Resarchers found that, compared to nonrunners, runners tended to live about three additional years, even if they run slowly or sporadically and smoke, drink or are overweight. No other form of exercise that researchers looked at showed comparable impacts on life span. The findings come as a follow-up to a study done three years ago, in which a group of distinguished exercise scientists scrutinized data from a large trove of medical and fitness tests. That analysis found that as little as five minutes of daily running was associated with prolonged life spans.

Over all, this new review reinforced the findings of the earlier research, the scientists determined. Cumulatively, the data indicated that running, whatever someone's pace or mileage, dropped a person's risk of premature death by almost 40 percent, a benefit that held true even when the researchers controlled for smoking, drinking and a history of health problems such as hypertension or obesity. Perhaps most interesting, the researchers calculated that, hour for hour, running statistically returns more time to people's lives than it consumes. Figuring two hours per week of training, since that was the average reported by runners in the earlier study, the researchers estimated that a typical runner would spend less than six months actually running over the course of almost 40 years, but could expect an increase in life expectancy of 3.2 years, for a net gain of about 2.8 years. In concrete terms, an hour of running statistically lengthens life expectancy by seven hours, the researchers report.

The gains in life expectancy are capped at around three extra years, however much people run. The good news is that prolonged running does not seem to become counterproductive for longevity, according to the data. Improvements in life expectancy generally plateaued at about four hours of running per week, but they did not decline. Meanwhile, other kinds of exercise also reliably benefited life expectancy, the researchers found, but not to the same degree as running. Walking, cycling and other activities, even if they required the same exertion as running, typically dropped the risk of premature death by about 12 percent. Why running should be so uniquely potent against early mortality remains uncertain, but it raises aerobic fitness, and high aerobic fitness is one of the best-known indicators of an individual's long-term health.

Running is a popular and convenient leisure-time physical activity (PA) with a significant impact on longevity. In general, runners have a 25-40% reduced risk of premature mortality and live approximately 3 years longer than non-runners. Recently, specific questions have emerged regarding the extent of the health benefits of running versus other types of PA, and perhaps more critically, whether there are diminishing returns on health and mortality outcomes with higher amounts of running. This review details the findings surrounding the impact of running on various health outcomes and premature mortality, highlights plausible underlying mechanisms linking running with chronic disease prevention and longevity, identifies the estimated additional life expectancy among runners and other active individuals, and discusses whether there is adequate evidence to suggest that longevity benefits are attenuated with higher doses of running.

This recent study builds upon a previous finding that when one part of the body suffers an injury, adult stem cells in uninjured areas throughout the body enter a primed or "alert" state. Alert stem cells have an enhanced potential to repair tissue damage. In this new study, researchers identified a signal that alerts stem cells and showed how it could serve as a therapy to improve healing. Searching for a signal that could alert stem cells, the researchers focused their attention on the blood. They injected blood from an injured mouse into an uninjured mouse. In the uninjured mouse, this caused stem cells to adopt an alert state. The researchers identified the critical signal in blood that alerted stem cells: an enzyme called Hepatocyte Growth Factor Activator (HGFA). In normal conditions, HGFA is abundant in the blood, but inactive. Injury activates HGFA, so HGFA signaling can alert stem cells to be ready to heal.

Leveraging this discovery, the researchers asked the question: What happens if HGFA alerts stem cells before an injury occurs? Does this improve the repair response? They injected active HGFA into mice that received either a muscle or skin injury a couple of days later. The mice healed faster, began running on their wheels sooner and even regrew their fur better than mice that did not receive the HGFA booster. These findings indicate that HGFA can alert many different types of stem cells, rousing them from their normal resting or "quiescent" state, and preparing them to respond quickly and efficiently to injury. "This work shows that there are factors in the blood that control our ability to heal. We are looking at how HGFA might explain declines in healing, and how we can use HGFA to restore normal healing."

Tissue damage induces the activation of quiescent stem cells, initiating a cascade in which stem cells enter the cell cycle, divide, and proliferate to generate the cells required to repair or regenerate damaged tissue. Stem cell activation is a limiting step in the process of tissue repair. In many stem cell pools, the first cell division following activation is slow and can take many days to complete, whereas subsequent cell divisions are much more rapid. Defects in stem cell activation, such as a lengthening in the time of first cell division or a failure in stem cells to activate, can result in significant impairments in the healing process. Little is known about the biologic regulation of stem cell quiescence and activation. Approaches to accelerate the rate-limiting step of stem cell activation could have broad therapeutic applications in regenerative medicine.

We previously reported an acceleration of the activation properties of quiescent stem cells in response to a prior injury, distant from the tissue in which the stem cells were residing. We described this regulation as a transitioning of stem cells from the G0 to the GAlert state of quiescence, where GAlert stem cells are poised to activate quickly in response to injury and to repair tissue damage more effectively. Because of the enhanced functional properties of GAlert stem cells, there may be clinical applications for factors that induce the GAlert state. However, the endogenous signals that stimulate the G0-to-GAlert transition of stem cells in response to distant injuries have not been previously described. Here, we show that a single systemic factor, hepatocyte growth factor activator (HGFA), is sufficient to induce the transition of multiple pools of stem cells into GAlert and that administration of HGFA to animals, prior to an injury, improves the subsequent kinetics of tissue repair.

For decades, researchers have studied the effects of young blood on ageing in mice through a technique called parabiosis, in which an old mouse is sewn together with a younger one so that they share a circulatory system. Until now, the rejuvenating properties of young blood had only been demonstrated in mouse-to-mouse transfers. Nevertheless, the work has inspired ongoing clinical trials by at least two companies in which elderly people are infused with blood from younger adult donors and then tested for physical improvements. In one of the clinical trials researchers have started testing plasma collected from the umbilical cords of newborn babies. Their goal is to find out how very young human blood might affect the symptoms of ageing.

Infusing this human plasma into the veins of elderly mice, they found, improved the animals' ability to navigate mazes and to learn to avoid areas of their cages that deliver painful electrical shocks. When the researchers dissected the animals' brains, they found that cells in the hippocampus - the region associated with learning and memory - expressed genes that caused neurons to form more connections in the brain. This didn't happen in mice treated with blood from older human donors.

The researchers then compared a slate of 66 proteins found in umbilical cord plasma to the proteins in plasma from older people, and to proteins identified in the mouse parabiosis experiments. They found several potential candidates, and injected them, one at a time, into the veins of old mice. The team then ran the animals through the memory experiments. Only one of these proteins, TIMP2, improved the animals' performance. It did not, however, result in regeneration of brain cells that are lost during normal ageing. Injections of human umbilical cord plasma lacking TIMP2 had no effect on memory. The researchers don't yet know how TIMP2, which is known to be involved in maintaining cell and tissue structure, exerts its effect on memory. And although it is expressed in the brains of young mice, TIMP2 has never before been linked to learning or memory. Researchers suspect that the protein functions as a 'master regulator' of genes involved in the growth of cells and blood vessels, and that increasing its levels affects many pathways simultaneously.

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown.

We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

Neoplastic disease is inextricably associated with aging. Five out of six cancer-related deaths occur in patients aged 60 years and older. However, the intimate nature of this association is yet to be fully clarified. An important concept emerging from the literature is that aging and cancer do not merely represent two chronologically parallel processes, but they share relevant pathogenetic mechanisms. Along these lines, in a recent study we have provided evidence to indicate that aging promotes the growth of pre-neoplastic cells through alterations imposed on the tissue microenvironment, i.e. by generating an age-associated, neoplastic-prone tissue landscape. Similarly, it has been reported that aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors; it was proposed that cell competition may in fact drive the emergence of oncogenically altered cells in a background of age-induced decline in tissue fitness, in a process that has been referred to as "adaptive oncogenesis".

The notion that age-associated tissue changes may play a direct role in the origin of neoplasia has far-reaching implications. It suggests that strategies aimed at modulating the rate of aging may have a direct impact on early and/or late steps of neoplastic disease, i.e. the quest for a longer lifespan may coincide, at least in part, with the goal to defer the occurrence of cancer.

A most effective and consistent means to delay aging is by reducing caloric intake compared to ad libitum (AL) feeding. Caloric restriction (CR) is the most studied and reproducible non-genetic intervention known to extend lifespan in organisms ranging from unicellular yeast to mammals, including non-human primates, although the latter observation is disputed. On the other hand, it is also well documented that CR exerts a beneficial effect on the incidence of chronic diseases related to old age, including cancer, consistent with the notion that changes occurring during the aging process may bear direct relevance to the pathogenesis of neoplasia. However, the precise mechanisms responsible for the CR-induced delay on carcinogenic process are yet to be identified.

Based on the above, in the present studies we tested the hypothesis that the modulatory effect of CR on age-associated neoplastic disease might be related, at least in part, to a CR-induced delay in the emergence of age-related tissue alterations promoting the growth of pre-neoplastic cells. Using a well characterized cell transplantation system in the rat, we report that when pre-neoplastic hepatocytes were infused in aged animals exposed to either AL or CR diet, their growth was significantly reduced in the latter group. Analysis of donor-derived cell clusters performed at 10 weeks post-transplant revealed a significant shift towards smaller class sizes in the group receiving CR diet. Clusters comprising more than 50 cells, including large hepatic nodules, were thrice more frequent in AL vs. CR animals. Incidence of spontaneous endogenous nodules was also decreased by CR. These results are interpreted to indicate that CR delays the emergence of age-associated neoplastic disease through effects exerted, at least in part, on the tissue microenvironment.

Understanding which molecular processes contribute to aging is critical to developing interventions capable of extending healthy human lifespan and delaying onset of age-associated diseases. A key step in this process is building a comprehensive model encompassing the range of genetic and environmental factors that influence lifespan and describing the complex interaction between these factors in an aging organism. Directly screening interventions for lifespan phenotypes in mammals is limited by long lifespans. Despite evolutionary distance and orders-of-magnitude differences in lifespan, processes that contribute to aging are sufficiently conserved that mechanistic knowledge gleaned from short-lived invertebrates can be beneficially applied to mammalian systems. Genetic screens in the nematode, Caenorhabditis elegans, have identified hundreds of genes capable of influencing lifespan.

An approach that is tractable in humans is to characterize systemic changes that occur during normal aging. This approach identifies traits that change with age or during age-associated disease and employs targeted studies to determine which play a causative role in aging. Early applications focused on easily measurable physiological traits, such as body weight or circulating molecules, but has now expanded into the '-omics' realm to provide systems-level insight into molecular changes that occur with age. As part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, we published a large meta-analysis of gene expression in human peripheral blood from 14,983 individuals representing ages across the adult lifespan. This study identified 1,497 genes with significantly different expression at different ages. Gene sets with a defined age-associated expression pattern provide information about molecular processes with altered activity during aging and provide a valuable diagnostic tool for determining individual biological rate of aging and predicting risk of age-associated disease, as demonstrated in follow-up analyses. On a gene-by-gene basis, differential expression alone is insufficient to distinguish between genes that play a causative role in aging and genes that merely respond to the altered physiological environment in an aging organism.

In this study, we selected the human genes with the most significant differential expression with age from the CHARGE meta-analysis and used RNAi to screen C. elegans orthologs for lifespan phenotypes. This selection criterion ensured that every gene identified in the lifespan screen was already of interest in the context of human aging. The short lifespan of C. elegans allowed genes capable of directly influencing lifespan to be rapidly identified and characterized. The resulting C. elegans candidate list was substantially enriched in genes for which knockdown extends lifespan. The five genes with the greatest impact on lifespan (more than 20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator.

Chronological age is a major risk factor for functional impairments, chronic diseases and mortality. However, there is still great heterogeneity in the health outcomes of older individuals. Some individuals appear frail and require assistance in daily routines already in their 70s whereas others remain independent of assistance and seem to escape major physiological deterioration until very extreme ages. In keeping with the unprecedented growth rate of the world's aging population, there is a clear need for a better understanding of the biological aging process and the determinants of healthy aging. Towards this aim, a quest for (biological) markers that track the state of biophysiological aging and ideally lend insights to the underlying mechanisms has been embarked upon.

During the past decades, extensive effort has been made to identify such aging biomarkers that, according to the stage-setting definition, are "biological parameters of an organism that either alone or in some multivariate composite will, in the absence of disease, better predict functional capability at some late age, than will chronological age". Later on, the American Federation for Aging Research (AFAR) formulated the criteria for aging biomarkers as follows: (1) It must predict the rate of aging. In other words, it would tell exactly where a person is in their total life span. It must be a better predictor of life span than chronological age. (2) It must monitor a basic process that underlies the aging process, not the effects of disease. (3) It must be able to be tested repeatedly without harming the person. For example, a blood test or an imaging technique. (4) It must be something that works in humans and in laboratory animals, such as mice. This is so that it can be tested in lab animals before being validated in humans.

However, to date, no such marker or marker combination has emerged. Moreover, the existence of such markers has been questioned, because the effects of many chronic diseases are inseparable from normal aging. The rate of biological aging can also vary across different tissues, and hence it may not be feasible to assume a measurable overall rate. Recently, however, several new biomarkers for biological aging have come into play. They can be separated into molecular (based on DNA, RNA, etc.) or phenotypic biomarkers of aging (clinical measures such as blood pressure, grip strength, lipids, etc.), although we include both types. The focus of this review is on novel biological age predictors, and we define them as markers that predict chronological age, or at least can separate "young" from "old". They should also be associated with a normal aging phenotype or a non-communicable age-related disease independent of chronological age in humans. Promising developments consider multiple combinations of these various types of predictors, which may shed light on the aging process and provide further understanding of what contributes to healthy aging. Thus far, the most promising new biological age predictor is the epigenetic clock; however its true value as a biomarker of aging requires longitudinal confirmation.

Researchers have identified a pathway that, when mutated, drives fibrosis in many organs of the body. The pathway underlies what have been considered somewhat disparate conditions, including scleroderma, idiopathic pulmonary fibrosis, liver cirrhosis, kidney fibrosis and more, the researchers found. These diseases are often incurable and life-threatening. Importantly, the researchers were able to reverse lung fibrosis in mice by administering an antibody called anti-CD47 now being tested as an anti-cancer treatment. "The variety of diseases caused by overproduction of fibroblasts has made finding a common root cause very challenging, in part because there has been no good animal model of these conditions. Now we've shown that activating a single signaling pathway in mice causes fibrosis in nearly all tissues. Blocking the CD-47 signal, which protects cancer cells from the immune system, can also ameliorate these fibrotic diseases even in the most extreme cases."

Fibrosis occurs when the body's normal response to injury goes astray. An overenthusiastic or inappropriately timed proliferation of cells called fibroblasts, which make up the connective tissue surrounding and supporting all of our organs, can lead to many devastating diseases. In a mouse model she developed, researchers found that fibroblasts were producing unusually high levels of an important signaling molecule called c-Jun. C-Jun is a transcription factor that drives the production of many proteins involved in critical cellular processes. It's been implicated in many types of human cancer. In the current study, researchers investigated c-Jun expression levels in 454 biopsied tissue samples from patients with a variety of fibrotic diseases. They found that in every case the fibroblasts from the patients with fibrosis expressed higher levels of c-Jun than did control fibroblasts collected from people with nonfibrotic conditions.

Blocking the expression of c-Jun in laboratory-grown lung fibroblasts collected from people with idiopathic pulmonary fibrosis substantially decreased the proliferation of these cells, but not of lung fibroblasts collected from people without fibrosis. Furthermore, mice genetically engineered to overexpress c-Jun in all their body's tissues developed fibrosis in nearly every organ, including lung, liver, skin and bone marrow. "We found that c-Jun overexpression and over-activation is a unifying mechanism in many types of fibrosis. But an even more exciting part of the story is the fact that we observed that the diseased, c-Jun-expressing fibroblasts are surrounded by immune cells called macrophages. This is reminiscent of what's often seen in human cancers." Over the past eight years, researchers have shown that many human cancers evade the immune system by expressing high levels of a protein called CD47 on their surfaces. Blocking this protein with an anti-CD47 antibody restores the ability of the macrophages to gobble the cancer and has proven to be a promising treatment in animal models of the disease. Anti-CD47 antibody is currently undergoing a phase-1 clinical trial in humans with advanced solid tumors.

When researchers treated mice with c-Jun-induced lung fibrosis with daily injections of anti-CD47 antibody, the animals exhibited significantly better lung function, lived longer than their peers and cleared the fibrosis. The researchers plan to investigate whether any patients in the phase-1 trial of the anti-CD47 antibody also suffered from any fibrotic conditions. If so, they are eager to learn whether they experienced any relief as a result of participating in the trial. "We have hit upon something unique in this study. We identified a highly activated pathway that causes fibrosis in many tissues in mice, and we've showed that treating the animals with an anti-CD47 antibody reverses the fibrosis. We're hopeful that this could be a potential treatment for people with many types of fibrotic conditions."

Autophagy is a self-degradative, highly regulated process that involves the non-specific degradation of cytoplasmic macromolecules and organelles via the lysosomal system. There are three different autophagic pathways based on the mechanisms for delivery of cargo to lysosomes: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Macroautophagy (herein referred to as autophagy) is the major lysosomal pathway for the turnover of cytoplasmic components. Emerging evidence indicates that autophagy protects cells by removing long-lived proteins, aggregated protein complexes, and excess or damaged organelles. Defects in autophagy, therefore, are associated to various pathological conditions within organisms, including tumorigenesis, defects in developmental programs and the build-up of toxic, protein aggregates involved in neurodegeneration such as Amyloid precursor protein (APP). It has been recently suggested that the progressive age-related decline of autophagic and lysosomal activity may also be responsible for the continuous intraneuronal accumulation of lipofuscin, or "age pigment".

For this study, we aimed to investigate the expression of autophagic markers and the accumulation of pathologic proteins such as APP and lipofuscin in aged bovine brains. Microscopic findings in the brains of our aged bovines are similar to those previously described in old animals of other species as well as in cattle. In this study, the age-dependent intraneuronal accumulation of lipofuscin is one of the most striking features of aged brains. This finding is not actually new, as it has been described for more than 150 years. In the past, lipofuscin was generally thought to be an innocent end product of oxidation which has no significant influence on cellular activities, but in the last decade several authors have investigated about the possible detrimental and pathogenic potential of this material.

The so-called "mitochondrial-lysosomal axis theory of aging" tries to explain the possible relationship between lipofuscin accumulation, decreased autophagy, increased Reactive Oxygen Species (ROS) production, and mitochondrial damage in senescent long-lived postmitotic cells. According to this theory, in senescent cells lysosomal enzymes are directed towards the plentiful lipofuscin-rich lysosomes and, subsequently, they are lost for effective autophagic degradation because lipofuscin remains non-degradable. The consequences are a progressive impairment of autophagy and the gradual accumulation of damaged mitochondria, other organelles and misfolded proteins that lead to neurodegeneration. Unfortunately, our results cannot support a direct association between lipofuscin accumulation and autophagy impairment in aged bovine brains. According to recent scientific literature, we can only hypothesize that progressive and severe lipofuscin accumulation may irreversibly lead to functional decline and death of neurons by diminishing lysosomal degradative capacity and by preventing lysosomal enzymes from targeting to functional autophagosomes.

Further studies are indeed necessary to better understand how lipofuscin accumulation can influence the neuronal autophagic and apoptotic pathways in bovine brains. It would be interesting to perform double-staining techniques in order to show whether lipofuscin is directly related to autophagic and apoptosis markers and/or to pathologic protein deposition. Unfortunately, to our knowledge, a specific antibody for lipofuscin is not available since this complex substance is mainly composed of cross-linked protein and lipid residues. Alternatively, combined histochemical and immunohistochemical staining protocols can be performed to simultaneously localize lipofuscin and the antigen of interest. However, since lipofuscin progressively accumulates throughout the life of neurons, this combined immunohistochemical/histochemical protocol is not perfectly indicated to investigate the mechanism and relative timing of intraneuronal lipofuscin accumulation and the deposition of other proteins. Primary cultured neuronal cells exhibit, in vitro, a variety of features that are frequently observed in physiologically aged neurons in vivo, including lipofuscin accumulation. Thus, long-term aging culture of primary cultured neurons would be a remarkable model to unravel, at least in part, the molecular mechanisms behind lipofuscin accumulation and its pathological effects on neuronal cells.

Caenorhabditis elegans has been an invaluable experimental organism for the discovery and characterization of conserved pathways that extend lifespan. In particular, reduced signaling through the stress and nutrient-sensing insulin/insulin-like growth factor 1 (IGF-1) pathway was first shown to double the lifespan of C. elegans and was later found to increase the longevity of other species, including mammals. C. elegans with partial loss-of-function mutations in daf-2, the C. elegans insulin/IGF-1-receptor gene, not only live longer but also maintain more youthful characteristics, such as active movement, neuronal function, and memory, indicating an extension of healthspan as well as lifespan. However, a recent study followed the functional ability of daf-2 mutants and found that the daf-2 healthspan, although chronologically longer than that of the wild-type, did not scale with lifespan, resulting in a disproportionately extended period of age-related decrepitude. This report was disconcerting because such an outcome would be undesirable in a human society, where population aging has already increased healthcare costs substantially. It also brought into question the validity of C. elegans as a model organism to study healthy life extension.

In this study, we set out to accomplish three goals: to undertake a quantitative large-scale analysis to corroborate the reported disproportionately extended end-of-life decrepitude in a daf-2 mutant, to determine whether this phenotype could be due to behavioral particularities of the specific daf-2 allele that was examined, and, if not, to elucidate the cause of this apparently undesirable phenotype. We found that two very different daf-2 mutants both remain active longer and age more slowly than the wild-type, at least through mid-life, but then go on to stay alive but decrepit for a long time. We wanted to understand what might cause this extended decrepitude. Theoretically, eliminating a cause of death that kills relatively young individuals would result in a population's growing older and frailer.

We wondered whether resistance to bacterial toxicity might play a role. We measured bacterial colonization of a daf-2 mutant. Colonization of the upper digestive tract was delayed and never reached the same maximum as in the wild-type. This finding is consistent with the idea that resistance to colonization allows daf-2 mutants to survive into old age. Why bacterial colonization occurs in old C. elegans and how exactly it causes death remains unknown. Decreased immune function with age could contribute to bacterial accumulation and proliferation, and daf-2 mutants have higher expression of some antimicrobial genes that curtail the rate of bacterial proliferation in the intestine. If reduced risk of death due to bacterial colonization allows daf-2 mutants to live long enough to become decrepit, then eliminating bacterial colonization as a cause of "premature" death should allow wild-type worms, too, to live long enough to enter a state of end-of-life decrepitude. To test this hypothesis, we fed wild-type animals bacteria killed by gentamicin from the time of hatching. Using killed bacteria as a food source extended the wild-type lifespan by 40%. Eliminating bacterial colonization as a cause of death in wild-type worms copied the extended period of decrepitude seen in daf-2 mutants.

In summary, we find that the level of bacterial colonization predicts wild-type lifespan. The extent of colonization is significantly greater in the wild-type than in daf-2 mutants, and eliminating colonization in wild-type animals allows them to avoid an early death; instead, they remain alive for a longer time in a decrepit, aged state, just like daf-2 mutants. Therefore, we conclude that a beneficial trait (resistance to bacterial colonization) can explain the extended end-of-life frailty of daf-2 mutants. Surviving the hazard from bacterial colonization allows these mutants to grow biologically older and more decrepit than end-of-life wild-type animals. Together, these findings support the argument that C. elegans daf-2 mutants are valuable for studying healthy lifespan extension. daf-2 mutants live longer because of a two-part mechanism: a slower rate of aging (leading to extension of healthspan) and an increased ability to resist death due to bacterial colonization (leading to extension of decrepitude). More generally, the results presented here show how the healthspan of an organism can be affected in opposite ways at different times of life by an intervention that both decreases the rate of aging and also mitigates a disease that kills old individuals. This is important to keep in mind when seeking to develop interventions that act by different demographic mechanisms to increase human lifespan.

Your work focuses on computational medicine, how would you explain this relatively new field of science to our readers?

Computational biomedicine is a very broad field of research, where computational methods and tools are applied for diagnosis, treatment and research. The field has been around since the invention of electronic analytical equipment, but in recent years it got a major boost due to the availability in Big Data, increases in computing power, breakthroughs in machine learning and convergence of the many fields of science and technology.

You are the CEO of Insilico Medicine. What are the main goals of the company for the next 5 years? Can we expect breakthroughs in personalised medicine?

Our long-term goal is to continuously improve human performance and prevent and cure the age-related diseases. In 5 years we want to build a comprehensive system to model and monitor the human health status and rapidly correct any deviations from the ideal healthy state with lifestyle or therapeutic interventions. Considering what we already have, I hope that we will be able to do it sooner than in 5 years. One reason why we can manage over 170 projects is because we use agile development practices and approach every project as a software development project. We treat aging as a salami, constantly "cutting" thin slices and I think we are halfway through.

In 5 years you can definitely expect breakthroughs in personalized medicine and we are not the only company working in the field, so there will be many breakthroughs on the many fronts. The main breakthroughs I can promise from Insilico are in the area of multi-modal biomarkers of aging, where we take as much data available for an individual from simple pictures and regular blood tests to very expensive molecular and imaging data and turn it into a model, which can be used to make a broad range of predictions, recommendations and treatments. We are entering the era of personalized drug discovery and regenerative medicine.

One of our major contributions to the field was the application of deep neural networks for predicting the age of the person. People are very different and have different diseases. But if you want to find just one feature, which is biologically relevant and can be predicted using many data types - it is the person's date of birth. So we build all kinds of predictors of chronological age and then look at what features and at what levels are most important and can be used to infer causality and be targeted with interventions. I think that this approach is novel and will result in many breakthroughs.

How do you decide what projects to get involved in?

The way we prioritize projects at Insilico Medicine is by looking at the number of quality-adjusted life years (QALY) each project can generate. Most pharmaceutical companies, governments, and philanthropists do not realize that aging research generates the maximum number of QALY for the resources spent. It is the most altruistic cause and the most effective investment. If you add just one year of life to everyone on the planet, you generate over 7 billion QALY. The average reasonable cost per QALY is around 50,000. So it is possible to generate several hundred trillion in value by extending life of everyone on the planet with a simple intervention.

What is your estimate, when we could expect the first powerful treatment to slow down aging appear on the market?

I think that there are several very powerful treatments that are already available on the market and to get the extra 10-20 years or even more we just need to devise a way to turn these into therapeutic regimens. I think that a comprehensive regimen involving metformin, targeted rapalogs, senolytics, anti-inflamatory agents, aspirin, NAC, ACE inhibitors, beta-blockers, PDE5, PCSK9 inhibitors, NAD+ activators and precursors in combination with the regenerative medicine procedures and also a set of cosmetic and lifestyle interventions could easily add 20 years to our life span. And I am sure that some people are already trying these interventions on themselves. Unfortunately, nobody is tracking this data.

Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions.

The first senolytic drugs, compounds that selectively eliminate senescent cells by causing apoptosis, were discovered using a hypothesis-driven approach. This approach was based on the observation that senescent cells are resistant to apoptosis, suggesting senescent cells have up-regulated pro-survival pathways that protect them from their own pro-apoptotic SASP. Up-regulation of these Senescent Cell Anti-apoptotic Pathways (SCAPs) might be related to senescence-associated mitochondrial dysfunction (SAMD). An essential part of SAMD appears to be a decrease in mitochondrial membrane potential related to mitochondrial membrane permeabilization. SAMD could explain why senescent cells depend on upregulated pro-survival pathways and why they are more sensitive to drugs that interfere with these SCAP pathways than non-senescent cells.

The first SCAPs were identified through expression profiling of senescent vs. non-senescent human cells and confirmed in RNA interference studies. Drugs that target these SCAPs were tested for senolytic activity. The tyrosine kinase inhibitor, dasatinib (D) and the flavonoid, quercetin (Q), were shown to induce apoptosis in senescent cells. Ten months later, two groups simultaneously reported that navitoclax (N; ABT-263), which targets components of the Bcl 2 pathway, is senolytic. Recently, the specific BCL-XL inhibitors A1331852 and A1155463, were found to be senolytic. Fisetin, related to Q, was discovered to be senolytic. Fisetin is an especially promising candidate because of its favorable side-effect profile. Piperlongumine, which is also related to Q, was noted to be senolytic in vitro in some senescent cell types. None of the individual agents reported so far selectively induces apoptosis of all senescent cell types. N, A1155463, and possibly A1331852 appear to be more toxic than D, Q, piperlongumine, or fisetin. A number of additional senolytic drugs are currently being developed. Some of the most promising senolytic agents are already being moved through preclinical studies towards clinical application.

To conduct clinical trials with senolytics, it will be important to have ways to track changes in senescent cell burden. It might be feasible to do so using biopsies, blood assays, other body fluids, and imaging, but more research on developing and optimizing assays needs to be done and reported. Complicating matters, the definition of cellular senescence is somewhat vague, particularly since several potentially pro-inflammatory cell types, such as macrophages or osteoclasts as well as pre-cancerous or cancer cells share many characteristics of senescent cells and could arguably be the same as what are currently regarded as being senescent cells. Few tissue assays are very sensitive or specific for senescent cells. Work needs to be done to establish, optimize, and validate these assays. Novel assays, such as of the microvesicles shed into blood or urine by senescent cells, need to be developed and optimized for use in clinical trials of senolytic drugs.

Healthspan, lifespan, or other very long-term potential endpoints for clinical trials of interventions that target basic aging processes, including SASP-inhibitors or senolytics, would be difficult or next to impossible to study for reasons that are obvious, as would endpoints occurring in old age as a consequence of beginning to administer a drug in adulthood or middle-age. Initial trials of senolytics or other agents that target fundamental aging processes will need to test effects on endpoints that can be measured weeks to a couple of years after initiating treatment. Furthermore, because the risk:benefit ratio must favor benefits for the ethical conduct of clinical trials, new interventions would have to be tested in situations in which side-effects would be considered to be acceptable. In diseases for which no effective treatment is available, some side effects may be acceptable in individuals who are already symptomatic or who are almost certain to become symptomatic within a short time. If any consequential side effects are anticipated, the treatment would also need to address a problem that would cause serious harm if left untreated.

There is a possibility that senolytics and SASP inhibitors could be transformative, substantially benefiting the large numbers on patients with chronic diseases and enhancing healthspan. That said, as this is a very new treatment paradigm, there are many obstacles to overcome. Treatments that appear to be highly promising in mice frequently fail once clinical trials start, with lack of effectiveness in humans compared to mice related to the unique aspects of human biology, unforeseen side-effects, and a host of other issues. At least one reassuring advantage of targeting cellular senescence is the conservation of fundamental aging mechanisms such as senescence across mammalian species. In diseases like Alzheimer's dementia, atherosclerosis, or non-injury-related osteoarthritis, which do not occur naturally in mice, translation from genetically- or surgically-induced mouse models of these conditions to humans is more likely to fail than conditions that are more evolutionarily conserved, such as aging. Furthermore, unlike the situation for developing drugs to eliminate infectious agents or cancer cells, not every senescent cell needs to be eliminated to have beneficial effects. Unlike microbes or cancer cells, senescent cells do not divide, decreasing risk of developing drug resistance and, possibly, speed of recurrence. With respect to risk of side-effects, single or intermittent doses of senolytics appear to alleviate at least some age- or senescence-related conditions in mice. This suggests that intermittent treatment may eventually be feasible in humans.

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Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown.

Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ.

Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region - but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RIα subunit was largely removed from, while PKA RIIα and RIIβ are enriched at, the NMJ - again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RIα and reduced PKA RIIα at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ. This knowledge could inform useful targets for prevention and therapy of age-related decline in muscle function.

Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown.

NFTs do not appear to be the main toxic entities leading to disease. In Alzheimer's disease, tau pathology and neuronal cell loss coincide in the same brain regions, and as brain dysfunction progresses, NFTs are found in greater anatomical distributions. However, the role of NFTs in the progression of the disease is poorly understood. Compared to non-demented controls, Alzheimer's brains exhibit up to 50% of neuronal loss in the cortex, exceeding the number of NFTs. In addition, neurons containing NFTs are functionally intact in vivo and have been found in brains of cognitively normal individuals. Further, intra-neuronal NFTs do not affect post-synaptic function and signaling cascades responsible for long-term synaptic plasticity, suggesting that synaptic deficits cannot be attributed to NFTs.

While evidence indicates that these deposits are not toxic, many studies suggest that the tau oligomer, an intermediate entity, is likely responsible for disease onset. Hyper-phosphorylated tau assembles into small aggregates known as tau oligomers in route of NFT formation. As hyper-phosphorylated tau dislodges from microtubules, its affinity for other tau monomers leads individual tau to bind each other, forming oligomeric tau, an aggregate. These tau oligomers potentiate neuronal damage, leading to neurodegeneration and traumatic brain injury. As these granular tau oligomers fuse together, they form tau fibrils, which ultimately form NFTs. These steps hint that tau oligomers may be involved in neuronal dysfunction prior to NFT formation.

When tau oligomers, rather than tau monomers or fibrils, are injected into the brain of wild-type mice, cognitive, synaptic, and mitochondrial abnormalities follow. Additionally, studies have discovered that aggregated tau inhibits fast axonal transport in the anterograde direction at all physiological tau levels, whereas tau monomers have had no effect in either direction. This suggests that monomers are not the toxic entity either. Most noteworthy, tau oligomers induce endogenous tau to misfold and propagate from affected to unaffected brain regions in mice, whereas fibrils do not. This indicates that tauopathies progress via a prion-like mechanism dependent upon tau oligomers. With this concept, tau may be able to translocate between neurons and augment toxic tau components; in fact, evidence suggests probability of tau oligomer propagation between synaptically connected neurons. If true, then pathology begins in a small area and becomes symptomatic as it spreads to other areas of the brain.

Discovering the pathological role of tau oligomers within the brain along with related mechanisms of cellular tau oligomer secretion, propagation, and uptake will allow for a better understanding of tauopathies. Further, mitochondrial dysfunction caused by internalized tau oligomers may play an important role in pathogenesis. Admittedly, little is known regarding cellular tau oligomer release. Yet with greater knowledge regarding disease pathogenesis, better therapeutic approaches can be generated. We hypothesize that preventing tau oligomers from cellular release and uptake will relieve some toxic effects induced by tau oligomers in tauopathies.