A certain immune reaction is the key, not to slowing atherosclerosis as cholesterol-lowering drugs do, but instead to reversing a disease that gradually blocks arteries to cause heart attacks and strokes. The study in mice focuses on reversing the effects of "bad cholesterol," which is deposited into the walls lining blood vessels in levels influenced by both genetics and a person's diet. By the fourth decade of life, and thanks to the chronic reaction to cholesterol, most people have inflamed "wounds" in their arteries, called plaques, which when severe enough can rupture to cause blood clots that block arteries. "Even the latest, most potent cholesterol-lowering drugs, PCSK9 inhibitors, let alone widely used statins, cannot fully reverse damage done to arteries over time. We need the next generation of drugs to go beyond cholesterol lowering to address the immune reaction to accumulated cholesterol, and to dismantle plaques as part of reversing or regressing mature disease."

Once deposited into arteries, bad cholesterol - known to physicians as low density lipoprotein - triggers the body's immune system, which is meant to destroy invading microbes but can drive inflammatory disease in the wrong context. Immune cells in the bloodstream called monocytes swarm to cholesterol deposits, and become either inflammatory or healing cell types based on signals there. In situations where disease is worsening in a plaque, past studies have shown that monocytes become M1 macrophages that amplify immune responses, increase inflammation, and secrete enzymes that gnaw at plaques until they rupture. The current study confirmed that monocytes arriving in plaques where disease is regressing instead become M2 "healing" macrophages, which dampen inflammation and prevent the ruptures that precede clotting.

When mice were engineered to lose the ability of monocytes to become M2 macrophages, they could no longer achieve normal disease regression. By surgically transplanting plaques from diseased mice into the arteries of healthy mice, the research team brought about dramatic drops in cholesterol levels. This drop has been shown to trigger a second benefit in mice, where monocytes automatically become M2 instead of M1 macrophages as plaques rapidly regress. It is not known whether cholesterol lowering alone triggers this M2 switch in humans, but new imaging techniques may soon be able to detect changes in the type and number of macrophages in plaques. In the meantime, if researchers learn how to boost the M2 switch, a number of clinical applications may become possible just as methods arrive that can measure their success. "A race is underway to develop treatments that enhance the decision of human monocytes to become M2 macrophages in cases where the disease has not yet caused clot formation, at which point it becomes irreversible."

Using a number of mouse models of atherosclerosis regression, including the aortic arch transplant used in the present study, we have previously shown that aggressive lipid lowering promotes the resolution of plaque inflammation, which is characterized by a decreased content of macrophages and an increase in the level of markers of the M2 state. We now extend these findings to show that plaque regression and the attendant resolution of inflammation surprisingly require the recruitment of new monocytes, which assume the characteristics of M2 macrophages. Furthermore, contrary to the prevailing paradigm, the newly recruited monocytes are drawn from the Ly6Chi circulating subset, generally considered to be "inflammation-prone" precursors of M1 macrophages.

The characteristic rapid reversal of hyperlipidemia in mouse atherosclerosis regression models is likely to reduce the continuous stimulation of the plaque inflammatory response by atherogenic lipoproteins, but clearly is not sufficient for the resolution of inflammation. Based on our results, M2 enrichment must also occur, and how the change in lipoprotein environment causes this to happen also remains to be determined. Our finding that it depends on STAT6-dependent signaling in the newly recruited monocytes suggests that local factors in the regressing plaque stimulate this signaling pathway. STAT6 is activated by two key cytokines, IL-4 and IL-13. However, which of these cytokines is the main player, as well as their cellular source(s), in promoting plaque regression is unclear.

Though many questions remain, the present results provide insights into the dynamic nature of the inflammatory process and the role of Ly6Chi monocytes in plaques. These cells were previously thought to contribute only to plaque progression and inflammation, but are now shown here to be important in regression and inflammation resolution. One clinically relevant insight raised by our studies is that strategies that promote the accumulation of M2 macrophages in atherosclerotic lesions may be a promising approach toward promoting plaque regression, consistent with recent studies in mice in which treatment with IL-13- or IL-4-based therapy was protective against atherosclerosis progression.

A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in Parkinson's disease (PD) pathogenesis. In the central nervous system (CNS), the innate immune response is predominantly mediated by microglia and astrocytes. Microglia play a vital role in both physiological and pathological conditions. Microglia appear to be involved in several regulatory processes in the brain that are crucial for tissue development, maintenance of the neural environment and, response to injury and promoting repair. Similar to peripheral macrophages, microglia directly respond to pathogens and maintain cellular homeostasis by purging said pathogens, as well as dead cells and pathological gene products.

Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. When classically activated, microglia acquire the M1 phenotype, characterized by pro-inflammatory and pro-killing functions that serve as the first line of defense. The alternative M2 microglial activation state is involved in various events including immunoregulation, inflammation dampening, and repair and injury resolution.

Upon activation to the M1 phenotype, microglia elaborate pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD, and the distribution of microglial M1/M2 phenotypes depends on the stage and severity of the disease. Understanding stage-specific switching of microglial phenotypes and the capacity to manipulate these transitions within appropriate time windows might be beneficial for PD therapy. The transition from the M1 pro-inflammatory state to the regulatory or anti-inflammatory M2 phenotype is thought to assist improved functional outcomes and restore homeostasis. The induction of M1 phenotype is a relatively standard response during injury. For peripheral immune cells it is thought that M1 polarization is terminal and the cells die during the inflammatory response. Although a shift from M1 to the M2 phenotype is considered rare for peripheral immune cells, microglia can shift from M1 to M2 phenotype.

To inhibit the pro-inflammatory damage through M1 activation of microglia, its downstream signaling pathways could be targeted. The M1 phenotype is induced by IFN-γ via the JAK/STAT signaling pathway and targeting this pathway may arrest M1 activation. In fact, studies show that inhibition of the JAK/STAT pathway leads to suppression of the downstream M1-associated genes in several disease models. Another approach to suppress M1 activation would be to target the pro-inflammatory cytokines such as TNF-α, IL-1β and IFN-γ, and decrease its ability to interact with its receptors on other cell types. Alternatively, molecules with the capability to activate the anti-inflammatory M2 phenotype or promote the transition of pro-inflammatory M1 phenotype to anti-inflammatory M2 could be useful in the treatment of PD. Anti-inflammatory molecules such as IL-10 and beta interferons produce neuroprotection by altering the M1 and M2 balance.

The critical role of microglia in most neurodegenerative pathologies including PD is increasingly documented through many studies. Until recently, microglial activation in pathological conditions was considered to be detrimental to neuronal survival in the substantia nigra of PD brains. Recent findings highlight the crucial physiological and neuroprotective role of microglia and other glial cells in neuropathological conditions. Studies on anti-inflammatory treatments targeting neuroinflammation in PD and other diseases by delaying or blocking microglial activation failed in many trials due to the lack of a specific treatment approach, possibly the stage of disease and an incorrect understanding of mechanisms underlying microglial activation. With the updated knowledge on different microglial activation states, drugs that can shift microglia from a pro-inflammatory M1 state to anti-inflammatory M2 state could be beneficial for PD. The M1 and M2 microglial phenotypes probably need further characterization, particularly in PD pathological conditions for better therapeutic targeting. We support targeting of microglial cells by modulating their activation states as a novel therapeutic approach for PD.

Supercentenarians, such as Jeanne Calment who famously lived to be 122 years old, continue to fascinate scientists and have led them to wonder just how long humans can live. A study published last October concluded that the upper limit of human age is peaking at around 115 years. Now, however, a new study comes to a starkly different conclusion. By analyzing the lifespan of the longest-living individuals from the USA, the UK, France and Japan for each year since 1968, researchers found no evidence for such a limit, and if such a maximum exists, it has yet to be reached or identified.

"We just don't know what the age limit might be. In fact, by extending trend lines, we can show that maximum and average lifespans, could continue to increase far into the foreseeable future." Many people are aware of what has happened with average lifespans. In 1920, for example, the average newborn Canadian could expect to live 60 years; a Canadian born in 1980 could expect 76 years, and today, life expectancy has jumped to 82 years. Maximum lifespan seems to follow the same trend. Some scientists argue that technology, medical interventions, and improvements in living conditions could all push back the upper limit. "It's hard to guess. Three hundred years ago, many people lived only short lives. If we would have told them that one day most humans might live up to 100, they would have said we were crazy."

A recent analysis of demographic trends led to the claim that there is a biological limit to maximum human lifespan (approximately 115 years). Although this claim is not novel - others have also identified a biological 'barrier' at 115 years - the methodology that the authors used is. Here we show that the analysis does not allow the distinction between the hypothesis that maximum human lifespan is approximately 115 years and the null hypothesis that maximum lifespan will continue to increase. The central difficulty with this exercise is accurately extrapolating onwards from a limited, noisy set of data.

Beyond a plateauing of maximum life span, there are other different trajectories that maximum lifespan could follow over time if the null hypothesis (that maximum lifespan will continue to increase) were true, with maximum lifespans continuing to increase to an eventual future plateau or continuing to increase indefinitely. All three models appear equally consistent with the known maximum lifespan data used. How the authors differentiated between these possibilities is important. Their claim rests on their identification of a plateau in the ages of maximum lifespan beginning around 1995. They separated the data into two groups, 1968-1994 and 1995-2006, and modelled each group using linear regression. While the first partition shows a trend for increasing maximum lifespan, the second partition does not. It is this latter partition upon which their conclusions are largely based. This is problematic, because, even within a dataset showing an overall trend for an increase with time, normal variability can generate apparent plateaus and even temporary decreases over small intervals.

Furthermore, the authors do not describe how they identified the lifespan plateau, nor the partition site, indicating that these were products of casual visual inspection. This is a critical point for the validity of their argument because even slight changes to the assumptions that they made can notably alter the results of their analysis, with markedly different outcomes. In conclusion, the analyses do not permit us to predict the trajectory that maximum lifespans will follow in the future, and hence provide no support for their central claim that the maximum lifespan of humans is "fixed and subject to natural constraints". This is largely a product of the limited data available for analysis, owing to the challenges inherent in collecting and verifying the lifespans of extremely long-lived individuals.

The authors of the accompanying comment disagree with our finding of a limit to human lifespan. Although we thank them for alerting us to other work reporting a limit of around 115 years, we disagree with the arguments presented and remain confident in our results. We feel that the scenarios presented, although imaginative, are not informative. They argue that their three different models (which they extrapolate until the year 2300) are not statistically differentiable based on the data available. We used a data-driven approach to identify the trend in the maximum reported age at death (MRAD) by analysing actual data rather than arbitrary simulations; although the authors criticize us for visually inspecting our data, graphing data in order to evaluate the choice of model has long been acknowledged as a useful and important technique by statisticians. Taken together, and in the absence of solid statistical underpinning of various possible future scenarios, we feel that our interpretation of the data as pointing towards a limit to human lifespan of about 115 years remains valid.

The dramatic increase in average life expectancy has led to a rapid rise in the aging population across the globe. Age is a robust and independent risk factor for a range of non-communicable diseases like cancer, diabetes, cardiovascular disease, and neurodegenerative disease, and so it follows that this newfound increase in longevity creates a substantial burden in disease incidence and health care costs. Overwhelming evidence suggests that processes intrinsic to aging contribute to the pathogenesis of age-related diseases. Ongoing international efforts have made great strides in advancing our knowledge of the biology of aging and several "hallmarks" of aging have been identified that may play a causative role in the age-related increase in disease vulnerability.

These last few years have seen a shift in emphasis from the investigation of individual age-related diseases in isolation toward a broader context to define the basic biology of aging. The concept behind the recently coined pursuit of geroscience is that a strategy to delay the aging process itself would decrease vulnerability across the age-related disease spectrum leading to lower morbidity and comorbidity. Indeed the concept that aging might be a suitable drug target in a clinical context is gaining traction and there is considerable effort being applied to bring this idea to fruition. One of the most valuable tools in aging research is caloric restriction (CR), a proven intervention to delay aging and age-related disease. If we could understand what mechanisms are employed by CR to impinge on the aging process we could potentially identify causal networks that contribute to the increase in disease vulnerability as a function of normative aging.

To investigate the translatability of CR's beneficial effects from rodents to primates, three independent rhesus monkey studies were initiated in the late 1980s. The take home message from this joint initiative is that CR delays aging in primates, where lower food intake is associated with improvements in health and survival. The implications of this work are broader, first that aging in primates can be manipulated, supporting the concept that aging is a valuable target for intervention and eventual clinical application, and second, that the mechanisms recruited by CR to impinge on aging will likely have utility in the development of treatments to delay or abrogate age-related disease vulnerability.

With evidence that CR is effective in long-lived species the next question is whether its beneficial effects and mechanistic underpinnings are conserved in humans. The hallmarks of mammalian CR include lower adiposity, increased insulin sensitivity, favorable lipid profiles, and increased levels of the adipose-derived hormone adiponectin. Short-term studies of CR in humans have been conducted as part of the multicenter study CALERIE in 2 phases. In the first phase of CALERIE studies (CALERIE-I), the metabolic effects of 6 or 12 months of CR was evaluated in overweight individuals with a target level of restriction of 20-30%. Favorable changes in body weight, body composition, glucoregulatory function and serum risk factors for cardiovascular disease were reported in CR individuals. These outcomes were consistent with those reported for monkeys on CR. Overall, these studies are highly suggestive that CR's effect on aging is translatable to humans and confirm that nonhuman primates do indeed bridge the gap between human and rodent studies.

CR impinges on multiple signaling pathways that regulate growth, metabolism, oxidative stress response, damage repair, inflammation, autophagy, and proteostasis, to modulate the aging process. The relationship between calorie intake and longevity follows a U-shaped curve, dietary excess and malnutrition both negatively impact survival. Between the extremities there is an inverse linear relationship between lifespan and calorie/energy intake, suggesting that adaptive metabolism is a key component in the response to CR. Caloric restriction as an intervention is likely to be very difficult to implement in humans. Indeed the goal of CR research is to figure out how it works, not to promote it as a lifestyle. In order to gain the beneficial effects of CR without the restriction of calories, a number of nutraceuticals and established drugs are being explored as a means to mimic the effects of CR. The National Institute on Aging (NIA) has created the Interventions Testing Program (ITP) to investigate treatments with the potential to extend lifespan and delay age-related disease and dysfunction. To date several effective compounds have been identified some of which have been used in human clinical applications such as rapamycin (inhibitor of mTOR), metformin (activator of AMPK), and others that are only recently being applied in human studies such as resveratrol (activator of AMPK and SIRT1).

Aging research has entered a very exciting period where traditional scientific approaches to understanding the biology of aging are converging with clinical research and epidemiology. Technological advances in the last few decades have brought aging research to a place that could not even have been imagined back in the days when the establishment of the National Institute on Aging first officially recognized the science of aging. We have already seen the identification of genes and biomarkers associated with healthy aging and exceptional aging, and studies in laboratory animals have laid out a rich framework of factors that have established roles in regulation of longevity.

Outstanding questions include the molecular basis for the role of energy metabolism in aging. How do differences in mitochondrial function create vulnerability to disease? How do defects in mitochondrial efficiency and adaptation arise? To what extent do minor differences in energetic capacity or fuel utilization influence other cellular functions? What networks within the cell are responsive to these relatively small age-related changes? Another important avenue of investigation is the role of lipid metabolism in aging and disease vulnerability. Lipid transport and lipid handling are common themes in human and laboratory aging studies, and differences in lipid metabolism have been strongly implicated in the mechanisms of CR, but how does this translate to a change in disease vulnerability as a function of age?

Taking a broader view, it will be necessary to distinguish between events that are coincident with aging and those that are driving aging. Does aging arise first within discrete systems or is it orchestrated simultaneously across systems? To what extent are failures in individual processes such as repair or induction of senescence responsible for age-related disease vulnerability? To resolve these and other questions future directions must include synergistic collaborative efforts focused on aligning insights from human and laboratory aging studies. Caloric restriction research will also have a role to play, where interdisciplinary approaches can be brought to bear to determine the molecular details of CR's mechanisms and thereby identify the most promising candidate factors for targeted intervention.

Several explanations have been offered for how age contributes to cardiovascular disease. Aging is associated with the acquisition and exposure duration of other established risk factors for cardiovascular disease, including high systolic blood pressure and increased levels of low-density lipoprotein cholesterol. However, analyses that adjust for the concomitant burden of other risk factors consistently identify age as an independent predictor of cardiovascular disease. Modifiable risk factors account for only about 12% of the age effect in men and 40% in women. Thus, the aging process itself must promote cardiovascular risk, although the mechanisms that are involved are poorly understood.

Researchers now provide new insight into how aging can promote atherosclerosis and cardiovascular events in their investigation of a phenomenon termed clonal hematopoiesis of indeterminate potential, or CHIP. This condition is an age-related disorder characterized by the acquisition of somatic mutations in hematopoietic stem cells that confer on these cells a selective advantage. As a consequence, instead of the normal polyclonal generation of blood cells, mutation-containing clones expand over time and make up an increasing percentage of the stem cells and their progeny and may include granulocytes, lymphocytes, and monocytes. CHIP is rarely found in patients who are younger than 40 years of age, whereas this condition may exist in up to 10% of persons over the age of 70 years. Patients with CHIP have a higher rate of death from noncancer causes (particularly cardiovascular disease) than do age-matched controls without CHIP.

To address the cause of excess cardiovascular mortality, researchers identified CHIP (which they define as clonal dominance of hematopoietic cells bearing pathogenic mutations in any of 74 known driver genes of hematologic cancers) among participants in several studies that ascertained cardiovascular disease. In studies involving participants with a mean age of 60 years or older, carriers of CHIP had nearly twice the risk of coronary heart disease as noncarriers. Among younger participants (below 50 years of age), CHIP carriers had four times the risk of myocardial infarction as noncarriers. Preclinical coronary disease, as assessed on imaging as coronary-artery calcification, was also associated with CHIP. Finally, four of the most commonly mutated genes in CHIP (DNMT3A, TET2, ASXL1, and JAK2) were each individually associated with coronary heart disease.

Collectively, the work supports the hypothesis that CHIP is linked to the clinical events of atherosclerosis and that certain CHIP driver genes are involved in regulating inflammation. Both TET2 and DNMT3A appear to inhibit inflammation, so loss-of-function mutations in these genes could plausibly promote inflammatory responses. Similarly, there is a large body of literature suggesting that JAK2 regulates both inflammation and thrombosis, two important factors in the clinical manifestations of atherosclerosis. Thus, the data is consistent with established paradigms that inflammation is an accelerator of atherosclerosis and coronary heart disease. Moreover, their findings should prompt a discourse about studying the use of anti-inflammatory agents in patients with CHIP to limit the most common cause of death in these patients - cardiovascular disease.

GenSight Biologics has raised €22.5 million to prepare to bring gene therapy GS010 to market in the U.S. and Europe. The financing gives the Novartis-backed biotech enough cash to deliver data from two phase 3 trials next year and gear up for anticipated approvals on both sides of the Atlantic. Paris-based GenSight raised the cash from a mix of new and existing institutional investors, most of which are based in the US. Strong interest from these backers saw GenSight ease past its initial target of €20 million to pull in €22.5 million in the private placement. When added to the €48.8 million GenSight had in the bank at the end of March, management thinks the money moves its runway out to the first quarter of 2019.

That runway covers a critical period for GenSight. Topline 48-week data from two phase 3 trials of GS010 in patients with Leber hereditary optic neuropathy (LHON) are due in the second and third quarters of next year. GenSight is looking to the trials for evidence GS010 improves the clarity of the vision of patients with LHON, a hereditary form of vision loss caused by mitochondrial defects. GS010 is injected into the eye to deliver the human wild-type ND4 gene via an adeno-associated virus to deliver. This gene encodes for a protein typically produced by mitochondria.

One trial is assessing GS010 in patients who started losing their vision in the six months prior to enrolling in the study. The other is recruiting patients whose vision started deteriorating between seven and 12 months ago. Both trials are injecting GS010 into one eye of each participant and pretending to inject it into the other eye. Data from an earlier phase 1/2 trial suggest the gene therapy is most effective in patients whose vision started deteriorating less than two years ago. A recent 96-week update found the treated eyes of such patients had a mean gain of 29 ETDRS letters, as compared to an increase of 15 letters in untreated eyes. ETDRS is the test showing progressively smaller letters opticians use to gauge vision. The performance of GS010 to date has enabled GenSight to secure the support of some big-name backers. Following the latest financing, its biggest shareholders are Novartis, Versant, Abingworth, and Fidelity.

Oisin Biotechnologies' ground-breaking research and technology is demonstrating that the solution to mitigating the effects of age-related diseases is to address the damage created by the aging process itself. Our first target is senescent cells. When cells detect that they have been irretrievably damaged, they enter a non-dividing condition known as cell-cycle arrest, or senescence. It's believed this occurs to prevent cells from going rogue and turning cancerous. Ideally, they should die by the process known as apoptosis, but as we age, more and more frequently they don't. They become zombie cells - unable to kill themselves or resume normal function.

Senescent cells secrete molecules that cause inflammation in an effort to attract immune cells that would usually clear them. But for reasons that are not fully known, as we age, persistently senescent cells accumulate, leading to a vast number of age-related diseases. Oisin is developing a highly precise, patent-pending, DNA-targeted intervention to clear these cells. As a recent study has shown, clearing senescent cells both reduces negative effects of aging pathologies and also extends median lifespan and survival.

There are two major challenges to clearing senescent cells using our approach. First is to design and create the DNA construct that recognizes that a cell has become senescent, and then destroys it. Second is to safely and efficiently deliver this construct into cells throughout the body. Both goals have been achieved in our pioneering proof of concept experiments in 2016. We've first demonstrated the ability to transduce cells both in vitro (cell culture) and in vivo (in aged mice). Then we showed that p16 positive senescent cells can be killed on demand in both in vitro and in vivo environments. Now we are embarked on experiments that will show improvements in both healthspan and lifespan in model organisms from mice to primates. And then, everything changes.

Our proprietary technology gives persistently senescent cells a helping hand to "do the right thing." By providing an exogenous apoptotic gene, which is only transiently expressed in cells that already have the p16 gene active, we can precisely induce the senescent cell to commit suicide. Oisin has shown as much as an 80% reduction in senescent cells in cell culture and significant reductions of senescent cell burden in naturally aged mice. SENSOlytics is an Oisin proprietary platform technology that enables precise targeting of a senescent cell based on the DNA expression of the cell, not on surface markers or other characteristics that might be shared with normal, undamaged cells.

Multicellular organisms continually accumulate mutations within their somatic tissues, constituting a significant, but poorly quantified, burden on tissue maintenance. To investigate this burden in a specific, well-parameterized context, we model the mammalian intestine and quantify the expected impact of mutation accumulation in stem cell populations. Furthermore, we explore how the population size of the stem cell niche influences mutation accumulation and demonstrate the expected trade-off between the risk of accumulating deleterious mutations, population size, and the risk of tumorigenesis. However, we further characterize how this trade-off can be expected to manifest over the lifetime of two well-studied mammalian systems, mice and humans, by estimating the expected effect of mutation accumulation on cellular homeostasis.

The intestinal epithelium is in constant flux, with populations of stem cells distributed throughout the intestine differentiating into other, transient, cell populations. These stem cells exist within small discrete populations in intestinal crypts, a compartmentalization thought to have evolved as a mechanism to deter tumorigenesis, as cells accumulating mutations that are beneficial to cellular fitness have a physical hindrance to spreading throughout the tissue. However, small populations are subject to significant genetic drift, that is, random changes in allele frequency that eventually lead to fixation or loss, and less effective selection.

The accumulation of damage causing the loss of cellular fitness is a hallmark of aging and is especially relevant when DNA damage occurs in stem cells, compromising their role in tissue renewal. Indeed, several mouse models with the diminished ability to maintain cellular genome integrity succumb to accelerated age-related phenotypes through the loss of tissue homeostasis caused by stem and progenitor cell attrition. Just as stem cell mutations conferring a beneficial fitness effect will increase cell production, mutations conferring a deleterious fitness effect will lead to decreased cell production and the diminished maintenance of healthy tissue.

When mutations confer a selective advantage or disadvantage within the niche, there exists an intermediate crypt size that minimizes the probability that any crypt accumulates the large beneficial mutations necessary to initiate a tumor. By modeling the fixation of mutations drawn from a full distribution of mutational effects and accumulating throughout the populations of the entire intestinal epithelium, we show that a secondary trade-off exists - populations maintained at a size that results in the lowest rate of tumorigenesis are expected to accumulate deleterious mutations that manifest in tissue attrition and contribute to organismal aging.

At small stem cell niche sizes, there exists a large number of crypts to maintain homeostasis, and a higher probability that any one crypt will obtain a rare mutation of large effect that would result in tumorigenesis. As stem cell niche size increases, the number of crypts needed to maintain the same amount of epithelium decreases, and so does the probability of fixing mutations within the crypts, and therefore the chance of fixing a rare mutation of large effect. However, for larger values of stem cell niche size, the strength of selection increases, thus increasing the chance that a fixed mutation was beneficial, leading to higher chances of tumorigenesis. At the observed intermediate population size in mice, the whole tissue size is expected to decline with age as deleterious mutations accumulate in stem cell niches. If selective pressures against tumorigenesis have selected for intermediate stem cell niche population sizes in mammalian species, then it has been at the expense of increasing epithelial attrition.

In a large cohort of predominantly male community-dwelling elderly veterans, centenarians had a lower incidence of chronic illness than those in their 80s and 90s. The centenarian population is one of the fastest growing in the country, according to the United States Social Security Administration. They are predicted to exceed one million by the close of this century, little is known about why this generation has achieved such longevity. In a recent study, researchers looked primarily at octogenarians, nonagenarians, and centenarians within the Veterans Affairs medical system. The sample that they studied comprised mostly of white males that had fought in World War II. "Additionally, this generation lived through the Great Depression. It is a wonder, considering the hardships they had faced, that they have achieved such longevity."

A key factor that the research team observed in these individuals is that, due to their military background, many had a developed sense of discipline and therefore were keen to make healthy decisions; many did not smoke or drink. The team also offered the hypothesis of compression of morbidity as a potential explanation for the extended health span in an individual's life span. The hypothesis states that the lifetime burden of illness could be reduced if the onset of chronic illness is postponed until very late in life, or in other words "the older you get, the healthier you have been."

Ninety-seven percent of centenarians were male, 88.0% were white, 31.8% were widowed, 87.5% served in World War II, and 63.9% did not have a service-related disability. The incidence rates of chronic illnesses were higher in octogenarians than centenarians (atrial fibrillation, 15.0% vs 0.6%; heart failure, 19.3% vs 0.4%; chronic obstructive pulmonary disease, 17.9% vs 0.6%; hypertension, 29.6% vs 3.0%; end-stage renal disease, 7.2% vs 0.1%; malignancy, 14.1% vs 0.6%; diabetes mellitus, 11.1% vs 0.4%; stroke, 4.6% vs 0.4%) and in nonagenarians than centenarians (atrial fibrillation, 13.2% vs 3.5%; heart failure, 15.8% vs 3.3%; chronic obstructive pulmonary disease, 11.8% vs 3.5%; hypertension, 27.2% vs 12.8%; end-stage renal disease, 11.9% vs 4.5%; malignancy, 8.6% vs 2.3%; diabetes mellitus, 7.5% vs 2.2%; and stroke, 3.5% vs 1.3%).

Thanks to advances in medicine and improvements in healthy living, we benefiting from longer lifespans and also experiencing longer "healthspans". So, what do we need to do to enhance the length and quality of our lives even more? Researchers worldwide are pursuing various ideas, but for some researchers, the answer is a simple change in diet. They believe that the key to a better old age may be to reduce the amount of food on our plates, via an approach called "calorie restriction". This diet goes further than cutting back on fatty foods from time-to-time; it's about making gradual and careful reductions in portion size permanently.

Since a foundational study in 1935 in white rats, a dietary restriction of between 30-50% has been shown to extend lifespan, delaying death from age-related disorders and disease. Of course, what works for a rat or any other laboratory organism might not work for a human. Long-term trials, following humans from early adulthood to death, are a rarity. "I don't see a human study of longevity as something that would be a fundable research programme. Even if you start humans at 40 or 50 years old, you're still looking at potentially 40 or 50 more years of study." That's why, in the late 1980s, two independent long-term trials - one at NIA and the other at the University of Wisconsin - were set up to study calorie restriction and ageing in Rhesus monkeys. Not only do we share 93% of our DNA with these primates, we age in the same way too.

They are far from malnourished or starving. Take Sherman, a 43-year-old monkey from NIA. Since being placed on the CR diet in 1987, aged 16, Sherman hasn't shown any overt signs of hunger that are well characterised in his species. Sherman is the oldest Rhesus monkey ever recorded, nearly 20 years older than the average lifespan for his species in captivity. Even into his 30s he would have been considered an old monkey, but he didn't look or act like one. The same is true, to varying extents, for the rest of his experimental troop at NIA. "We have demonstrated that ageing can be manipulated in primates. It kind of gets glossed over because it's obvious, but conceptually that's hugely important; it means that ageing itself is a reasonable target for clinical intervention and medical treatment."

If ageing can be delayed, in other words, all of the diseases associated with it will follow suit. "Going after each disease one at a time isn't going to significantly extend lifespan for people because they'll die of something else. If you cured all cancers, you wouldn't offset death due to cardiovascular disease, or dementia, or diabetes-associated disorders. Whereas if you go after ageing you can offset the lot in one go."

In the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy trial, also known as Calerie, over two years, 218 healthy men and women aged between 21 and 50 years were split into two groups. In one, people were allowed to eat as they normally would (ad libitum), while the other ate 25% less (CR). Both had health checks every six months. Unlike in the Rhesus monkey trials, tests over two years can't determine whether CR reduces or delays age-related diseases. There simply isn't enough time for their development. But the Calerie trials tested for the next best thing: the early biological signs of heart disease, cancer, and diabetes. The results after two years were very positive. In the blood of calorie-restricted people, the ratio of "good" cholesterol to "bad" cholesterol had increased, molecules associated with tumour formation - called tumour necrosis factors (TNFs) - were reduced by around 25%, and levels of insulin resistance, a sure sign of diabetes, fell by nearly 40% compared to people who ate their normal diets. Overall, blood pressure was lower.

With less food, is the metabolism forced to be more efficient with what it has? Is there a common molecular switch regulating ageing that is turned on (or off) with fewer calories? Or is there an as of yet unknown mechanism underpinning our lives and deaths? Answers to such questions might be long in coming. "If I cloned 10 of myself and we all worked furiously, I don't think we'd have it solved. The biology is inordinately complicated." It's a worthwhile undertaking - understand how CR works and other treatments could then be used to target that specific part of our biology. Ageing could be treated directly, that is, without the need of calorie restriction.

Intense investigation in aging research has led to the identification of over five hundred evolutionarily conserved genes, the mutational or RNA interference-mediated inactivation of which slows down the rate of the aging process in divergent eukaryotic species. While many of these genetic interventions can significantly promote longevity, they are unable to halt aging. Even mutant animals with extreme longevity continue to age, albeit at a diminished rate when contrasted with their corresponding controls. A related problem in aging research is that of the mortality rate, which displays an exponential growth throughout the adult life in numerous animal species. As the accumulation of mutations and harmful metabolic factors, such as reactive oxygen species, causing cellular damage, is known to occur at a nearly constant rate during the lifespan, this has bred speculations regarding potential genetic or metabolic components that are likely to be generated exponentially, and to primarily contribute to aging.

Triggered by unrepaired mutations, genomic instability is a key feature of aging cells. Nonaging biological systems however show either no or only limited signs of genome disintegration. Such potentially immortal systems involve the germline that genetically interconnects the subsequent generations, somatic cancer stem cells with indefinite proliferation capacity, and certain organisms from some 'lower' animal taxa, somatic cells of which display stem cell-like features. The term of 'nonaging cells' refers to cells constituting a tissue that traces an essentially immortal lineage. Nonaging tissues display an indefinite renewal capacity. In nonaging cells, genome integrity remains largely stable during the lifespan.

Genomic instability in aging cells progressively increases during adulthood, thereby limiting their capacity to proliferate and survive. A molecular machinery primarily responsible for maintaining the integrity of genetic material is the Piwi-piRNA pathway. This small RNA-based gene regulatory system operates predominantly in nonaging cells. The pathway was originally discovered in the Drosophila male germline, and established to function in repressing the activity of mobile genetic elements, also called transposable elements (TEs), transposons, or 'jumping genes'. In addition planarian flatworms and freshwater hydra somatically express components of the Piwi-piRNA pathway, rendering the self-renewal ability of their somatic cells apparently unlimited.

In the absence of active Piwi-piRNA pathway components, aging somatic cells tend to increasingly lose heterochromatin, which normally maintains TEs under transcriptional repression. Thus, during adulthood, the gradual release of TEs may generate considerable levels of molecular damage that overwhelm the capacity of the cellular maintenance and DNA repair systems. In addition to their increasing mobilization during adult life, TEs can inactivate genes that function in the repair and maintenance systems, further contributing to the age-associated accumulation of cellular damage. In contrast, the Piwi-piRNA pathway protects the germline and nonaging somatic cells from TE-mediated mutagenesis. Occasional mutations generated by chemical and physical mutagens are effectively recognized and eliminated by cellular maintenance and repair mechanisms.

Alternatively, the Piwi-piRNA pathway may have a different, TE-independent, but as of yet unexplored function to ensure genomic integrity in nonaging cells. For example, the pathway may regulate the transcription of certain key genes via modulating chromatin organization. It is also possible that besides the Piwi-piRNA system, another molecular mechanism operates in nonaging cells to preserve the stability of their genomes. Such a mechanism however has not yet been identified. Nevertheless, the activity of the Piwi-piRNA pathway is a shared feature of all nonaging cells identified so far.

Cancer is surpassing cardiovascular disease (CVD) as the leading cause of death in many high income populations and is projected to become a leading cause of morbidity and mortality worldwide in the coming decades. While substantial progress in reducing mortality from CVD has been shown, equivalent global assessment of cancer remains challenging, requiring a multifaceted and multi-indicator approach. Cancer mortality rates are declining in most highly developed countries, largely due to recent successes in the control of common cancers through programs of effective prevention, early detection, and treatment. In contrast, mortality rates of many types of cancer, including breast cancer and prostate cancer, are still increasing in transitioning countries, or at best stabilizing.

There is a need to quantify and better understand the position of cancer among other leading causes of avoidable death, including CVD, and the specific impact of major cancers as barriers to attaining old age. In this study, we quantify the contributions of changing cancer mortality rates on changes in life expectancy in ages 40-84 (LE40-84) over the period 1981-2010, adjusting for other causes of deaths, while making benchmark comparisons with equivalent gains achieved through the reduction of CVD mortality rates.

Only ages 40-84 were included, as individuals within this age group comprise the majority of cancer cases. In addition, in this age group there is also a lower probability of the causes of death being misreported and the existence of comorbid conditions compared with in those aged 85 or more, reducing bias related to competing causes of deaths. As a sensitivity test, we replicated the analysis for ages 0-39 and found that the contributions of cancer to change in life expectancy are negligible in this age group. Accordingly, LE40-84 throughout this article refers to life expectancy in ages 40-84, the expected number of years lived between ages 40 and 84, whereas we truncated years lived above age 85.

An overall decrease in mortality rates from all causes led to a noticeable increase in LE40-84 over the study period. In particular, very high Human Develpment Index (HDI) populations experienced gains of on average 3.7 and 2.5 years in LE40-84 among men and women, respectively, while respective values for medium and high HDI populations were lower, at 1.1 and 1.4 years. Decline in mortality rates from CVD was the main contributor, accounting for an average of more than 60% and 50% of declines in overall mortality rates in very high and medium and high HDI populations, respectively. Although decreasing overall cancer mortality rates were observed, they were greater in very high HDI populations (declines of 20% and 15% over the 30 year period for men and women, respectively) compared with medium and high HDI populations (4% and 5% decreases, respectively).

The past three decades have been marked by several triumphs in cancer control, which are clearly reflected in our results. For example, the increase in LE40-84 among men can be considered partly the result of corresponding declines in lung cancer mortality rates linked to improved tobacco control measures. Gains in life expectancy from a reduction of stomach cancer mortality rates links socioeconomic advancement to successes in combating infectious diseases through both "unplanned" prevention as well as treatment. In most of the very high HDI populations, the progress seen in terms of reductions in mortality rates from breast, prostate, and colorectal cancer can be related to a broad spectrum of cancer control interventions, including early detection, improved diagnosis, and better access to effective treatment.

For the first time, researchers demonstrate a surprising effect of microglia, the scavenger cells of the brain: If these cells lack the TDP-43 protein, they not only remove Alzheimer's plaques, but also synapses. This removal of synapses by these cells presumably leads to neurodegeneration observed in Alzheimer's and other neurodegenerative diseases. Alzheimer's is a disease in which the cognitive abilities of afflicted persons continuously worsen. The reason is the increasing loss of synapses, the contact points of the neurons, in the brain. In the case of Alzheimer's, certain protein fragments, the β-amyloid peptides, are suspected of causing the death of neurons. These protein fragments clump together and form the disease's characteristic plaques.

In an initial step, the researchers looked at the effect that certain risk genes for Alzheimer's have on the production of the β-amyloid peptide. They found no effect in neurons. This led the researchers then to examine the function of these risk genes in microglia cells - and made a discovery: If they turned off the gene for the TDP-43 protein in these scavenger cells, these cells remove β-amyloid very efficiently. This is due to the fact that the lack of TDP-43 protein in microglia led to an increased scavenging activity, called phagocytosis.

In the next step, researchers used mice, which acted as a disease model for Alzheimer's. In this case, as well, they switched off TDP-43 in microglia and observed once more that the cells efficiently eliminated the β-amyloid. Surprisingly, the increased scavenging activity of microglia in mice led also to a significant loss of synapses at the same time. This synapse loss occurred even in mice that do not produce human amyloid. This finding that increased phagocytosis of microglia can induce synapse loss led researchers to hypothesize that perhaps, during aging, dysfunctional microglia could display aberrant phagocytic activity. The results show that the role of microglia cells in neurodegenerative diseases like Alzheimer's has been underestimated. It is not limited to influencing the course of the disease through inflammatory reactions and the release of neurotoxic molecules as previously assumed. Instead, this study shows that they can actively induce neurodegeneration.

The Methuselah Fund (M Fund) is designed to accelerate results in the longevity field, extending the healthy human lifespan. Our success is measured by financial return on investments and furthering the mission, with the mission being the priority. Our DNA stems from The Methuselah Foundation, which has been working hard during the last 16 years to extend the healthy human lifespan. Our access to the key players in this space is significant and our ability to help our companies thrive is proven.

Our strategies are meant to be accessible to everyone since elegantly simple ideas can move masses. Our portfolio companies are achieving one or more of the our anti-aging strategies. New parts for people: technologies that will create new organs, bones, vasculature (with the probable near-term exception of the brain). Get the crud out: Safely remove senescent and other destructive biological structures, intercellular damage or waste (i.e. amyloid), etc. Restore the rivers: restore the circulatory system to full competence. Debug the code: restore informational integrity and viability of cells. Restock the shelves: replenish building blocks such as stem cells and immune system antibodies. Lust for life: restore the capacity for joy. For instance, rejuvenated senses and athletic competence.

Our portfolio companies include Leucadia Therapeutics and Oisin Biotechnologies. Leucadia Therapeutics has a unique and compelling approach on how to potentially predict, halt and cure early stage Alzheimer's Disease. 25 years of research have focused on plaques and tangles as the cause of Alzheimer's. At Leucadia, it is known that those are pathological effects of a more serious underlying condition. The science allows for the creation of a sophisticated surgical procedure bypassing the small molecule approach that has shown no progress until now. Oisin Biotechnologies' ground-breaking research and technology is demonstrating that one of the solutions to mitigating the effects of age-related diseases is to address the damage resulting from the aging process itself. Oisin is developing a highly precise, DNA-targeting platform to clear senescent cells. Oisin's platform has shown as much as an 80% reduction in senescent cells in cell culture and significant reductions of senescent cell burden in naturally aged mice.