 60 to 69

This study examined associations between sedentary time and fitness among Canadians in their sixties. The main findings were that, after adjusting for moderate-to-vigorous physical activity (MVPA): 1) objectively measured sedentary time was inversely associated with cardiorespiratory fitness and grip strength; 2) the number of breaks in sedentary time was positively associated with cardiorespiratory fitness; 3) the percentage of sedentary time spent in bouts of at least 20 minutes was inversely associated with cardiorespiratory fitness; 4) associations between sedentary time in bouts of at least 20 minutes and breaks in sedentary time and cardiorespiratory fitness were not consistent between sexes, nor were associations between sedentary time and grip strength; and 5) self-reported sedentary time was not related to any fitness variable. The last conforms with previous work showing measured sedentary time to be more consistently related to health outcomes than are self-reported measures.Note

Earlier research indicates that sedentary time and patterns of sedentary time are associated with older adults' health and functional fitness. In the present study, the percentage of total sedentary time spent in bouts of at least 20 minutes was inversely associated with cardiorespiratory fitness, and a greater number of breaks in sedentary time was associated with better cardiorespiratory fitness. These findings are important because cardiorespiratory fitness is a strong predictor of morbidity and all-cause mortality. In 2015, it was demonstrated that non-exercising older adults with higher cardiorespiratory fitness have better vascular function and lower cardiovascular risk. It was suggested that greater amounts of non-exercise activity, such as activities of daily living, may partly explain the fitness and vascular health of some older individuals who do not engage in purposeful physical actvity. It is possible that adaptations in the vasculature, and likely other components such as muscle oxidative capacity, are stimulated by light intensity activities.

Total sedentary time was inversely related to grip strength in men and women, even after adjusting for MVPA. As well, the association between breaks in sedentary time and sit-and-reach scores was positive among men. Therefore, sedentary time may also influence musculoskeletal fitness, which is crucial for independent living and autonomy. These data demonstrate a significant relationship between directly measured sedentary time, breaks in sedentary time, and fitness among Canadians in their sixties. Given long-established associations between fitness and both health and functional autonomy for older adults, this study underscores the importance of minimizing total sedentary time and breaking up sedentary time, in addition to increasing physical activity.

Older adults who exercise regularly may lower chances for severe mobility problems

Based on the proven health benefits of exercise for older adults, a team of researchers theorized that exercise might also help adults prevent or delay disabilities that interfere with independent living. The researchers enrolled 1,635 adults between the ages of 70 and 89. All of the participants were at high-risk for becoming physically disabled. At the beginning of the study, the participants were able to walk about five city blocks (one-quarter of a mile) without assistance. The participants were split into two groups. One group was encouraged to exercise regularly. In addition to taking a daily 30-minute walk, they performed balance training and muscle strengthening exercises. The other group attended weekly workshops for 26 weeks, followed by monthly sessions. The workshops provided information about accessing the healthcare system, traveling safely, getting health screenings, and finding reliable sources for health and nutrition education. The workshop instructors also led the participants in 5- to 10-minute flexibility or stretching exercise sessions. Researchers gave all participants thorough tests for disability at the beginning of the study and then at 6, 12, 24, and 36 months after the study started. The researchers reported that people in both groups experienced about the same level of disability after the study. However, people in the exercise group experienced a lower level of severe mobility problems than did people who attended the health workshops.

Researchers Report on More New Senolytic Drug Candidates

Now that clearing senescent cells as a therapy for aging finally has meaningful support in the research community, there is far more funding available to turn the wheels of the standard drug discovery and evaluation process. Researchers are in search of senolytic drugs, those that can kill senescent cells without harming normal cells. The process starts at first with an evaluation of the performance of each molecule in the standard compound libraries in cell cultures, in search of molecules that preferentially kill senescent cells. This can be automated to a fair degree, especially when the desired result is as black and white as destroying one distinctive class of cell. It is very similar to the sort of cancer drug screening that the research community has a great deal of experience in carrying out. In fact, the existing candidates for senolytic drugs have largely emerged from the cancer drug candidate databases, and were tested for their effects on cancer for some years without noticing their strong effects on senescent cells - it wasn't in the list of items to evaluate at the time.

Given the starting point of a few promising compounds, preferably already tried in animals and humans, and thus with decent pharmacology data, researchers then branch out to examine other chemically similar compounds. It is usually the case that a better version with greater primary effects and lesser side-effects can be established one way or another. The level of work to achieve that end varies greatly, however, ranging from finding another well-characterized small molecule drug candidate in the archives to the researchers having to carry out all of the work to model and synthesize a novel molecule and prove it to be effective. It is usually the case that researchers and developers are far more willing to push ahead with a suboptimal compound that is already fairly well tested than to work with a less well explored but potentially better compound. Nonetheless, in theory the competition in the system weeds out worse drugs in favor of better drugs, though that process may never seem as efficient in practice or as fast as we'd like it to be. Personally, I'd like to see more funding going towards the sort of programmable gene therapy pioneered by Oisin Biotechnologies, a better approach than mining cancer chemotherapy drugs in search of those with side-effects that are minimal enough for patients to accept.

Then it is on to animal studies, starting companies, and human trials, the standard process for moving forward with the development of new medicine. Many candidates will turn out to be not so useful in human medicine, others will pass all the way through. Insofar as senolytic drug discovery goes, all of the groundwork has already taken place for a number of cancer drug candidates that can promote apoptosis in senescent cells, such as navitoclax and dasatinib, some of which are being carried forward into clinical trials by UNITY Biotechnology. In animal studies, these appear to remove on the order of 10-50% of senescent cells in a single course of treatment, varying widely by tissue type. The research community isn't resting on its laurels, however, and is turning up new candidates on a fairly regular basis at the moment, such as piperlongumine. The paper below offers another few candidates for consideration, though I would say that they are less interesting in and of themselves at this stage, but rather as an indication that we should expect the list of potential drugs to expand quite rapidly in the next few years, and hopefully the quality of the best candidates along with it.

New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463

Senescent cells accumulate in numerous tissues with aging and at sites of pathogenesis of multiple chronic diseases. Small numbers of senescent cells can cause extensive local and systemic dysfunction due to their pro-inflammatory senescence-associated secretory phenotype (SASP). For example, transplanting only 200,000 senescent ear chondroblasts or preadipocytes around knee joints induces osteoarthritis in mice, while injecting similar numbers of non-senescent cells does not. Clearing senescent cells by activating a drug-inducible "suicide" gene in progeroid or naturally-aged mice alleviates a range of age- and disease-related phenotypes, including sarcopenia, frailty, cataracts, adipose tissue dysfunction, insulin resistance, and vascular hyporeactivity.

To decrease the burden of senescent cells in non-genetically-modified individuals, we used a hypothesis-driven approach to identify senolytic compounds, which preferentially induce apoptosis in senescent rather than normal cells. Our approach was based on the observation that senescent cells are resistant to apoptosis. This suggested that senescent cells either have reduced engagement of pro-apoptotic pathways that serve to protect them from their own pro-apoptotic SASP or they have up-regulated pro-survival pathways. We demonstrated the latter to be the case and identified senescence-associated pro-survival pathways based on expression profiling of senescent vs. non-senescent cells. We confirmed the requirement of these pathways for survival of senescent but not non-senescent cells by RNA interference. These pathways included pro-survival networks related to PI3K / AKT, p53 / p21 / serpins, dependence receptor / tyrosine kinases, and BCL-2 / BCL-XL, among others.

We tested drugs that target these pro-survival pathways. We initially reported that the dependence receptor/ tyrosine kinase inhibitor, dasatinib (D) and the flavonoid, quercetin (Q), are senolytic in vitro and in vivo. D and Q induced apoptosis in senescent primary human preadipocytes and HUVECs, respectively. Combining D+Q broadened the range of senescent cells targeted, and, in some instances, proved synergistic in some types of senescent cells. D+Q alleviated cardiovascular, frailty-related, osteoporotic, neurological, radiation-induced, and other phenotypes and disorders in chronologically aged, progeroid, and high fat-fed atherosclerosis-prone mice, consistent with our observations in mice from which senescent cells had been removed by inducing the suicide gene in transgenic INK-ATTAC mice. Expanding upon our findings with Q, we tested if the related flavonoid fisetin is senolytic. Fisetin is widely available as a nutritional supplement and has a highly favorable side-effect profile.

Based on our earlier hypothesis-driven identification of senolytic drugs and identification of the BCL-2 pro-survival pathway as one of the "Achilles' heels" of senescent cells, we and others simultaneously reported that the BCL-2 / BCL-W / BCL-XL inhibitor, navitoclax (ABT263; N), is senolytic. Like D and Q, N is senescent cell type-specific, being effective in inducing apoptosis in HUVECs but not human preadipocytes. We also found that the related BCL-2 family inhibitor, TW-37, is not senolytic. TW-37, unlike N, does not target BCL-XL. Others confirmed that N targets senescent cells, but Bcl-2 family inhibitors that do not target BCL-XL are not senolytic. We therefore tested if the relatively specific BCL-XL inhibitors, A1331852 and A1155463, are senolytic. Unlike N, these agents do not target BCL-2. Consequently, A1331852 or A1155463 may cause less BCL-2-induced neutrophil toxicity, a serious side-effect of N.

We found that fisetin and the BCL-XL inhibitors, A1331852 and A1155463, are senolytic in vitro, inducing apoptosis in senescent, but not non-senescent HUVECs. This adds three new agents to the emerging repertoire of senolytics reported since early 2015, which currently includes D, Q, N, and piperlongumine. Fisetin has a plasma terminal half-life of just over 3 hours in mice. It alleviates dysfunction in animal models of chronic disease, including diabetic kidney disease and acute kidney injury, attributes consistent with those expected from a senolytic agent. Here we demonstrate that fisetin is indeed senolytic in senescent HUVECs, but not in senescent IMR-90 cells or human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR-90 cells but not primary human preadipocytes. We noted that these drugs increased cellular ATP levels significantly in senescent human preadipocytes, but not HUVECs, through an as yet unknown mechanism.

We predict many more senolytic drugs will appear at an accelerating pace over the next few years. Initially, most are likely to be based on re-purposed drugs or natural products. Increasingly, new senolytics will likely be derived using medicinal chemical approaches based on optimizing properties of the repurposed agents. Consistent with this, it appears that small changes in the senolytic drugs already discovered can interfere with senolytic activity, such as in the case of D vs. imatinib, with the latter not being senolytic, or N vs. the closely-related agent, TW-37. Conversely, we speculate that small structural changes to repurposed senolytic drugs could enhance senolytic activity, with increases in the percent and range of types of senescent cells eliminated, as well as better stability, bioavailability, and side-effect profiles.

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Age-Related Failure of Autophagy Contributes to Stem Cell Decline

Researchers here provide evidence that points to declining autophagy as a cause of the faltering stem cell activity that accompanies aging. Autophagy is an important process of cellular maintenance, a part of recycling damaged structures and proteins within cells. Increased levels of autophagy are a feature of numerous methods of modestly slowing aging demonstrated in mice and other laboratory species. Unfortunately autophagy fails with age; like all systems it is impacted by the accumulation of molecular damage, and in particular in this case, by the growing amounts of metabolic waste making up lipofuscin, a mix of various compounds that mammalian biochemistry struggles to break down. Lipofuscin ends up accumulated in lysosomes, recycling systems in the cell that play an important role in autophagy, and degrades their function. If repairing this problem will not only improve the quality of cells, but also restore more youthful levels of stem cell activity, that would be a considerable victory. It is all the more reason to support the work of the SENS Research Foundation and others on ways to safely clear out the constituents of lipofuscin and thus restore lysosomal function in aged tissues.

Researchers have discovered that in addition to its normal role in cellular waste-processing, autophagy also is needed for the orderly maintenance of blood-forming hematopoietic stem cells (HSCs), the adult stem cells that give rise to red blood cells, which carry oxygen, and to platelets, which prevent bleeding, as well as the entire immune system, which fights infections and disposes of pathogens. The researchers found that autophagy keeps HSCs in check by allowing metabolically active HSCs to return to a resting, quiescent state akin to hibernation. This is the default state of adult HSCs, allowing their maintenance for a lifetime.

Failure to activate autophagy has profound impacts on the blood system, leading to the unbalanced production of certain types of blood cells. Defective autophagy also diminished the ability of HSCs to regenerate the entire blood system when they were transplanted into irradiated mice, a procedure similar to bone marrow transplantation. The researchers determined that 70 percent of HSCs from old mice were not undergoing autophagy, and these cells exhibited the dysfunctional features common among old HSCs. However, the 30 percent of old HSCs that did undergo autophagy looked and acted like HSCs from younger mice.

In a large series of experiments and analyses, the scientists compared characteristics of HSCs from old mice with those of HSCs from younger mice that had been genetically programmed so that they could not undergo autophagy. They found that loss of autophagy in young mice was sufficient to drive many of the defects that arise naturally in the blood of old mice, including changes in the cellular appearance of HSCs and a disruption in the normal proportions of the various types of blood cells, characteristics of old age. Previous research had shown that autophagy causes the formation of "sacs" within cells that can engulf and enzymatically digest molecules and even major cellular structures, including mitochondria, the cell's biochemical power plants. But in the new study, the researchers found that genetically programmed loss of autophagy resulted in the accumulation of activated mitochondria with increased oxidative metabolism that triggered chemical modifications of DNA in HSCs.

These "epigenetic" DNA modifications altered the activities of genes in a way that changed the developmental fate of HSCs. They triggered disproportionate production of certain blood cells and reduced the ability of HSCs to regenerate the entire blood system when transplanted. This result was similar to what the researchers observed in the majority of old HSCs that failed to activate autophagy. In contrast, the minority of old HSCs that still exhibited significant levels of autophagy were able to keep their mitochondria and metabolism in check, and could re-establish a healthy blood system following transplantation, similar to HSCs from young mice. However, in a hopeful sign for potential future therapies to rejuvenate blood stem cells, the researchers succeeded in restoring autophagy to old HSCs by treating them with pharmacological agents in a lab dish.

Modest Life Extension in Yeast by Reducing Intentional DNA Damage

Double-strand breaks in nuclear DNA are one of the more severe forms of DNA damage, though not as bad as large deletions as little to no information is lost, and in a healthy and young cell even a double-strand break is quickly repaired. Interestingly, double-strand breaks can occur intentionally in the cell, a part of its normal operation, and are thus not only the result of haphazard chemical reactions. This does make age-related failure of DNA repair mechanisms a more serious matter: unrepaired double-strand breaks are harmful to cells, and a higher rate of such breaks could promote, for example, more cellular senescence, known to contribute to the aging process. You might look way back in the archives at the late Robert Bradbury's double-strand break view of aging for related thoughts on this topic. Could we get by with fewer intentional double-strand breaks, and would that somewhat slow the course of aging? Here, an initial study on this question suggests the answer is yes, at least in yeast cells, though I suspect the situation to be more complex in higher forms of life.

Researchers have demonstrated a causal relationship between reduced DNA damage and extended lifespan, identifying a cellular factor - an enzyme called topoisomerase 2, or Top2, implicated in DNA damage - that can be targeted to reduce that damage. Top2 introduces double strand breaks into DNA as part of its catalytic cycle. The breaks must then be resealed. "Every once in a while Top2 gets trapped on the DNA before it can seal the breaks. When that happens, at least in young cells, there are a number of back-up systems that recognize the breaks and repair them." However, researchers have shown that DNA damage repair systems decline as cells age, causing the unrepaired DNA breaks created by Top2 to persist. The unrepaired double strand breaks cause aging, diseases like cancer, and, ultimately, death.

"Many investigators are trying to reverse aging by boosting the backup DNA repair systems in aging cells. A simpler therapeutic approach may be to administer drugs that reduce the activity of enzymes like Top2 that cause DNA damage in the first place." A three- to five-fold reduction in Top2 activity in aging yeast cells resulted in a 20 to 30 percent increase in lifespan.

The lab would not have uncovered Top2's role if it had not first discovered LS1, an unusual Top2 poison. Unlike other Top2 poisons, which are usually highly toxic, LS1 shortens lifespan without affecting the health of young cells. When introduced into yeast cells, LS1 prevents Top2 from repairing its DNA double strand breaks. That's not a problem in young cells with healthy DNA repair systems, but deadly in older cells. However, by transiently stopping Top2 from repairing its own breaks, LS1 enhances the potency of anti-cancer drugs that themselves target Top2 in human cancer cells. For example, the chemotherapy drug doxorubicin causes cardiotoxicity when overused. However, if the potency of doxorubicin were increased by also administering LS1, the same therapeutic affects might be achieved by using less of the drug, reducing the chance of side effects, and extending the utility of these frontline cancer drugs.

A Popular Science Article on Treating Aging as a Medical Condition

The popular press, even the popular science press, generally does a terrible job of reporting on the state of longevity science. They'll pull a random set of activities, rank them all equally, whether calorie restriction, complete nonsense involving supplements, or serious efforts to achieve rejuvenation after the SENS model of damage repair, and thus fail to achieve or convey any sort of meaningful understanding of what is going on in the field. The nature of the approach taken to treating aging as a medical condition is of very great importance, and the various options currently on the table are far from equal in their potential. Most are either a waste of time and effort, or are going to produce marginal results at best. Most of the time spent on practical implementations is wasted, because it follows paths that cannot plausibly produce good results, sad to say. This article is above average, but that is a low bar to pass at the moment.

Wander down a supplement aisle at your local pharmacy or hop on the internet, and it's not hard to find products that promise to "slow the normal signs of aging" or that offer "long-term well-being at the cellular level." Humans have been trying to outsmart the inevitable for centuries. After hundreds of years of effort, there is still no miracle pill that can turn back time, despite the claims of zealous entrepreneurs. Some pseudoaging treatments over the years have been risky, capable of doing more harm than good. Others have just yielded disappointing scientific results. But there's a silver lining to the snake oil. "If there's such a big market for stuff that doesn't work, imagine how much money there would be for something that does."

Over the past few centuries, modern medicine and other innovations have doubled our life span, but these treatments have focused on curing diseases that spring up during old age, such as cancer and heart disease, rather than decoding the underlying cellular and molecular processes that make the elderly vulnerable to these afflictions in the first place. Given the financial incentive and the enormous demand, one might ponder why aging science still has not yielded clinically proven therapies to combat our decline. The short answer is that aging is mind-bogglingly complicated. Despite the challenges, there's hope for those who want to live healthier for longer. Researchers are uncovering ways to turn back time on aging cells, and several existing drugs are being reborn as antiaging candidates. And big players with deep pockets have jumped into the aging game, eager to wield genomics, big data tools, and machine-learning techniques as weapons against humanity's oldest rival.

"If you talk about increasing life span, some people say, 'Whoa, what about overpopulation? I don't want to be old for 100 years. Life span extension raises natural concerns. On the other hand, if you say, 'I don't want you to develop Alzheimer's, ever,' nobody is going to argue against that." As a result, many in the field of aging have stopped talking about extending life span, preferring to describe their goal as extending "health span," especially because age is the number one risk factor for many diseases.

One of the most promising avenues of aging research is the inroads researchers have made in understanding senescent cells. Like aging in general, senescent cells evolved to benefit young, reproductive members of the species, but they become increasingly problematic for the elderly. When you're young, senescent cells are programmed to stop dividing if they are in danger of becoming cancerous. Not only that, but senescent cells also secrete a host of molecules that, in young people, stimulate regeneration and repair. But over time, as more and more cells turn senescent, levels of these secreted molecules stop positively influencing their neighbors and begin causing inflammation. Groups of senescent cells produce such high levels of these chemicals that other, normal cells are persuaded to turn senescent. The secreted cocktail can even activate a variety of age-related pathologies, including heart disease and certain types of cancer - a disease that senescent cells evolved to thwart in the first place.

There's been a recent "gold rush" of researchers identifying therapeutic compounds that target senescent cells and can periodically deactivate them in older people. Cell-penetrating peptides, dietary flavonols, small interfering RNA, and the cancer drug dasatinib are a few of the many research routes being taken. UNITY Biotechnology aims to clear senescent cells from the kidney, eyes, arteries, and joints using a compound called navitoclax, or ABT-263, that had previously been investigated for cancer. "If chemists can come up with drugs that can kill senescent cells in humans, we think this is going to revolutionize modern medicine. No longer would you have a pill for your blood pressure and a pill for your glaucoma and a pill to stabilize your heart and a pill to improve your kidney function. You'd have a pill that would hit multiple problems that affect the elderly. It is very unlikely that these are drugs that you would have to take every day. Just when enough senescent cells had accumulated again."

A Demonstration in Mice of Whole Mitochondria Delivered as a Therapy

Mitochondria, the swarming power plants of the cell, become damaged and dysfunctional with age. Can this be addressed by delivering complete, whole, new mitochondria as a therapy? There have been signs in past years that cells can ingest and incorporate mitochondria from the surrounding environment, but few useful demonstrations to show whether or not this is common in living tissues. In the research here, researchers achieve that result, delivering mitochondria into tissues as a therapy, and using this approach to treat an animal model of Parkinson's disease. This neurodegenerative condition is associated with degraded mitochondrial function, especially in the dopamine-generating neurons in the brain; depletion of that cell population produces the visible symptoms of the disease.

Unfortunately it isn't clear as to whether usefulness in addressing mitochondrial dysfunction in Parkinson's will translate to usefulness in addressing the type of mitochondrial dysfunction thought to cause aging in general. The contribution to aging is based on damage to mitochondrial DNA resulting in mutant mitochondria that are both malfunctioning and capable of outcompeting the normal mitochondria present in a cell quite quickly. Delivering new, fully functional mitochondria might not do much in this situation; they would simply be outcompeted again. It still seems worth the attempt if it turns out to be comparatively easy to replicate this demonstration in mice, on the grounds that you never know in certainty until you try, but I'm not optimistic based on the current understanding of the situation. On the other hand, one potentially interesting application of mitochondrial uptake might be to provide people an upgrade from a comparatively poor mitochondrial haplotype to a comparatively better mitochondrial haplotype, as different mitochondrial genomes have different performance characteristics.

Mitochondrial dysfunction is associated with a large number of human diseases, including neurological and muscular degeneration, cardiovascular disorders, obesity, diabetes, aging and rare mitochondrial diseases. Replacement of dysfunctional mitochondria with functional exogenous mitochondria is proposed as a general principle to treat these diseases. Here we found that mitochondria isolated from human hepatoma cell could naturally enter human neuroblastoma cell line, and when the mitochondria were intravenously injected into mice, all of the mice were survived and no obvious abnormality appeared. The results of in vivo distribution suggested that the exogenous mitochondria distributed in various tissues including brain, liver, kidney, muscle and heart, which would benefit for multi-systemically mitochondrial diseases.

In normal mice, mitochondrial supplement improved their endurance by increase of energy production in forced swimming test; and in experimental Parkinson's disease (PD) model mice induced by respiratory chain inhibitor MPTP, mitochondrial replacement prevented experimental PD progress through increasing the activity of electron transport chain, decreasing reactive oxygen species level, and preventing cell apoptosis and necrosis. Since effective drugs remain elusive to date for mitochondrial diseases, the strategy of mitochondrial replacement would provide an essential and innovative approach as mitochondrial therapy.

Quantifying the Effects of Exercise on Mitochondria and Other Cellular Structures

Exercise is good for you, the evidence is overwhelmingly in support of that conclusion, and most people should probably undertake more activity than they do. One of the interesting outcomes produced by advances in biotechnology is an increased ability to quantify the results of different types of exercise where they differ. Personally, I'm a firm believer in the idea that optimization of diet, activity, and other lifestyle choices beyond the 80/20 point is largely a waste of time at present, as you'll never know whether or not your attempts at optimization are actually producing further improvements in life expectancy. That may not be true in the future, however, given much more knowledge and better and more widely available tools. That said, in the future we'll have also have access to rejuvenation and enhancement therapies that will produce such profound effects on health as to make optimization of everyday health practices such as exercise pointless for other reasons.

It's oft-repeated but true: exercise keeps you healthy. It boosts your immune system, keeps the mind sharp, helps you sleep, maintains your muscle tone, and extends your healthy lifespan. Researchers have long suspected that the benefits of exercise extend down to the cellular level, but know relatively little about which exercises help cells rebuild key organelles that deteriorate with aging. A study has found that exercise - in particular high-intensity interval training in aerobic exercises such as biking and walking - caused cells to make more proteins for their energy-producing mitochondria and their protein-building ribosomes. "Based on everything we know, there's no substitute for these exercise programs when it comes to delaying the aging process. These things we are seeing cannot be done by any medicine."

The study enrolled 36 men and 36 women from two age groups - "young" volunteers who were 18-30 years old and "older" volunteers who were 65-80 years old - into three different exercise programs: one where the volunteers did high-intensity interval biking, one where the volunteers did strength training with weights, and one that combined strength training and interval training. Then the researchers took biopsies from the volunteers' thigh muscles and compared the molecular makeup of their muscle cells to samples from sedentary volunteers. The researchers also assessed the volunteers' amount of lean muscle mass and insulin sensitivity. They found that while strength training was effective at building muscle mass, high-intensity interval training yielded the biggest benefits at the cellular level. The younger volunteers in the interval training group saw a 49% increase in mitochondrial capacity, and the older volunteers saw an even more dramatic 69% increase. Interval training also improved volunteers' insulin sensitivity. However, interval training was less effective at improving muscle strength, which typically declines with aging.

As we age, the energy-generating capacity of our cells' mitochondria slowly decreases. By comparing proteomic and RNA-sequencing data from people on different exercise programs, the researchers found evidence that exercise encourages the cell to make more RNA copies of genes coding for mitochondrial proteins and proteins responsible for muscle growth. Exercise also appeared to boost the ribosomes' ability to build mitochondrial proteins. The most impressive finding was the increase in muscle protein content. In some cases, the high-intensity biking regimen actually seemed to reverse the age-related decline in mitochondrial function and proteins needed for muscle building. The high-intensity biking regimen also rejuvenated the volunteers' ribosomes, which are responsible for producing our cells' protein building blocks. The researchers also found a robust increase in mitochondrial protein synthesis. Increase in protein content explains enhanced mitochondrial function and muscle hypertrophy. Exercise's ability to transform these key organelles could explain why exercise benefits our health in so many different ways.

A Mechanism by Which Inflammation Spreads in the Brain

Increased inflammation in brain tissues is an important aspect of many age-related neurodegenerative conditions, and reducing that inflammation can help matters. Some chronic inflammation results from poor lifestyle choices, such as carrying excess visceral fat tissue, but the rest results from the molecular damage of aging and disarray of the immune system, both of which we can do comparatively little about at present. Better approaches to medicine are needed. Here, researchers investigate the spread of inflammation in the aging brain, and identify a mechanism that might be sabotaged in order to reduce the impact of localized increases in inflammation. This is another of many approaches to the dysfunction of aging tissues that fails to address root causes, but might nonetheless product enough of a benefit in the short term to be considered worth development into a therapy:

Researchers have identified a new mechanism by which inflammation can spread throughout the brain after injury. This mechanism may explain the widespread and long-lasting inflammation that occurs after traumatic brain injury, and may play a role in other neurodegenerative diseases. This new understanding has the potential to transform how brain inflammation is understood, and, ultimately, how it is treated. The researchers showed that microparticles derived from brain inflammatory cells are markedly increased in both the brain and the blood following experimental traumatic brain injury (TBI). These microparticles carry pro-inflammatory factors that can activate normal immune cells, making them potentially toxic to brain neurons. Injecting such microparticles into the brains of uninjured animals creates progressive inflammation at both the injection site and eventually in more distant sites.

Chronic inflammation has been increasingly implicated in the progressive cell loss and neurological changes that occur after TBI. These inflammatory microparticles may be a key mechanism for chronic, progressive brain inflammation and may represent a new target for treating brain injury. "These results potentially provide a new conceptual framework for understanding brain inflammation and its relationship to brain cell loss and neurological deficits after head injury, and may be relevant for other neurodegenerative disorders such as Alzheimer disease in which neuroinflammation may also play a role. The idea that brain inflammation can trigger more inflammation at a distance through the release of microparticles may offer novel treatment targets for a number of important brain diseases."

The researchers studied mice, and found that in animals who had a traumatic brain injury, levels of microparticles in the blood were much higher. Because each kind of cell in the body has a distinct fingerprint, the researchers could track exactly where the microparticles came from. The microparticles they looked at in this study are released from cells known as microglia, immune cells that are common in the brain. After an injury, these cells often go into overdrive in an attempt to fix the injury. But this outsized response can change protective inflammatory responses to chronic destructive ones. The researchers also found that exposing the inflammatory microparticles to a compound called PEG-TB could neutralize them. This opens up the possibility of using that compound or others to treat TBI, and perhaps even other neurodegenerative diseases.

Investigating Retrotransposons in Alzheimer's Disease

A number of research groups are involved in the study of retrotransposons in the context of aging. These are genetic sequences that can copy themselves within the genome, and that activity increases with age. Linking this definitively to specific manifestations of aging is still to be accomplished, however. There are all the same challenges in making this connection as are inherent in proving that increased levels of stochastic nuclear DNA damage are a significant cause of dysfunction in aging beyond cancer risk. Correlations can be demonstrated, but evidence for causation is elusive. In the speculative research noted here, scientists investigate the behavior of retrotransposons in connection with the development of Alzheimer's disease:

The dominant idea guiding Alzheimer's research for 25 years has been that the disease results from the abnormal buildup of hard, waxy amyloid plaques in the parts of the brain that control memory. But drug trials using anti-amyloid drugs have failed, leading some researchers to theorize that amyloid buildup is a byproduct of the disease, not a cause. This study builds on an alternative hypothesis. First proposed in 2004, the "mitochondrial cascade hypothesis" posits that changes in the cellular powerhouses, not amyloid buildup, are what cause neurons to die. Like most human cells, neurons rely on mitochondria to stay healthy. But unlike other cells, most neurons stop dividing after birth, so they can't be replaced if they're damaged. In Alzheimer's patients, the thinking goes, the mitochondria in neurons stop working properly. As a result they are unable to generate as much energy for neurons, which starve and die with no way to replenish them. But how mitochondria in neurons decline with age is largely unknown.

Most mitochondrial proteins are encoded by genes in the cell nucleus before reaching their final destination in mitochondria. In 2009, researchers identified a non-coding region in a gene called TOMM40 that varies in length. The team found that the length of this region can help predict a person's Alzheimer's risk and age of onset. The researchers wondered if the length variation in TOMM40 was only part of the equation. They analyzed the corresponding gene region in gray mouse lemurs, teacup-sized primates known to develop amyloid brain plaques and other Alzheimer's-like symptoms with age. They found that in mouse lemurs alone, but not other lemur species, the region is loaded with short stretches of DNA called Alus. Found only in primates, Alus belong to a family of retrotransposons or "jumping genes," which copy and paste themselves in new spots in the genome. If the Alu copies present within the TOMM40 gene somehow interfere with the path from gene to protein, the researchers reasoned, they could help explain why mitochondria in nerve cells stop working.

When the researchers looked across the human genome, they found that Alus were more likely to be lurking in and around genes essential to mitochondria than in other protein-coding genes. Alus are normally held in check by clusters of atoms called methyl groups that stick to the outside of the DNA and shut off their ability to jump or turn genes on or off. But in aging brains, DNA methylation patterns change, which allows some Alu copies to re-awaken. The TOMM40 gene encodes a barrel-shaped protein in the outer membrane of mitochondria that forms a channel for molecules - including the precursor to amyloid - to enter. Researchers used 3D modeling to show that Alu insertions within the TOMM40 gene could make the channel protein it encodes fold into the wrong shape, causing the mitochondria's import machinery to clog and stop working. The TOMM40 gene is one example, but if Alus disrupt other mitochondrial genes, the same basic mechanism could help explain the initial stages of other neurodegenerative diseases too, including Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS).

Infection and Inflammation in Neurodegenerative Conditions

Increased levels of chronic inflammation accompany aging, and this drives faster progression of a range of age-related conditions, spurring greater damage and loss of function in tissues. Researchers here ask to what degree this is due to opportunistic infections and a weakened immune system rather than being caused by the more general dysfunction and overactivation of the aged immune system that would occur even absent such infections, the state known as inflammaging. Like many such investigations, this serves to emphasize the need for effective means to rejuvenate the age-damaged immune system, such as through clearing and recreating immune cell populations, restoring the thymus to youthful levels of activity, or replacing blood stem cells.

The immune system undergoes many changes with age that leaves the elderly more susceptible to infection, indeed older individuals are more vulnerable to bacterial or viral infections of the urinary or respiratory tract, with influenza-related morbidity also increased in this group. Sepsis, which is caused by severe infection, can also lead to permanent cognitive dysfunction, particularly in older individuals. Importantly, infectious burden in the elderly is associated with mini-mental state examination (MMSE) scores below 24, which indicate dementia. Unfortunately, the symptoms of infection often present atypically in this group and, as dementia patients are often unable to communicate their symptoms, diagnosis is difficult. To further complicate matters, bacterial resistance is often increased in older patients.

Individuals with Alzheimer's disease (AD) are even more vulnerable to the effects of peripheral infection. In a 10-year follow-up study, delirium (which is often caused by infection) correlated with an eightfold increase in dementia development. Furthermore, the cognitive capabilities of AD patients worsened significantly after an episode of delirium, which has been confirmed by others. Indeed poor health and viral burden have been linked with cognitive impairment and AD development in the elderly. It was found that the incidence of many infectious conditions such as pneumonia, lower respiratory tract, or urinary tract infections is higher in AD patients than healthy, age-matched controls. Previous studies have demonstrated that numerous infections over a 4-year period doubled the risk of AD development. Indeed cognitive decline has been observed just 2 or 6 months after a resolved peripheral infection, with an association between cognitive impairment and circulating proinflammatory cytokines.

The emerging evidence strongly indicates that infection has a significant role in the development of, and progression to, dementia, with a growing list of pathogens specifically associated with AD or amyloid-β deposition. This may be due in part to some of the changes that are known to occur to the immune system with age. One of the key changes in the adaptive immune system is the involution of the thymus, resulting in a dramatic decrease in the production of new T cells. With age, there is an overall decrease in naive T cells, and a corresponding increase in memory T cells. This is associated with a reduction in naive T cell diversity after the age of 65, with clonally expanded subsets of memory T cells often observed in this age group, which can occur from chronic or repeat infections. Together, this can limit the capacity of the individual to induce a sufficient immune response to new infectious challenges.

It is clear from the evidence that AD patients are more vulnerable to the effects of peripheral infection than their age-matched, healthy counterparts. Importantly, it is indisputable that many specific viral, bacterial, and fungal infections are associated with AD development, although whether these pathogens are a direct cause of dementia or instead are advantageous, infiltrating microorganisms that exacerbate the neuroinflammation already ongoing in these individuals remains to be confirmed. Importantly, the blood-brain barrier of AD patients is significantly leakier than in healthy subjects, which facilitates infiltration of peripheral immune cells and possibly these infectious pathogens. Together, this demonstrates the critical need for early detection and treatment of infections in the elderly and in those with dementia. As infectious diseases can present atypically in this group, frequent screening and vaccination are key to preventing infection-related deterioration of cognition until new therapies are established that can protect the elderly from these unnecessary insults.

GABA and Retinal Regeneration in Zebrafish

Researchers here investigate the mechanisms by which zebrafish can regenerate their retina, a form of regrowth that does not occur in mammals. This is one part of much broader efforts to understand whether or not the basis for the proficient regeneration of organs observed in zebrafish also exists in mammals, part of a shared evolutionary heritage from common ancestors, but suppressed in mammalian species. There is at this point no real consensus on the odds, nor enough information to estimate how hard it might be to safely coerce mammalian tissues into zebrafish-like regenerative prowess.

If you were a fish and your retina was damaged, it could repair itself and your vision would be restored in a few weeks. Sadly, human eyes don't have this beneficial ability. However, new research into retinal regeneration in zebrafish has identified a signal that appears to trigger the self-repair process. And, if confirmed by follow-up studies, the discovery raises the possibility that human retinas can also be induced to regenerate, naturally repairing damage caused by degenerative retinal diseases and injury, including age-related macular degeneration and retinitis pigmentosa. "The prevailing belief has been that the regeneration process in fish retinas is triggered by secreted growth factors, but our results indicate that the neurotransmitter GABA might initiate the process instead. All the regeneration models assume that a retina must be seriously damaged before regeneration takes place, but our studies indicate that GABA can induce this process even in undamaged retinas."

It turns out that the structure of the retinas of fish and mammals are basically the same. Although the retina is very thin - less than 0.5 millimeters thick - it contains three layers of nerve cells: photoreceptors that detect the light, horizontal cells that integrate the signals from the photoreceptors and ganglion cells that receive the visual information and route it to the brain. In addition, the retina contains a special type of adult stem cell, called Müller glia, that span all three layers and provide mechanical support and electrical insulation. In fish retinas, they also play a key role in regeneration. When regeneration is triggered, the Müller glia dedifferentiate (regress from a specialized state to a simpler state), begin proliferating, and then differentiate into replacements for the damaged nerve cells. Müller glia are also present in mammalian retinas, but don't regenerate.

Reseachers designed a series of experiments with zebrafish which determined that high concentrations of GABA in the retina keep the Müller glia quiescent and that they begin dedifferentiating and proliferating when GABA concentrations drop. They tested their hypothesis in two ways: By blinding zebrafish and injecting them with drugs that stimulate GABA production and by injecting normal zebrafish with an enzyme that lowers the GABA levels in their eyes. When the biologists injected drugs that kept GABA concentrations in the retinas of newly blinded fish at a high level, they found that it suppressed the regeneration process. On the other hand, when they injected an enzyme that lowers GABA levels in the eyes of normal fish, they found that the Müller glia began dedifferentiating and proliferating, the first stage in the regeneration process.

"Our theory is that a drop in GABA concentration is the trigger for regeneration. It initiates a cascade of events that includes the activation of the Müller glia and the production of various growth factors that stimulate cell growth and proliferation. If we are correct, then it might be possible to stimulate human retinas to repair themselves by treating them with a GABA inhibitor. Last month a paper was published that reports GABA levels play a central role in the regeneration of pancreas cells. We now have three instances where GABA is involved in regeneration - the hippocampus, the pancreas, and the retina - so this could be an important, previously unknown role for the neurotransmitter."

A Recent Example of Progress in the Quality of Bone Tissue Engineering

The state of the art in tissue engineering generally involves some form of biodegradable gel scaffolding material, a supply of patient-matched cells to populate that scaffold, and the delivery of a mix of proteins to induce growth and steer cells towards other desired behaviors. This effort to regrow sections of the skull is an example of the type:

A team of researchers repaired a hole in a mouse's skull by regrowing "quality bone," a breakthrough that could drastically improve the care of people who suffer severe trauma to the skull or face. The work was a resounding success, showing that a potent combination of technologies was able to regenerate the skull bone with supporting blood vessels in just the discrete area needed without developing scar tissue - and more rapidly than with previous methods. Injuries or defects in the skull or facial bones are very challenging to treat, often requiring the surgeon to graft bone from the patient's pelvis, ribs, or elsewhere. But if all goes well with this new approach, it may make painful bone grafting obsolete.

In the experiment, the researchers harvested skull cells from the mouse and engineered them to produce a potent protein to promote bone growth. They then used a hydrogel, which acted like a temporary scaffolding, to deliver and contain these cells to the affected area. It was the combination of all three technologies that proved so successful. Using calvaria or skull cells from the subject meant the body didn't reject those cells. The protein, BMP9, has been shown to promote bone cell growth more rapidly than other types of BMPs. Importantly, BMP9 also appeared to improve the creation of blood vessels in the area. Being able to safely deliver skull cells that are capable of rapidly regrowing bone in the affected site, in vivo as opposed to using them to grow bone in the laboratory, which would take a very long time, promises a therapy that might be more surgeon friendly, and not too complicated to scale up for the patients.

The scaffolding is a material based on citric acid and called PPCN-g, is a liquid that when warmed to body temperature becomes a gel-like elastic material. "When applied, the liquid, which contains cells capable of producing bone, will conform to the shape of the bone defect to make a perfect fit. It then stays in place as a gel, localizing the cells to the site for the duration of the repair. As the bone regrows, the PPCN-g is reabsorbed by the body. What we found is that these cells make natural-looking bone in the presence of the PPCN-g. The new bone is very similar to normal bone in that location. A reconstruction procedure will be a lot easier when you can harvest a few cells, make them produce the BMP9 protein, mix them in the PPCN-g solution, and apply it to the bone defect site to jump-start the new bone growth process where you want it."


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