The positive relationship between income and life expectancy has been demonstrated across many different time periods but the causes of the relationship are much debated. In particular, there is a pertinent question about the direction of the relationship - does higher income lead to higher life expectancy or does higher life expectancy lead to higher income? This report is devoted to exploring the latter relationship. More specifically, based on previous theory and evidence, we develop a statistical method for assessing the extent to which differences in life expectancy explain cross country variation in productivity - measured in terms of GDP per hour worked, per worker, and per capita. We also explore two of the potential channels through which life expectancy might influence productivity - increased educational attainment and greater participation in the labour market.

While our previous research focussed on possible reasons why different age dynamics might affect productivity differently, this report is focussed more exclusively on the role of life expectancy. According to the wider economic literature, there are many reasons why increased life expectancy might boost economic output. Healthier workers are likely to be more productive, while longer lives may result in greater incentives to invest in schooling. The latter point is worth emphasising - if parents only expect their child to live to 40, the expected lifelong returns to investing in their education is likely to be far lower than if they are expected to live to 80.

We explore the relationship between life expectancy and various measures of productivity across OECD countries between the years 1970-2015. We use all three measures of GDP (per hour worked, per worker, and per capita) because population dynamics may impact the productivity of the workforce differently to the productivity of the population as a whole. For instance, an increased share of older retired people is likely to act as a drag on GDP per capita but its effects on the productivity of the workforce itself remain contentious.

We found life expectancy to be positively associated with productivity and that this relationship was robust to different productivity measures, the inclusion of a range of explanatory and control variables and different instruments. Moreover, we found life expectancy to be a more powerful determinant of productivity than either the young or old age dependency ratios. When investigating the channels through which life expectancy boosts productivity, we found education to be more important than employment. Regarding the latter, due to changes to public policy, such as the abolition of default retirement ages and raising pensionable age, the link between life expectancy and employment at older ages has been recoupled so there is increased capacity for life expectancy improvements to translate into higher employment rates at older ages.

Overall, this analysis suggests that there may well be a longevity dividend, whereby improvements to health result in wider economic and productivity improvements. Improving health and raising life expectancy must therefore remain a key goal not only for a nation's health and wellbeing but also for the wider economy. This is important, since in many debates about long run government spending, health spending is simply seen as a drain on fiscal resources, yet if by raising life expectancy it results in productivity improvements, this could support increased tax revenue for the exchequer. Public policy and economic forecasters should consider how best to take into account the potential fiscal benefit of better health and not neglect it in discussions of our long run sustainability.

Researchers have identified a three-pronged treatment that triggers axons - the tiny fibers that link nerve cells and enable them to communicate - to regrow after spinal cord injury in rodents. Not only did the axons grow through scars, they could also transmit signals across the damaged tissue. "Previous studies had tested each of the three treatments separately, but never together. The combination proved to be the key."

Many decades of research have shown that a human's nerve fibers need three things to grow: genetic programming to switch on axon growth; a molecular pathway for the fibers to grab and grow along; and a trail of protein "bread crumbs" that spur the axons to grow in a particular direction. All three of these conditions are active when humans develop in the womb. After birth, these processes shut down, but the genes that control the growth programs are still sleeping in the body. The goal was to reawaken these genes and then launch the entire process anew with the three-pronged approach.

Not only had axons grown robustly through the scar tissue, but many fibers also had penetrated into the remaining spinal cord tissue on the other side of the lesion and made new connections with neurons there. When we stimulated the animal's spinal cord with a low electrical current above the injury site, the regrown axons conducted 20 percent of normal electrical activity below the lesion. In contrast, the untreated animals exhibited none. Despite the finding suggesting that the newly formed connections can conduct signals across the injury, the rodents' ability to move did not improve. "We expect that these regrown axons will behave like axons newly grown during development - they do not immediately support coordinated functions. Much like a newborn must learn to walk, axons that regrow after injury will require training and practice before they can recover function."

Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury, but efficient reversal of this regrowth failure remains elusive. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults - (i) neuron intrinsic growth capacity, (ii) growth-supportive substrate and (iii) chemoattraction - are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents.

We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor delivered via spatially and temporally controlled release from biomaterial depots, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions.

Life extension - slowing or halting human aging - is now being taken seriously by many scientists. Although no techniques to slow human aging yet exist, researchers have successfully slowed aging in yeast, mice, and fruit flies, and have determined that humans share aging-related genes with these species. In New Methuselahs, John Davis offers a philosophical discussion of the ethical issues raised by the possibility of human life extension. Why consider these issues now, before human life extension is a reality? Davis points out that, even today, we are making policy and funding decisions about human life extension research that have ethical implications. With New Methuselahs, he provides a comprehensive guide to these issues, offering policy recommendations and a qualified defense of life extension.

After an overview of the ethics and science of life extension, Davis considers such issues as the desirability of extended life; whether refusing extended life is a form of suicide; the Malthusian threat of overpopulation; equal access to life extension; and life extension and the right against harm. In the end, Davis sides neither with those who argue that there are no moral objections to life enhancement nor with those who argue that the moral objections are so strong that we should never develop it. Davis argues that life extension is, on balance, a good thing and that we should fund life extension research aggressively, and he proposes a feasible and just policy for preventing an overpopulation crisis.

Life extension - using science to slow or halt human aging so that people live far longer than they do naturally - may one day be possible. Big business is taking this possibility seriously. From my perspective as a philosopher, this poses two ethical questions. First, is extended life good? Second, could extending life harm others?

Not everyone is convinced that extending life would be good. In a 2013 survey, some respondents worried that it might become boring, or that they would miss out on the benefits of growing old, such as gaining wisdom and learning to accept death. On the other hand, not everyone is persuaded that extended life would be a bad life. I'm not. But that's not the point. No one is proposing to force anyone to use life extension, and - out of respect for liberty - no one should be prevented from using it.

However, our liberty right is limited by the "harm principle." The harm principle says that the right to individual liberty is limited by a duty not to harm others. There are many possible harms: Dictators might live far too long, society might become too conservative and risk-averse, and pensions might have to be limited, to name a few. One that stands out to me is the injustice of unequal access.

It is unjust when some people live longer than the poor because they have better health care. It would be far more unjust if the rich could live several decades or centuries longer than anyone else. Some philosophers suggest that society should prevent inequality by banning life extension. This is equality by denial - if not everyone can get it, then no one gets it. However, "leveling-down" - achieving equality by making some people worse off without making anyone better off - is unjust. Indeed, most of us reject leveling-down in other situations. For example, there are not enough human organs for transplant, but no one thinks the answer is to ban organ transplants.

Another possible harm is that widespread life extension might make death worse for some people. All else being equal, it is better to die at 90 than nine. At 90 you're not missing out on many years, but at nine you lose most of your potential life. In a world where some people get life extension and some don't, what's the right measure for how many years death takes from you? If so, then the fact that some people can get life extension makes your death somewhat worse. This is a more subtle kind of harm than living in an overpopulated world, but it's a harm all the same.

However, not just any harm is enough to outweigh liberty. After all, expensive new medical treatments can extend a normal lifespan, but even if that makes death slightly worse for those who can't afford those treatments, no one thinks such treatments should be banned. I believe that life extension is a good thing, but it does pose threats to society that must be taken seriously.

Haematopoiesis is the process of the generation of all differentiated blood cells in the organism, including red blood cells, platelets, innate immune cells, and lymphocytes; all found to fade in functionality in aged individuals. Haematopoiesis is carried out by a rare population of haematopoietic stem cells (HSCs), which in adults, reside mainly in the bone marrow. There, they either remain dormant, i.e., in a quiescent state, or undergo proliferation and differentiation, depending on their cell-intrinsic transcriptional programs and the external cues from the surroundings.

Adult HSCs seem to be a heterogeneous subset of mainly multipotent and unipotent progenitors affiliated to specific lineages, and the ratio of their skewing shifts when homeostasis is perturbed. HSC maintenance relies on the support from the microenvironment or niche, necessary to preserve the self-renewing potential of HSCs. Extensive research on HSC niches composition shows that they are closely related to the vasculature in the bone marrow, with mainly endothelial, perivascular, and mesenchymal stromal cells secreting factors that support HSC maintenance. In this scenario, the effects of ageing on haematopoiesis may be the result of age-related alterations in all blood cell subsets, including HSCs and progenitors, as well as in the HSC niche.

In mice, the number of phenotypically defined HSCs can increase up to tenfold with ageing. In contrast, their functionality in terms of self-renewal and repopulating ability is remarkably reduced. Clonal HSC composition in old mice shows increased variability of clones derived from a single stem cell with smaller size per clone, when compared to young mice. Competitive transplantation of these HSCs proved that young HSCs perform better, with three-fold higher yield of mature granulocytes and lymphocytes. Furthermore, age-related defective HSCs seem to be able to differentiate into the myeloid lineage, but are incapable of the balanced generation of lymphocytes following transplantation. Thus, HSC defects are reflected in insufficiencies in their progeny of differentiated cells and contribute to poorer systemic performance of the haematopoietic system, i.e., immunosenescence.

At the molecular level, DNA damage and telomere shortening seem to be major mechanisms underlying the age-related decrease in the functionality and durability of HSCs. DNA damage accumulation is intimately related to increased reactive oxygen species (ROS) levels. In fact, HSCs reside in hypoxic bone marrow niches, which maintain their long-term self-renewal by mechanisms such as limiting their ROS production. Stressors, such as infections or chronic blood loss, shift HSCs from the quiescent to cycling state, which consequently leads to increased ROS levels and DNA damage.

Inflammageing is the characteristic process of chronic inflammation that has been described in aged individuals, with an increase of inflammatory cytokine levels that correlate with morbidity and age-related diseases. The HSC compartment is tightly connected to inflammatory processes, as a producer of innate immune cells. Furthermore, HSCs express pattern recognition receptors required for the identification of dangers, and a variety of cytokines and their receptors. Activation of these signalling pathways elicits HSC differentiation and myeloid skewing, aimed at mediating rapid myeloid cell recovery. However, when not finely regulated, they may cause HSC exhaustion.

HSC survival and function relies on the support from the microenvironment or niche in the bone marrow. Stem cell niches are complex and unique structures, yet they share many features that include cellular interactions, secreted factors, extracellular matrix, physical factors, metabolic conditions, and importantly, processes of scarring and inflammation. The changes in the bone marrow niche of aged mice include differences in gene expression and molecular structure in perivascular cells, arteries, and capillaries. In aged mice, enhancement of the Notch signalling pathway in endothelial cells can partially address some of these changes. Niche-forming vessel improvements are followed by increased HSC numbers, but no changes in their functionality. This suggests that niche-based rejuvenating strategies may have only partial efficiency to recover HSCs to a youthful state.

In conclusion, HSC ageing is characterised by reduced self-renewal, myeloid and platelet HSC skewing, and expanded clonal haematopoiesis that is considered a preleukaemic state. The underlying molecular mechanisms seem to be related to increased oxidative stress due to ROS accumulation and DNA damage, which are influenced by both cell- and cell non-autonomous mechanisms such as prolonged exposure to infections, inflammageing, immunosenescence, and age-related changes in the HSC niche. Thus, HSC ageing seems to be multifactorial and we are only beginning to connect all the dots.

Prevention and treatment of Alzheimer's disease (AD) by 2025 has been articulated as a goal of the US government and has been endorsed by other countries. The failure rate of AD drug development is 99%; the failure rate of the development of disease-modifying therapies for AD is 100%. Despite these discouraging outcomes in drug development programs, the urgent need to address the socioeconomic crisis posed by AD requires that we continue to advance understanding of AD drug development.

To advance the research agenda in AD, financial resources are required including funding from government, industry, venture capital, foundations, and philanthropy. Federal research funding programs include the National Institutes of Health (NIH), National Science Foundation (NSF), Food and Drug Administration (FDA), Department of Defense, and Veterans Administration (VA). Private sector funding includes sources in the biopharma industry, venture capital, foundations, advocacy organizations, and support from philanthropists. Funding and financing resources form a complex financial ecosystem.

Total costs of an AD drug development program are estimated at 5.6 billion, and the process takes 13 years from preclinical studies to approval by the FDA. This compares to an estimated cost of cancer treatment development of 793.6 million per agent (assuming 9% cost of capital). Considering the pharmaceutical industry as a whole bringing a new agent to approval has an estimated cost of 2.8 billion. AD drug development costs substantially exceed most estimates for drugs in other therapeutic areas. Phase III trials are the most costly part of AD drug development, and pharmaceutical companies are among the few enterprises that can sustain such costs.

The principle public funder of research is the US NIH, investing more in health research than any other public enterprise in the world with an annual budget of approximately 34 billion. Non-NIH federal agencies have smaller research budgets and grant portfolios related to AD. There is a mismatch between the cost of disease to society and the amount of research devoted to it. AD, for example, costs the US society more than 216 billion annually, and it has an NIH budget of 1.8 billion; of the funds spent on AD, less than 1% of that amount is devoted to research.

Biotechnology companies can be defined as venture-backed drug development firms using technological applications centered on biological systems, living organisms, or their derivatives. Success in AD drug development will produce a very high return on investment. This possibility attracts venture capital to AD research, but the high rate of failure has kept this funding stream small. Venture capital funding in Central Nervous System disease declined 40% in the 2009-2013 period compared with the 2004-2008 period.

Angel investors or seed capital providers have high risk tolerance and supply small amounts of money to encourage novel ideas. If the concepts begin to mature and promise to lead to a successful program, venture capital may be attracted to allow more advanced drug development. Candidate therapies may pass from smaller to larger biotech companies as biotechs seek to strengthen their pipelines, progress toward vertically integrated Central Nervous System companies, or attract investors interested in a broader portfolio. This can be a healthy process allowing drugs to progress in testing before major pharmaceutical companies invest; however, the process also may lead to abuse by passing flawed agents from company to company and attracting capital from enthusiastic but under-informed investors.

The Alzheimer Association is the largest private noncorporate funder of AD research. In 2016, the association invested 90 million in research, including 25 million in new project investments and the rest in support of on-going multi-year commitments. Philanthropists make contributions to advocacy organizations or directly to universities and scientists to support research projects. Philanthropy plays a critically important role in the AD research ecosystem. Philanthropy often provides seed money for small projects that do not yet have preliminary data that would support a federal grant application. Philanthropy can fund high-risk/high-reward projects that might be too risky to receive funding from other sources such as the NIH.

The pharmaceutical industry is the largest funder of drug discovery and development research in the world, exceeding that of NIH or any other funding organization. Biopharma funds approximately 60% of all annual US research and development activities. The total annual research and development budget for biopharma (biotechnology and pharmaceutical industry) in 2016 was 75 billion. Over 70% of all AD clinical trials are sponsored or co-sponsored by the pharmaceutical industry. Payments from biopharma support much of the AD drug development ecosystem. New agents may be accessed through academic medical center collaborations, in-house discovery teams, acquisitions of biotechnology companies, mergers with other pharmaceutical companies, in-licensing of promising compounds, and partnering and co-development arrangements. Each of these has corresponding financial support by the pharmaceutical company.

The extreme expense of current drug development for AD is not sustainable, discourages companies from working in the AD research arena, dissuades venture capital from investing in AD drug development, and diminishes the opportunity to advance new therapies for patients with AD. Innovation is needed to improve the financial underpinnings of AD drug development and translational research.

Lobbyists have made more progress towards classifying aging as a disease. The World Health Organization (WHO) has implemented the extension code "Ageing-related" (XT9T) in the latest version of the International Classification of Diseases (ICD). The previous version, the ICD-10, was released in 1983 and is now replaced by the new version, the ICD-11, which is expected to serve the medical community for many years, much as its predecessor has.

In the new ICD code, 'ageing-related' means "caused by pathological processes which persistently lead to the loss of organism's adaptation and progress in older ages". This is an important step forward for our field because ICD codes are a prerequisite for the registration of new drugs and therapies. It also marks the recognition that aging is a pathological process and represents a solid step forward in overcoming regulatory barriers to developing therapies that directly target the aging processes themselves.

WHO reports that by 2050, around 2 billion people (22% of the world's population) will be age 60 or over. This is commonly referred to as the "Silver Tsunami", and it is a real concern because society will become increasingly unable to cope with the rising numbers of elderly and potentially sick people, as aging is the greatest risk factor for multiple age-related diseases. The solution to this problem is to develop therapies that address the aging processes to keep older people healthy, active, and contributing to society rather than being burdens on healthcare systems, and that is without even considering the personal benefit of keeping people alive and healthy.

While the inclusion of the new code in the ICD-11 cannot be regarded as the WHO officially accepting aging as a disease, it does show that the WHO recognizes that aging is the primary risk factor for age-related diseases. There is also considerable debate as to if aging is a disease or not; we propose that it is a co-morbid syndrome. A syndrome is a set of medical signs and symptoms that are correlated with each other and, often, with a particular disease or disorder. This really does describe aging perfectly: it is a group of symptoms that consistently occur together and is a condition characterized by a set of associated symptoms. Ultimately, aging is an umbrella term describing a range of pathological changes; it may struggle to be accepted as a disease, but it already qualifies as a syndrome.

Early next year, a small clinical trial will begin in Japan, marking the first time reprogrammed stem cells will be deployed to help regenerate injured hearts. A team will implant sheets - each consisting of 100 million stem-cell derived cardiomyocytes - onto the hearts of three patients with advanced heart failure. The cardiac study is only the second-ever clinical application of induced pluripotent stem (iPS) cells, the first being an iPS-cell transplant to treat macular degeneration of the eye, which also took place in Japan. While it is a big deal to pioneer such a technology clinically, the trial also has its risks, unknowns, and critics.

Japan's health ministry conditionally approved the heart experiment in May, with the goal of assessing the safety of the procedure. If the first trial and a later one enrolling 10 patients prove successful, the treatment will be made commercially available soon under a new fast-track system in Japan designed to speed up the development of regenerative therapies. Since the trial was announced, several Japanese researchers have voiced their concerns. One of them notes that the trail participants will receive iPS-derived cells from a donor, instead of from their own tissue, and will have to be placed on immunosuppressants for three months to prevent rejection. The researchers running the trials say that creating cardiomyocytes derived from a patient's own cells is not always an option, because the reprogramming process takes a long time. Providing off-the-shelf treatments is a more feasible route to address heart failure. "Cell therapy using a patient's own cells seems to be not suitable for industrialization."

While preclinical work with iPS cells has proven effective in improving heart function in mice, pig, and monkey models, it's not quite clear by which mechanism the cells are promoting muscle regeneration. It's still unknown whether these cells actually integrate into the heart and become beating heart cells, or whether they just release factors and help existing heart cells. Research in pigs suggests that iPS cell-derived cardiomyocytes promote regeneration of the heart by secreting certain cytokines that stimulate the native heart muscle to grow.

A new study analysed data on stroke and dementia risk from 3.2 million people across the world, finding that people who have had a stroke are around twice as likely to develop dementia. The link between stroke and dementia persisted even after taking into account other dementia risk factors such as blood pressure, diabetes, and cardiovascular disease. Their findings give the strongest evidence to date that having a stroke significantly increases the risk of dementia.

The researchers analysed 36 studies where participants had a history of stroke, totalling data from 1.9 million people. In addition, they analysed a further 12 studies that looked at whether participants had a recent stroke over the study period, adding a further 1.3 million people. "We found that a history of stroke increases dementia risk by around 70%, and recent strokes more than doubled the risk. Given how common both stroke and dementia are, this strong link is an important finding. Improvements in stroke prevention and post-stroke care may therefore play a key role in dementia prevention."

Stroke characteristics such as the location and extent of brain damage may help to explain variation in dementia risk observed between studies, and there was some suggestion that dementia risk may be higher for men following stroke. "Around a third of dementia cases are thought to be potentially preventable, though this estimate does not take into account the risk associated with stroke. Our findings indicate that this figure could be even higher, and reinforce the importance of protecting the blood supply to the brain when attempting to reduce the global burden of dementia."

The activity of microglial cells plays an important role in brain aging. These cells are part of the brain's immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation. This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled.

Endocannabinoids play an important role in this control. These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells. Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. However, microglial cells have virtually no CB1 and very low level of CB2 receptors. Researchers have now found that the brake signals do not communicate directly with the glial cells, but via middlemen - a certain group of neurons, because this group has a large number of CB1 receptors.

This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons similarly regulator the other major glial cell type, the astroglial cells. During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle. Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running.

It may be possible to break this vicious circle with drugs in the future. Tetrahydrocannabinol (THC) is a powerful CB1 receptor activator, even in low doses. Last year, researchers were able to demonstrate that THC can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.

Accumulating evidence suggests that, in contrast to the cell-autonomous tumor-suppressive mechanism of senescence, the paracrine effects of senescent cells themselves, particularly those mediated by the senescence-associated secretory phenotype (SASP), are responsible for aging-related pathologies, among which cancer has attracted increasing attention. Optimizing the beneficial impact while minimizing the deleterious effects of cellular senescence remains a serious challenge for multiple fields of scientific and clinical research.

Transient induction of cellular senescence, followed by tissue remodeling and senescent cell elimination by the immune system, is beneficial because it facilitates removal of damaged cells from the affected tissue. However, chronic senescence or inability to eliminate the senescent cells is frequently observed in aged individuals or in pathological contexts, leading to the accumulation of senescent cells which produce adverse effects.

Increasing evidence shows that both pro-senescence and anti-senescence therapies can be beneficial to tissue homeostasis. For instance, in the case of cancer, pro-senescence therapies can minimize the damage by limiting aberrant activities such as hyperactive proliferation, and more specifically by preventing or delaying events of carcinogenesis, while anti-senescence treatments may help to remove accumulated senescent cells and allow tissue regeneration. Of note, the term "anti-senescence" in this field of research does not mean that senescence is blocked or prevented, but means that when senescence is engaged it is subsequently pushed into apoptosis.

A two-step anticancer strategy was recently suggested in which senescence-inducing treatments are followed by senotherapy, thus providing a novel option to maximize therapeutic efficacy and improve clinical outcome. Although the incidence of senescence can improve long-term outcomes for cancer, the potentially harmful properties of senescent cells persisting in vivo make their quantitative elimination an outstanding therapeutic priority.

The most promising senolytics appear to be inhibitors of pro-survival BCL family proteins, probably because senescent cells physiologically need these factors to circumvent apoptosis for long-term survival. This class of agents has undergone extensive investigation in patients with chronic leukemia, with final FDA approval of a selective BCL-2 inhibitor, venetoclax. However, venetoclax is not a potent senolytic agent in vitro, whereas its homolog navitoclax has recently been disclosed to be one of the strongest senolytics. Navitoclax effectively inhibits BCL-2, BCL-xL, and BCL-W, suggesting that senolysis requires suppression of a wider range of anti-apoptotic effectors than of BCL-2 alone. It is rational to propose a broad spectrum of BCL protein inhibitors as a potential senolysis treatment in patients, but such molecules would need to exhibit acceptable toxicity through new or optimized formulation, delivery, or administration schedule.

Up to a quarter of adults over the age of 60 and half of those over 80 have thinner arms and legs than they did in their youth. The good news is that exercise can stave off and even reverse muscle loss and weakness. Recent research has demonstrated that physical activity can promote mitochondrial health, increase protein turnover, and restore levels of signaling molecules involved in muscle function. But while scientists know a lot about what goes wrong in aging, and know that exercise can slow the inevitable, the details of this relationship are just starting to come into focus.

Mature muscle fibers are post-mitotic, meaning they do not divide anymore. As a result, in adulthood both muscle growth and repair are made possible only by the presence of muscle stem cells known as satellite cells. Elderly human satellite cells show dramatic changes in their epigenetic fingerprint. One gene, called sprouty 1, is known to be an important regulator of cell quiescence. Reduced sprouty 1 expression can limit satellite cell self-renewal and may partially explain the progressive decline in the number of satellite cells observed in human muscles during aging. Indeed, stimulation of sprouty 1 expression prevents age-related loss of satellite cells and counteracts age-related degeneration of neuromuscular junctions in mice.

Other likely culprits of muscle aging are the mitochondria, the powerhouses of muscle. To work efficiently, skeletal muscle needs a sufficient number of fully functional mitochondria. These organelles represent around 5 percent to 12 percent of the volume of human muscle fibers, depending on activity and muscle specialization (fast-twitch versus slow-twitch). And research suggests that abnormalities in mitochondrial morphology, number, and function are closely related to the loss of muscle mass observed in the elderly.

In 2005, researchers combined the circulation of young and old mice and found that factors in the blood of young mice were able to rejuvenate muscle repair in aged mice. It is now well known that the levels of circulating hormones and growth factors drastically decrease with age and that this has an effect on muscle aging. Indeed, hormone replacement therapy can efficiently reverse muscle aging, in part by activating pathways involved in protein synthesis. Moreover, the muscle itself is a secretory endocrine organ. Myokine proteins produced by the muscle when it contracts can act locally on muscle cells or other types of cells such as fibroblasts and inflammatory cells to coordinate muscle physiology and repair, or they can have effects in distant organs, such as the brain.

Although several of these myokines have been identified-in culture, human muscle fibers secrete up to 965 different proteins-researchers have only just begun to understand their role in muscle aging. The first myokine to be identified, interleukin-6 (IL-6), participates in muscle maintenance by decreasing levels of inflammatory cytokines in the muscle environment, while increasing insulin-stimulated glucose uptake and fatty-acid oxidation.

Researchers recently discovered a novel myokine, which they termed apelin. The researchers have demonstrated that this peptide can correct many of the pathways that are deregulated in aging muscle. When injected into old mice, apelin boosted the formation of new mitochondria, stimulated protein synthesis, autophagy, and other key metabolic pathways, and enhanced the regenerative capacity of aging muscle by increasing the number and function of satellite cells. Levels of circulating apelin declined during aging in humans, suggesting that restoring apelin levels to those measured in young adults may ameliorate sarcopenia.

In both normal aging and under pathological conditions, cognitive decline can diminish the quality of life. In the present study, we found that treatment with piperlongumine (PL), isolated from the long pepper, significantly improved cognitive function in novel object recognition and performance in nest building in 25-month-old female mice. These effects appear to be partly due to the modulation of neuronal activity and neurogenesis in the hippocampus.

PL is a primary constituent of Piper longum, which has been reported to kill multiple types of cancer cells through the targeting of the stress response to reactive oxygen species (ROS). Senescent cells can drive hyperplastic pathology and promote age-related neurodegeneration. Recently, PL has been reported to be a potential novel lead for the development of senolytic agents and the selective depletion of senescence cells as an anti-aging strategy may prevent cancer and aging-related degenerative diseases. Although in this study, we did not investigate the anti-tumour activities of PL in aged mice, PL treatment may be beneficial through the apoptosis of age-related senescence cells.

Cellular senescence is associated with oxidative stress and inflammation. An increase in the expression of GFAP has been the most common change to be observed in astrocytes with aging. The results of this study demonstrated that PL did not affect the size of area occupied by glia, such as microglia and astrocytes, in the hippocampus of the aged mice. We also observed that lipid peroxidation in the hippocampus was not altered in the aged mice. However, previously, we have demonstrated that PL effectively decreases astrogliosis and microglia activation in the parietal cortex in animal models of Alzheimer's disease. The results indicated that the inflammation and microglia activation that was triggered by pathological conditions were effectively suppressed by PL treatment.

In the present study, there were few DCX-positive neuroblasts in the dentate gyrus of 25-month-old female mice, but, the aged mice treated with PL exhibited significantly higher number of DCX-positive cells in the dentate gyrus than in controls. These results suggest that PL may have an effect on neurogenesis by preventing or reversing age-related decline. The precise mechanism of action through which PL improves cognitive function remains unclear. Further studies, therefore, are warranted to investigate the effects of PL on neurogenesis.

Protein homeostasis, or proteostasis, is critical to maintain cellular integrity and function. Dysregulation of the proteome, including accumulation of damaged and aggregated proteins, is a major hallmark of aging. Accumulation of protein aggregates is also associated with pathological conditions, including neurodegenerative diseases. Though not much is known about the etiology of aggregates in many cases, their clearance can extend lifespan and alleviate the symptoms of neurodegeneration in some model systems.

There are three main mechanisms or branches of the protein homeostasis and clearance network: the lysosome-autophagy proteolytic system, molecular chaperones, and the proteasome. Macroautophagy, generally referred to as autophagy, is a tightly regulated process by which cellular organelles, proteins, and cytoplasm are engulfed into autophagosomes for degradation and recycling. The lysosomal-autophagy pathway is also important for the degradation of potentially toxic protein aggregates. Cellular quality control through this system may be particularly important in tissue-specific stem cells, which are used for lifelong tissue regeneration and repair.

Evidence suggests that the flux through the autophagy-lysosomal system is necessary for the maintenance and lineage progression of the adult neural stem cell (NSC) pool. These findings also raised a number of interesting questions regarding the precise role of autophagy in the NSC lineage in the adult and aging brain. For example, is autophagy critical for all stages of neurogenesis, or are specific transitions during lineage progression particularly dependent on this process?

Comparison of the activated (aNSC) and quiescent (qNSC) neural stem cells revealed striking differences in the expression of genes involved in protein homeostasis between the two cell types. Further analysis revealed that genes specifically associated with lysosomal function were selectively upregulated in the quiescent population. This is in contrast to aNSCs, which had higher expression of various molecular chaperones and displayed a signature associated with the proteasome and ubiquitin-mediated proteolysis. The use of a reporter system with manipulation of autophagic flux revealed that qNSCs degrade their lysosomal contents at a much slower rate than aNSCs.

The correlation between lysosome activation and NSC activation raises the question of whether activation of lysosomes is sufficient to drive NSCs out of the quiescent state. NSC activation involves cell cycle re-entry in response to intrinsic or extrinsic cues from the neurogenic microenvironment, although the molecular mechanisms are not fully understood. Could lysosome activation be a novel intrinsic stimulus to break quiescence? Recent work provides compelling evidence that this may be the case.

The authors observed that blocking lysosomal acidification induced aggregate accumulation in qNSCs and significantly reduced their ability to become activated. In contrast, induction of autophagic flux reduced the quantity of aggregates and enhanced the response of qNSCs to activation cues. This evidence suggests that clearance of protein aggregates is sufficient to induce activation of qNSCs in response to growth factor stimulation, although it cannot be ruled out that other unidentified cargo are critical for activation. Nevertheless, pathological lysosome dysfunction and aggregate buildup may have a causative role in the age-associated decrease in NSC activation and neurogenesis.

How did your involvement in life extension begin; did you realize the problem of aging yourself, or were you introduced to it by someone else?

It started because of my awareness that the healthcare system was broken, like the growth of an unplanned city that has no rhyme or reason. Our healthcare system reacts to system failures rather than preventing them, because that is more lucrative. The incentives push science in poor directions, and then these become inferior technologies and treatments. I came to the conclusion that we need a system reset. After much research and reflection, it became my conviction that this reset should be to delay and reverse aging and rejuvenate robust health. I believe this will result in reduced suffering and the greatest opportunity for individual and civilizational growth.

Methuselah Foundation has given millions to regenerative medicine research, backing ventures such as Organovo, Oisin Biotechnologies, and SENS Research Foundation. Would you like to tell us about some of the results that these companies have obtained thanks to your charity?

Well, Organovo invented and is now selling high-fidelity 3D human liver and kidney tissues to the research market, is providing contract services, and is on track to deliver a 3D liver patch to the clinic in two years. Another portfolio alumnus, Silverstone Matchgrid, has saved the lives of over 1,000 people due to our investment in its paired kidney donation software. This software is now used in over 35 hospitals in the U.S., Europe, and soon, Saudi Arabia. I don't think I need to say anything about SENS Foundation - it is fantastic, and we at Methuselah Foundation couldn't be prouder of its success and contributions.

We have very high expectations for Oisin Bio and OncoSenX. We anticipate that it will be in Phase 1 safety trials by mid-2019. We hope to provide it to some patients much sooner than previously possible, as the FDA is liberalizing treatment availability via the recently passed "Right to Try" legislation. Leucadia Therapeutics is a startup focused on defeating Alzheimer's disease. This is progressing and promising. We hope to have major news later this year. Rather than go on, I'd like to say that we at Methuselah Foundation tend to be modest about proclaiming our successes. We prefer that the companies and scientists behind them get famous.

Can you tell us about the Methuselah Fund and how its mission differs from that of Methuselah Foundation?

The Methuselah Fund, or M Fund, is designed to give donors a chance to get a return on equity now that the longevity field is maturing. Many of our donors have been faithfully donating for years, and now that opportunities are emerging, we wanted to give them the first opportunity to invest. We are delighted to announce that we just successfully closed the M Fund's Founder's Round. We now have four companies in our portfolio and have been looking at helping form some promising new ventures. We are particularly proud to say that every single one of our members is a mission-driven individual who wants, more than anything, to see an end to the aging problem.

You were the first to put forward the concept of longevity escape velocity, or LEV. How far are we from LEV, assuming the current pace of research and no serious showstoppers?

Twelve years, or 2030, is my best guess based on what is known today. I anticipate that within 3 years, some interventions will be available via safety trials and that people who are treated will receive benefits that put them on a path toward LEV. I believe things will accelerate from there, as vastly more attention is triggered by early advances. We are seeing the first glimmers of this already.

Scientists have developed a technique to directly convert the cells in an open wound into new skin cells. The approach relies on reprogramming the cells to a stem-cell-like state and could be useful for healing skin damage, countering the effects of aging and helping us to better understand skin cancer. "Our observations constitute an initial proof of principle for in vivo regeneration of an entire three-dimensional tissue like the skin, not just individual cell types as previously shown."

The scientists knew that a critical step in wound recovery was the migration - or transplantation - of basal keratinocytes into wounds. These stem-cell-like cells act as precursors to the different types of skin cells. But large, severe wounds that have lost multiple layers of skin no longer have any basal keratinocytes. And even as these wounds heal, the cells multiplying in the area are mainly involved in wound closure and inflammation, rather than rebuilding healthy skin.

The researchers first compared the levels of different proteins of the two cell types (inflammatory versus keratinocytes) to get a sense of what they'd need to change to reprogram the cells' identities. They pinpointed 55 "reprogramming factors" (proteins and RNA molecules) that were potentially involved in defining the distinct identity of the basal keratinocytes. Then, through trial and error and further experiments on each potential reprogramming factor, they narrowed the list down to four factors that could mediate the conversion to basal keratinocytes.

When the team topically treated skin ulcers on mice with the four factors, the ulcers grew healthy skin (known as epithelia) within 18 days. Over time, the epithelia expanded and connected to the surrounding skin, even in large ulcers. At three and six months later, the generated cells behaved like healthy skin cells in a number of molecular, genetic, and cellular tests. The researchers are planning more studies to optimize the technique and begin testing it in additional ulcer models.