In just a few short years, the study of cellular senescence has grown enormously. It has become an area of intense interest and funding in comparison to its prior status as a thin sideline of cancer research and a yet another of the backwaters of aging research. Sadly, aging research considered as a whole is still a neglected, poorly funded field of medical science in comparison to its importance to all of our futures, but this will hopefully change soon. The 2011 demonstration of a slowing of degeneration in an accelerated aging lineage of mice via removal of senescent cells opened a great many eyes. A growing number of studies since then have shown reversal of many specific aspects of aging through clearance of senescent cells, and the potential for removal of senescent cells to form the basis for the effective treatment of many age-related diseases. These studies are accompanied by varied approaches to the selective destruction of these unwanted, harmful cells in aged tissues, including several classes of drug compound, gene therapies, and antibody therapies. This is an important transition for the study of aging as a medical condition: the first legitimate, working rejuvenation therapies now exist in their earliest stages. They have become a reality. From here the field will only become ever more promising.

The July issue of EBioMedicine gathers together papers from recent months to focus on aging and metabolism. Prominent in this collection are papers on the biology of senescent cells, the contribution of senescent cells to aging, and methods of selectively destroying senescent cells. I pointed out a few of these when they were first published online earlier this year, but I think it worth looking through the collection as it is presented here. This is the future: the stream that will become a flood, a huge new industry of medicine. It is impossible to work in the medical life sciences without having heard something of this newly important area of research and development. Senolytic therapies capable of safely clearing a large fraction of the burden of senescent cells in old individuals may well do more for health in later life than all of the heralded advances of the past thirty years, statins and early stem cell therapies included. These are exciting times that we live in - and then, I would hope, not too many years from now, we'll be able to say all of this again as glucosepane cross-link breakers become a reality as well, another line of rejuvenation research that should be just as influential, at the very least for cardiovascular health.

Aging and Metabolism: Two Sides of the Same Coin

The mounting challenges healthcare systems face with an aging population are largely due to increased prevalence of noncommunicable diseases (NCDs). In 2015, NCDs accounted for 70% of all deaths globally. 80% of NCD-related deaths are attributed to cardiovascular disease, cancer, respiratory diseases, and diabetes. In this issue find a series of articles discussing diverse aspects of geroscience - the relatively new field of understanding the biology of aging and age-related disease. At the core of geroscience research is the dogma that aging is not simply an immutable outcome of life, but that its biological underpinnings, once understood, can be manipulated to improve health. From the series of pieces presented in this issue, it becomes apparent that aging and age-related disease are intimately entangled with metabolic function, both at the molecular/cellular and organismal levels. The etiology of cardiovascular disease, cancer, lung, liver, and kidney dysfunction, and diabetes can be at least in part attributed to metabolic defects associated with increasing age.

Cellular senescence describes the phenomenon where somatic cells cease to divide, become resistant to apoptosis, and develop a senescence-associated secretory phenotype (SASP) that can have deleterious effects on surrounding tissues and throughout the body. One article discusses the role of mitochondrial dysfunction in cellular senescence and how breakdown of mitochondrial components (mitophagy) is likely involved in senescence and aging. How telomeres - irrespective of length, contrary to the previous notion that shortened telomeres were simply a readout of a cell's age - can both protect against and effect cellular senescence programs is discussed in another article. Translational approaches to targeting the biological basis of aging is a rapidly-developing field. A third article discusses targeting cellular senescence programs to improve fitness. Among these approaches are so-called senolytic agents, which selectively clear senescent cells and relieve the associated pathophysiology they confer.

Telomeres and Cell Senescence - Size Matters Not

So far, the best explanation for replicative senescence is the shortening of telomeres, regions composed of DNA repeats associated with proteins, found at the ends of chromosomes. In the 1990s, it was shown that telomere regions gradually shorten with cell division and that this correlates with the induction of cellular senescence. Importantly, it was demonstrated that ectopic expression of the enzyme telomerase, which is capable of elongating telomeres, counteracts telomere shortening driven by cell division and bypasses the senescence arrest. This experiment demonstrated that telomere length was the limiting factor in the senescence arrest and therefore played a causal role in the process. Since then, great advances have been made in the understanding of how telomeres are able to signal the senescence arrest. These mechanisms are of particular importance in the field of ageing, since cellular senescence, driven by telomere dysfunction, has been shown to be a causal driver of ageing and age-related pathology.

In recent years, important conceptual advances have been made in terms of our understanding of the role of senescent cells in vivo. It is now clear that the impact of senescence in vivo is not restricted to the loss of proliferative capacity. Apart from the cell-cycle arrest, senescent cells have been shown to experience dramatic changes in terms of gene expression, metabolism, epigenome and importantly, have been shown to have a distinct secretome profile, known as the Senescence-Associated Secretory Phenotype (SASP), which mediates the interactions between senescent and neighboring cells. The SASP includes pro-inflammatory cytokines as well as growth factors and extracellular matrix degrading proteins and is thought to have evolved as a way for senescent cells to communicate with the immune system (potentially to facilitate their own clearance), but also as an extracellular signal to promote the regeneration of tissues through the stimulation of nearby progenitor cells. Nonetheless, it has been shown that a "chronic" SASP is able to induce senescence in adjacent young cells, contributing to tissue dysfunction.

Recent data indicates that senescent cells play a variety of beneficial roles during processes such as embryonic development, tumor suppression, wound healing and tissue repair. On the other hand, senescent cells have been detected in multiple age-related diseases and in a variety of different tissues during ageing. The positive and negative effects of senescence in different physiological contexts may be a reflection of the ability of the immune system to effectively clear senescent cells. It has been speculated that an "acute" type of senescence plays generally beneficial roles in processes such as embryonic development and wound-healing, while a "chronic" type of senescence may contribute to ageing and age-related disease. The role of telomeres in the induction of these two types of senescence is still unclear. In this review, we will first describe evidence suggesting a key role for senescence in the ageing process and elaborate on some of the mechanisms by which telomeres can induce cellular senescence. Furthermore, we will present multiple lines of evidence suggesting that telomeres can act as sensors of both intrinsic and extrinsic stress as well as recent data indicating that telomere-induced senescence may occur irrespectively of the length of telomeres.

Mitochondria in cell senescence: Is mitophagy the weakest link?

Cell senescence is increasingly recognized as a major contributor to the loss of health and fitness associated with aging. Senescent cells accumulate dysfunctional mitochondria; oxidative phosphorylation efficiency is decreased and reactive oxygen species production is increased. In this review we will discuss how the turnover of mitochondria (a term referred to as mitophagy) is perturbed in senescence contributing to mitochondrial accumulation and Senescence-Associated Mitochondrial Dysfunction (SAMD). We will further explore the subsequent cellular consequences; in particular SAMD appears to be necessary for at least part of the specific Senescence-Associated Secretory Phenotype (SASP) and may be responsible for tissue-level metabolic dysfunction that is associated with aging and obesity. Understanding the complex interplay between these major senescence-associated phenotypes will help to select and improve interventions that prolong healthy life in humans.

Cellular Senescence: A Translational Perspective

There is a possibility that senolytics and SASP inhibitors could be transformative, substantially benefiting the large numbers on patients with chronic diseases and enhancing healthspan. That said, as this is a very new treatment paradigm, there are many obstacles to overcome. At least one reassuring advantage of targeting cellular senescence is the conservation of fundamental aging mechanisms such as senescence across mammalian species, however, reducing the risk of results in mice failing to translate to humans. Furthermore, unlike the situation for developing drugs to eliminate infectious agents or cancer cells, not every senescent cell needs to be eliminated to have beneficial effects. Unlike microbes or cancer cells, senescent cells do not divide, decreasing risk of developing drug resistance and, possibly, speed of recurrence. With respect to risk of side-effects, single or intermittent doses of senolytics appear to alleviate at least some age- or senescence-related conditions in mice. This suggests that intermittent treatment may eventually be feasible in humans, perhaps given during periods of good health. If so, this would reduce risk of side-effects. Progression from the discovery of the first senolytics to being at the point of initiating proof-of-concept clinical trials has been remarkably fast. With sustained effort and a lot of luck, these agents could be transformative.

Risk of neurodegenerative disease is strongly connected to the health of the cardiovascular system. Lack of exercise and putting on excess weight significantly increase the risk of both cardiovascular disease and forms of dementia. You can't use lifestyle choices to hold back aging entirely; the only way forward towards that goal is the research and development of therapies that can repair the cell and tissue damage that causes age-related degeneration. You can, however, at least make the choice to avoid self-sabotage, even if most other people do not do so in this sedentary age of cheap calories. How greatly can you benefit from a good lifestyle alone? Researchers here examine epidemiological data and estimate that about a third of dementia cases might be preventable, though I think the tone is a little self-congratulatory given the present poor state of treatment options and outcomes.

"There's been a great deal of focus on developing medicines to prevent dementia, including Alzheimer's disease. But we can't lose sight of the real major advances we've already made in treating dementia, including preventive approaches." A recent commission brought together international experts to systematically review existing research and provide evidence-based recommendations for treating and preventing dementia. About 47 million people have dementia worldwide and that number is expected to climb as high as 66 million by 2030 and 115 million by 2050.

The commission's report identifies nine risk factors in early, mid- and late life that increase the likelihood of developing dementia. About 35 percent of dementia - one in three cases - is attributable to these risk factors, the report says. By increasing education in early life and addressing hearing loss, hypertension and obesity in midlife, the incidence of dementia could be reduced by as much as 20 percent, combined. In late life, stopping smoking, treating depression, increasing physical activity, increasing social contact and managing diabetes could reduce the incidence of dementia by another 15 percent. "The potential magnitude of the effect on dementia of reducing these risk factors is larger than we could ever imagine the effect that current, experimental medications could have. Mitigating risk factors provides us a powerful way to reduce the global burden of dementia."

The commission also examined the effect of nonpharmacologic interventions for people with dementia and concluded that they had an important role in treatment, especially when trying to address agitation and aggression. "Antipsychotic drugs are commonly used to treat agitation and aggression, but there is substantial concern about these drugs because of an increased risk of death, cardiovascular adverse events, and infections." The evidence showed that psychological, social and environmental interventions such as social contact and activities were superior to antipsychotic medications for treating dementia-related agitation and aggression. The commission also found that nonpharmacologic interventions like group cognitive stimulation therapy and exercise conferred some benefit in cognition as well.

Link: https://www.eurekalert.org/pub_releases/2017-07/uosc-e1i071717.php

In this research, it is shown that centenarians have a lower burden of disease than people who die at earlier ages. You might compare it with very similar results noted last month. Aging is the accumulation of molecular damage and its consequences; the only way to reach later ages is to be less damaged or more resilient to the consequences of damage. It would be very surprising to find that the longest-lived people are more damaged, rather than less, so the results here are the expected outcome for such a study. Nonetheless, centenarians are still frail and greatly impacted by aging - their state of being is not a goal to aim for via medical technology. Instead we should be looking at ways to turn back the causes of aging for everyone, to produce outright rejuvenation, not merely a slightly slower decline.

Researchers have been studying illness trajectories in centenarians during the final years of their lives. According to their findings, people who died aged 100 or older suffered fewer diseases than those who died aged 90 to 99, or 80 to 89. Forty years ago, life expectancy was such that, in the industrialized world, only (approximately) one in 10,000 people were expected to reach the age of 100 or more. Today's estimates suggest that half of all children born in the developed world during this century will live to at least 100. Therefore, the question that poses itself is whether extreme old age is necessarily associated with increased morbidity. There is evidence to suggest that centenarians develop fewer diseases than younger cohorts of extreme old people. In discussions surrounding the issues associated with aging populations, this is referred to as the 'compression of morbidity' hypothesis - a term which describes the phenomenon of the onset of disability and age-related diseases being increasingly being well into old age, resulting in a shortening (or compression) of this phase.

Using diagnoses and health care utilization data routinely collected by the German statutory health insurance company Knappschaft, the researchers studied relevant events during the final six years of life of approximately 1,400 of the oldest old. For the purposes of analysis, this cohort was then divided into three groups. Data on persons who had died aged 100 or older were compared with random samples of persons who had died in their eighties or nineties. The analysis, which included data on very old persons living in their own homes as well as data on those living in residential care, focused on comorbid conditions classified by the Elixhauser Comorbidity Index as being usually associated with in-hospital mortality. "According to the data, centenarians suffered from an average of 3.3 such conditions during the three months prior to their deaths, compared with an average of 4.6 conditions for those who had died in their eighties."

If one includes disorders commonly associated with extreme old age, such as different types of dementia and musculoskeletal disorders, approximately half of all centenarians recorded a total of five or more comorbid conditions. The same number of comorbid conditions was found in 60 percent of persons who had died in their nineties and 66 percent of persons who had died in their eighties. While different types of dementia and heart failure were found to be more common among centenarians than among the younger cohorts, high blood pressure, cardiac arrhythmia, renal failure, and chronic diseases were less common in those who had died after reaching 100 years of age. The incidence of musculoskeletal disorders was found to be similar in all three age groups.

Link: https://www.charite.de/en/service/press_reports/artikel/detail/gesellschaft_im_wandel_100_ist_die_neue_80/

The immune system is highly influential in the processes of regeneration. Inflammation is a key marker of the types of immune cell involved and the sort of activities they are undertaking, either helping or hindering regeneration, and greater levels of inflammation are usually a bad thing. Researchers have demonstrated enhanced healing by ensuring that fewer of the more aggressive and inflammatory class of macrophage cell are present in injured tissue, for example. Further, it is known that aspects of aging such as immune system dysfunction and the growth in number of senescent cells can disrupt regeneration, and inflammation appears to be an important component there also. Is inflammation a direct cause of failing regeneration, or is it more of a signal that other processes are at work, and those processes happen to coincide with greater inflammation?

In the paper here, researchers investigate this question in a subset of the broader problem. They are interested in the development of stem cell therapies as a treatment to accelerate wound healing. Wounds are inflammatory environments, however, and this isn't helpful when it comes to the survival of transplanted cells. The researchers find that one approach to suppressing inflammation can be beneficial in this scenario; this extends the common theme of inflammation as a hindrance to healing found in other areas of research relevant to enhancing existing regenerative processes. We are probably going to see much more on this topic in the next few years, especially if other research groups can find ways to improve the outcome of cell therapies via similar methodologies. In the long run, however, more sophisticated means of suppressing inflammation may be of greater important when it comes to adjusting native cell behaviors and capacity for regeneration. This is very much needed in older individuals.

Reducing inflammation protects stem cells during wound repair

Inflammation is normal in wound healing. As wounds heal, white blood cells, such as those called macrophages, are attracted to the wound site and release substances called cytokines that cause an inflammatory response. At the wound site, enzymes such as cyclooxygenase-2 (COX-2) also become more active and contribute to the inflammation. This inflammation is important in the normal healing process, affecting tissue growth and blood flow changes that allow the tissue to heal; when the inflammation subsides, skin cells start growing to cover the wound and help the tissue knit together. In chronic wounds, however, inflammation can be more extensive and prolonged. This is bad news for any stem cells that might be injected into a chronic wound to help heal it. Stem cells are not like typical drugs - they are alive, and like all life forms, they can die in a hostile environment. The harsh inflammation in chronic wounds kills many of the injected cells, and this is one of the reasons why, so far, stem cells have not worked as a treatment for chronic wounds.

Researchers hypothesized that celecoxib, a common anti-inflammatory drug that selectively inhibits the pro-inflammatory enzyme COX-2, would improve stem cell survival and treatment outcomes for chronic wound therapy. To test their hypothesis, the group used an experimental wound model in mice. The researchers split the mice into four groups. They left a control group completely untreated and treated the second group using mouse stem cells from bone marrow, which they injected into the skin near the wound. They treated a third group orally using celecoxib, and the final group received celecoxib orally, as well as a stem cell injection into the skin near the wound. After a week, the scientists examined the wound tissue for healing and inflammation, and checked if the stem cells had survived.

As expected, the wounds showed an inflammatory response over the duration of the experiment. However, the mice treated using both celecoxib and stem cells showed better wound healing and more tissue growth a week later, compared with untreated mice or mice treated using stem cells or celecoxib alone. A significantly higher amount of stem cells had survived and integrated into the wound tissue in mice that had received celecoxib. So far so good, but did celecoxib have any direct effects on the stem cells themselves? The scientists found that celecoxib directly increased stem cell differentiation into keratinocytes - skin cells required for wound healing. By helping the stem cells to survive and encouraging them to differentiate into skin cells, celecoxib produced a two-pronged healing effect.

Cox-2 inhibition potentiates mouse bone marrow stem cell engraftment and differentiation-mediated wound repair

Engraftment of transplanted stem cells is often limited by cytokine and noncytokine proinflammatory mediators at the injury site. We examined the role of Cyclooxygenase-2 (Cox-2)-induced cytokine-mediated inflammation on engraftment of transplanted bone marrow stem cells (BMSCs) at the wound site. BMSCs isolated from male C57/BL6J mice were transplanted onto excisional splinting wounds in presence or absence of celecoxib, a Cox-2 specific inhibitor, to evaluate engraftment and wound closure. Celecoxib administration led to a significantly high percent of wound closure, cellular proliferation, collagen deposition, BMSCs engraftment and re-epithelialization at the wound site. Thus celecoxib protects transplanted BMSCs from Cox-2/IL-17-induced inflammation and increases their engraftment, differentiation into keratinocytes and re-epithelialization thereby potentiating wound tissue repair.

Macrophages are one of the types of immune cell responsible for destroying potentially dangerous cells, such as those that have become cancerous. Unfortunately cancerous cells tend to circumvent the immune system by displaying molecules on their outer surface that cause macrophages to leave them alone. This is an abuse of recognition mechanisms that exist to protect other cell types. Researchers here show that producing engineered macrophages that ignore this signal can be a viable approach to cancer therapy, even though past attempts have proven too harmful to normal cells to proceed towards the clinic. Their new methodology manages to avoid the destruction of non-cancerous cells to any significant degree, which is a promising step forward for the use of macrophages in cancer immunotherapy.

One reason cancer is so difficult to treat is that it avoids detection by the body. Agents of the immune system are constantly checking the surfaces of cells for chemical signals that say they belong, but cancer cells express the same chemical signals as healthy ones. Without a way for the immune system to tell the difference, little stands in the way of cancer taking over. Now, researchers have learned how to re-engineer macrophages, the "first responders" of the immune system, so that they can distinguish between healthy and cancerous cells. Armed with this ability, the engineered cells were able to circulate through the body of a mouse, invade solid tumors and specifically engulf human cancer cells therein.

​​​​​​​"Our new approach takes young and aggressive macrophages from the bone marrow of a human donor and removes a key safeguard that cancer cells have co-opted to prevent them from being engulfed. Combined with cancer-specific targeting antibodies, these engineered macrophages swarm into solid tumors and rapidly drive regression of human tumors without any measurable toxicity." Immune cell therapies using engineered T-cells have recently emerged as successful treatments for some blood cancers, which are referred to as "liquid" tumors. Tumors in other tissues are generally more solid, which can physically impede the ability of T-cells to penetrate into the mass of the tumor. Macrophages readily infiltrate diseased and damaged tissues, including tumors. As such, macrophage-based cancer therapies were investigated decades ago. While they were found to be safe in patients, they were not effective in destroying cancerous cells. It is now understood that such macrophages received the same "don't eat me" signal from both healthy and cancerous cells.

It was since shown that a protein on human cells called CD47 functions as a "marker of self" by interacting with a protein on the surface of macrophages called SIRPA. When SIRPA contacts CD47 on any other cell, it serves as a safeguard that prevents the macrophage from engulfing the other cell, even if it's cancerous. With that in mind, the researchers thought that controlling this protein might revitalize macrophage-based cell therapies. Injections of antibody molecules that block CD47 from interacting with SIRPA are already being tried in the clinic based on observations of some reduction in the sizes of tumors in mouse models. However, such molecular treatments reproducibly cause rapid loss of many circulating blood cells, as macrophages now attack some healthy cells as well. In addition to causing anemia, some mice with depleted CD47 die from autoimmune disease.

To get around these safety concerns and to potentially maximize therapeutic effects on tumors, researchers took fresh, young macrophages from human donors as well as mouse donors and directly blocked their SIRPA. They also injected various antibodies that bind to cancer cells, which help to activate macrophages that might enter the tumor. "The big surprise is that injected macrophages circulate all around the body but accumulate only within the tumors where they engorge on cancer cells." After two injections, cancer cells were depleted 100-fold from tumors the size of a dime, and tumors regressed 80 percent in size. Importantly, blood cells were unaffected by the treatments, which suggests that this approach is safe.

Link: https://news.upenn.edu/news/penn-researchers-engineer-macrophages-engulf-cancer-cells-solid-tumors

The latest Lifespan.io crowdfunding campaign is in support of AgeMeter development, an infrastructure technology used to assemble the data needed for compound biomarkers of aging built from existing simple health measures. The development of a reliable, accurate, and low-cost biomarker of biological age, that reflects an individual's burden of molecular damage, and thus risk of disease and mortality, is an important topic. Without such a measure, it is very time-consuming to test potential rejuvenation therapies, as the only practical approach is to wait and see what happens over the life span of the test subjects. That is a formidable expense even for mouse studies. With such a measure, most of that work could be replaced with a quick set of tests before and after the use of a potential therapy.

While a great deal of attention is given to biomarker development that is based on patterns of DNA methylation, there is a school of thought that suggests researchers could build something just as useful by suitably combining existing simple measures such as heart rate, blood pressure, grip strength, and so on. The greatest challenge in the development of such a biomarker lies in ensuring accuracy and reliability at the point of data collection, while still allowing large numbers of people to be tested cost-effectively. This initiative seeks to modernize and improve existing approaches, now a more pressing concern given the advent of potential rejuvenation therapies such as clearance of senescent cells.

Centers for Age Control has launched a fundraising campaign on Lifespan.io in support of the AgeMeter, a diagnostic system to measure human functional age. The device is meant to assist in the assessment of therapeutics that address the aging processes during clinical trials, as well as being a useful tool for the general practitioner. As research efforts intensify towards developing effective rejuvenation therapies, the need for cost-effective ways of measuring the rate of aging becomes all the more urgent. An effective functional age test would be a very useful tool in determining this, complementing the data from biochemical tests.

The list of biomarkers AgeMeter will assess includes auditory and visual reaction time, lung capacity, muscle coordination, decision-making time, memory, and a few others, which are reliable predictors of functional age in previous studies. AgeMeter will be used by physicians for the health assessment of patients and to help highlight areas of concern. This will allow a doctor to work with the patient to develop an effective personalised healthcare strategy and could be of great value in helping people to maintain health.

"AgeMeter is a modernized successor to the H-SCAN functional age test that was originally developed in 1990 to assess physical biomarkers of aging. We have gathered an impressive experience in measuring functional age with H-Scan. Now we can make it serve humanity even better. AgeMeter will be a low-cost, modular touch screen device with special peripherals for integrating multiple cognitive and biometric assessment technologies. We hope to not only make a functional prototype suitable for research needs, but also to create software for a user account system for each test participant. This will enable individual users to store and access multiple test results, and therefore analyze the progression of one's metrics over time and in response to potential anti-aging interventions. We believe this is the most valuable part of the project for people who care about their health and want to be sure their lifestyle is good for them."

Link: http://www.leafscience.org/introducing-agemeter/

Considering the whole of the past thirty years, it is fairly safe to say that studies showing improved longevity in animal models have a terrible track record when it comes to the reproduction of findings. Small gains in life expectancy in one study promptly evaporate when it is attempted by other groups. Very few approaches to slowing aging can be reliably reproduced, and the most well-studied of those, calorie restriction, is probably the cause of many of the early failures. It used to be the case that all too few researchers controlled for the effects of calorie restriction: it is easy to make animals eat more or less as a consequence of pharmaceutical interventions, and the results due to changed calorie intake are larger than the results due to most of the interventions tested. The Interventions Testing Program has spent much of the last fifteen years demonstrating that most prior mouse studies of interventions thought to modestly slow aging should be taken with a grain of salt. The same is also true of studies in lower animals, in species with much shorter life spans, but where length of life is affected to a greater proportional degree by environmental influences.

The authors of the open access paper below try to put some numbers to the difficulties involved in picking out small changes in the aging process due to an experimental intervention. The animals involved tend to have quite variable life spans, and are very prone to life expectancy changes based on the details of their environment. This state of affairs requires larger numbers of animals and better statistical approaches to have any confidence in sifting out useful data. But the wrong conclusions are drawn, I think. The point of view of these researchers is that the way forward is to keep on chasing small effects on aging, and to improve the state of experimental design in order to make it more practical to find those small effects.

This is a ridiculous position. What should in fact happen is for the research community to put aside the lines of work that produce only small and erratic effects, stop digging into the biochemistry of exercise and calorie restriction as a gateway to mediocre therapies, and focus instead on biotechnologies with results that are reliable, reproducible, and large enough to be clearly identified even given the challenges. Today that means senolytics capable of clearing senescent cells, cell therapies, amyloid clearance, other line items resulting from the SENS approach of damage repair, and little beyond that short list. If the last few decades has taught us anything, it should be that attempts to tinker with the operation of metabolism in order to slightly slow aging by recapturing some of the effects of calorie restriction are expensive, unreliable, and produce only small gains. Why then is this metabolic tinkering with poor outcomes still the primary choice for most of the research community? It makes little sense, at least to those of us interested in the development of working, effective therapies that can produce rejuvenation in old humans.

Computational Analysis of Lifespan Experiment Reproducibility

Over the last few years, science has been plagued by a reproducibility crisis. This crisis has also taken root in the aging research community, with several high-profile controversies regarding lifespan extensions. Frequently cited reasons for the failure of a result to reproduce are substandard technical ability, lack of attention to detail, failure to control environmental factors or that the initial positive result was a statistical outlier that was never real in the first place. One way to address these reproducibility problems would be to list the numerous controversies and to attempt to identify the individual underlying causes and to provide a possible explanation. This would be a long and arduous task resulting in largely speculative explanation and provide little in terms to resolve future controversies. An alternative way would be to assume that these controversies arise mostly through honest disputes of scientists standing by their results. If so, their frequency would suggest an underlying technical problem with standard practices in the field that foster such disputes. We decided to take the alternative way and to ask how reproducible lifespan experiments are under ideal conditions, in silico, allowing to control every environmental and technical aspect.

One important experimental consideration to minimize both false positive and false negative results is the power of detection (POD), or statistical power of a given experimental design. POD is defined as the probability to appropriately reject the null hypothesis in favor of the alternate hypothesis. For lifespan experiments, where the null hypothesis is that there is no effect on lifespan, the POD is the probability to correctly detect a true lifespan extension. Power calculations are a statistical tool to determine whether the experimental design is sufficient to detect the expected effects size. Power calculations are widely used in long term expensive mouse experiments or in clinical trials to ensure that the planned experiments have the necessary power to detect the expected effect. However, power calculations are rarely employed in experiments to measure the effects of genetic or environmental perturbations that could affect lifespan in invertebrate model organisms such as C. elegans.

In this study, we asked how POD is influenced by different experimental practices and how likely it is that underpowered experiments lead to scientific disputes between two groups conducting identical experiments. To address these questions, we generated a parametric model based on the Gompertz equation using lifespan data of 5,026 C. elegans. We then used this model to simulate lifespan experiments with different conditions to determine how experimental parameters affect the ability to detect lifespan increases of certain sizes. We considered two important experimental features that contribute to the workload of lifespan experiments: frequency of scoring and number of animals in each cohort. Our data show that the POD is greatly affected by the number of animals in each group, but less so by scoring frequency. We further show how inappropriately powered experiments negatively affect reproducibility. Our results make clear that current standard practices are unlikely to produce consistently reproducible results for real longevity effects below 20%, even under ideal conditions.

TDP-43 is known to increase with age, and also forms aggregates observed in ALS and frontemporal dementia, among other conditions. The increased amount of TDP-43 alone, even without aggregates, appears to diminish the cellular housekeeping process of autophagy, with detrimental long term consequences. Artificially reducing the levels of TDP-43 too far will produce other issues, however, as this disrupts correct microglial function in the brain, making the microglia too aggressive when it comes to dismantling synaptic connections between brain cells. Thus building a therapy that targets TDP-43 isn't as straightforward as it might be. Here, researchers look at breaking down the aggregates rather than targeting TDP-43 indiscriminately, an approach that may result in a therapy for TDP-43-related conditions.

Scientists have long known that a protein called TDP-43 clumps together in brain cells of people with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, and is associated with neuron death. This same protein is thought to cause muscle degeneration in patients with sporadic inclusion body myositis (sIBM), leading many researchers to think that TDP-43 is one of the causative factors. Now, researchers found that a specific chemical modification called acetylation promotes TDP-43 clumping in animals. Using a natural anti-clumping method in mouse models, the scientists reversed protein clumping in muscle cells and prevented the sIBM-related muscle weakness. "We suspect that getting rid of this abnormal TDP-43 clumping could be a potential therapy for these diseases. In principle, we think this reversal of clumping could be achieved by taking an injectable or oral medication. Though, we caution, that's still a long way off. The research community still has much more work to do."

TDP-43 normally works in the cell nucleus. It binds to DNA and to the RNA molecules transcribed from DNA. The protein appears to have many important functions in regulating how genes are expressed. Somehow - in people with sIBM, ALS, and a few other degenerative diseases - TDP-43 moves out of the nucleus and into the main volume of the cell, or cytoplasm, and then clumps together. The loss of TDP-43 from the nucleus leads to the failure of normal gene expression regulation. Many scientists suspect that this is the major reason why affected cells die. For many years, no one knew how TDP-43 moved out of its normal workspace in the cell nucleus, but a 2015 study identified one possible factor: a chemical modification known as acetylation.

Cells commonly use acetylation to switch the activity of proteins on or off. Acetylation at two spots on TDP-43 caused the protein to detach from RNA. The protein then drifted into the cytoplasm and started to aggregate. This research was done in cells grown in lab dishes. To underscore the potential relevance to human disease, the scientists examined spinal motor neurons from ALS patients and identified aggregates of TDP-43 that had been acetylated in the same way. For the new study, the researchers examined the effect of acetylated TDP-43 in living animals. In this case, they sought to mimic sIBM in mice, in which TDP-43 clumps in muscle cells. "We tend to see sIBM and ALS as resulting from essentially the same TDP-43-related pathological process - the clumping effect - but in different cell types. The advantage of studying sIBM is that muscle cells are much more accessible than are motor neurons, which are affected in ALS."

The team used a special method to inject acetylated TDP-43 proteins directly into mouse muscle cells. In contrast to ordinary TDP-43 proteins, these acetylated proteins quickly aggregated outside the nucleus. The aggregate-burdened cells showed multiple features that are also seen in human sIBM. The researchers observed cellular markers indicating that the muscle cells were actively trying to get rid of the TDP-43 aggregates. The team found that they could boost these cell defense mechanisms and swiftly remove most of the aggregates by adding heat shock factor 1 (HSF1), a naturally occurring protein that is known to work as a master switch for anti-aggregation processes in cells. The researchers now hope to identify compounds suitable for use in oral drugs that have the same anti-clumping effect.

Link: https://www.eurekalert.org/pub_releases/2017-07/uonc-anc071417.php

Despite an enormous amount of effort, researchers have discovered very few human gene variants with reliable effects on longevity across multiple study populations, and even those effects are small. FOXO3 is one of these genes. The current consensus in the face of this data is that variants in thousands of genes contribute to natural differences in human longevity, interacting strongly with one another and with environmental differences, such that the picture is somewhat different in every individual. The usual situation is for any genetic study of longevity to find a few correlations, but those correlations then fail to appear in any other study, even of people in the same region and community. Researchers here suggest that even for FOXO3, the picture is more complicated than thought, and it has less influence on aging than thought.

People who live into their 90s or 100s - beyond the typical life expectancy near 80 for adults - can offer important lessons about healthy aging. Centenarians experience slower aging throughout their lives; live independently well into their 90s and spend only the last relatively few years of their exceptionally long lives with significant diseases or disabilities. Unlike average aging, in the case of people who live into their late 90s and even into their 100s, centenarians appear to benefit from combinations of longevity-enabling genes that likely protect against aging and age-related diseases and disability. FOXO3 could be playing such a role for people who live into their early to mid-90s. The gene had gained quite a bit of attention over the last 10 years as a possible contributor to longevity, but despite a lot of study, the mechanism by which FOXO3 helps people remains murky. The goal of the new study was to better understand the gene's role in survival to not just the 90s but beyond to even more exceptional ages.

The researchers examined genetic data from blood samples of 2,072 extremely old subjects from four centenarian studies: the New England Centenarian Study; the Southern Italian Centenarian Study; the Longevity Genes Project; and the Long Life Family Study. Researchers conducting centenarian studies such as these are working together to discover the biological mechanisms that enable remarkable aging. The researchers found that while FOXO3 did seem to play a role in longevity to a degree, that role did not generally affect living to ages 96 or older for men, or 100 for women - the oldest one percent of the population. "We attended presentations and read scientific papers claiming associations between FOXO3 variants and longevity, yet when we tested for these associations among centenarians, we were unable to reproduce the findings. We suspect that part of the reason may be because these earlier claims were coming from studies made up mostly of people in their 80s and 90s, and not those in their 100s."

Link: http://oregonstate.edu/ua/ncs/archives/2017/jul/new-findings-suggest-genetic-influence-aging-90s-not-beyond

Today, I'll point out a few recent papers relevant to the decline of muscle mass and strength that takes place with aging. The research community is somewhere in the midst of the long process of formally defining this process as a disease called sarcopenia. Formally defined or not, sarcopenia is a significant contribution to the frailty of later aging: the weakness, the risk of falling, the loss of vigor. The papers below are one small part of a large body of work that suggests a fair degree of the total burden of sarcopenia is actually self-inflicted: we live in an age of lethargy, within the embrace of comparative wealth and new technologies of ease and transport. As a consequence some aspects of our decline into old age are faster than they might be, even though we benefit greatly from advances in medical technology in all other facets of health in later life. In short, muscle requires maintenance, and most people are far too quick to give up on that work at the first opportunity.

Beyond a lack of exercise, the remaining portion of sarcopenia is not one of the more simple consequence of aging, however. Rather, it is a twining, partially explored mess of interacting mechanisms. Various studies provide compelling evidence for the role of inflammation, stem cell decline, cellular senescence, neurological decline in the links between muscle and nervous system, reduced protein intake in the typical diet of older individuals, an age-related failure to process dietary amino acids, and many more. They are probably all correct, insofar as they each examine only one narrow portion of the progressive disarray of very complex systems. The parable of the blind men and the elephant is frequently invoked in relation to aging research, and with good cause.

I would say that the best approach to the treatment of sarcopenia, as for many portions of the whole of age-related degeneration, is to pursue efforts to repair the known forms of fundamental damage that cause aging. Even if we cannot yet fully trace the consequences of this damage from start to end, the research community should still attempt to reverse it. It is faster to fix the damage and see what happens as a result than it is to map the changing biochemistry of aging at the detail level. If both courses of action proceed in parallel, we can have our cake and eat it, first striking at the root of the problem and then going on to untangle the foliage at our leisure.

Epidemiology of Sarcopenia: Determinants Throughout the Lifecourse

This review of the epidemiology of sarcopenia documents evidence of the differential peak and rate of decline for three components linked to the disorder: muscle mass, strength, and physical function. Differences are also apparent in relation to the peak level and subsequent loss rate of these characteristics between men and women; between ethnic groups and over time. The data suggest that the rate of decline in muscle mass is much less rapid than that in muscle strength. This, in turn, is much less pronounced than the rate of decline in physical function. Men have significantly higher levels of muscle mass, strength and function at any given age than women. In contrast, rates of decline seem similar between the genders, for each of the three characteristics.

Environmental risk factors for all three components of sarcopenia include sedentary lifestyles, adiposity, and multi morbidity. The role of cigarette smoking and alcohol consumption are much less apparent than have been observed in studies of osteoporosis or cardiovascular disease. Nutrition has been identified as having an important influence on the development of sarcopenia; in particular, protein intake has the potential to slow the loss of muscle mass, but does not appear to be as influential as in maintaining muscle strength or physical function. Physical activity, in particular resistance training, when performed at higher intensities appears beneficial for muscle strength and functioning. Trials combining protein supplementation and physical activity show promising results in reducing the decline in muscle strength and function with advancing age.

Changes in health-related quality of life in elderly men after 12 weeks of strength training

Muscular strength is associated with functional ability in elderly, and older adults are recommended to perform muscle-strengthening exercise. Understanding how improved muscle strength and -mass influence general and specific domains of quality of life is important when planning health promotion efforts targeting older adults. The aims of the present study were to describe changes in health-related quality of life (HRQOL) in older men participating in 12 weeks of systematic strength training, and to investigate whether improvements in muscle strength and muscle mass are associated with enhancements in HRQOL.

We recruited 49 men aged 60-81 years to participate in an intervention study with pre-post assessment. The participants completed a 12-week strength training program consisting of three sessions per week. Tests and measurements aimed at assessing change in HRQOL, and changes in physical performance (maximal strength) and physiological characteristics. Muscle mass was assessed based on changes in lean mass (leg, trunk, arm, and total), and strength was measured as one-repetition maximum in leg extension, leg press, and biceps curl. Two of the eight HRQOL scores, role physical and general health, and the physical component summary scores, increased significantly during the intervention period. Small significant positive correlations were identified between improvements in muscle strength, and better physical and social function. Moreover, a significant increase in total muscle mass was seen during the intervention period.

Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle

Skeletal muscle accounts for approximately 40% of total body mass, and it plays an indispensable role in locomotion and metabolism. Skeletal muscle undergoes a gradual loss of fat-free mass, size, and function in the aging process, called sarcopenia. The etiology of sarcopenia is complex and involves the interplay of various factors such as oxidative stress, physical inactivity, imbalanced protein homeostasis, apoptosis, inflammation, malnutrition, and/or mitochondrial dysregulation. Mitochondria play an essential role in the aging-related muscle deterioration because of their importance in the production of energy and reactive oxygen species (ROS), apoptotic signaling, and calcium (Ca2+) handling. Thus, the natural aging process, along with coincident inactivity, progressively impairs mitochondrial integrity which might be a leading factor for sarcopenia.

Mitochondrial quality control in aging skeletal muscle is regulated via mitochondrial biogenesis and mitochondrial turnover; however, the regulation of these processes seems to be less sensitive to the effects of exercise compared to that in young, healthy muscle. Regulation of mitochondrial quality in skeletal muscle can be also accomplished by other cellular systems including ubiquitin proteasomal degradation, lysosomal regulation, and apoptosis. In particular, the lysosomal system has been recently suggested as a key player for regulating autophagy/mitophagy, as well as mitochondrial energy balance. Indeed, a key component of lysosomal biogenesis, the transcription factor TFEB, appears to determine exercise capacity, and we have suggested a coordinated function between TFEB and PGC-1α during both denervation- and CCA-induced skeletal muscle remodeling, suggesting an importance of maintaining a balance between mitochondrial biogenesis and lysosomal system for the muscle quality control. Therefore, it will be interesting for future studies to examine aging-related alterations in the lysosomal system in skeletal muscle, as well as to study how endurance and/or resistance exercise regulates lysosomal capacity in aging muscle. These findings will suggest a possible pharmaceutical target for improving aging-related mitochondrial dysregulation in skeletal muscle.

This open access review looks over present opinions on whether or not alternative splicing is important in aging, and in the creation and harmful activities of senescent cells in particular. Alternative splicing refers to the fact that a single gene can code for different proteins. Changes in the ratio of production for these alternative proteins for any specific gene might be either a form of disarray caused by molecular damage or a reaction to rising levels of cell and tissue damage - essentially another form of genetic regulation that, like epigenetic decorations to DNA, changes with age.

The summary in this paper is that the picture is very complicated and poorly understood at present, as is the case for much of the detail level of cellular metabolism and the ways in which it changes over the course of aging. Fortunately we don't need a full understanding in order to produce significant benefits by selectively destroying the lingering senescent cells found in old tissues; this is the great advantage of therapeutic approaches that target the known root causes of aging. A full accounting of the way in which these causes contribute to aging, in detail, over time, is unnecessary for first generation therapies, making this a much faster and cheaper road to treating aging as a medical condition.

At the cellular and molecular levels, the aging phenotype varies between tissues but can include common hallmarks such as genomic and epigenetic instability, mitochondrial dysfunction, telomere attrition, and the accumulation of senescent cells. Considered as one of the causes of age-related tissue degeneration, cellular senescence is an irreversible and programmed cell-cycle arrest that occurs in most diploid cell types. Senescence is associated with large-scale changes affecting a variety of processes such as cytokine secretion through the senescence-associated secretory phenotypes (SASPs), alterations in gene expression, and alternative splicing, as well as chromatin remodeling that includes senescence-associated heterochromatin foci (SAHF).

Although replicative senescence is linked to telomere attrition, telomere shortening is not necessarily required for the onset of senescence, implying the existence of different senescent programs. Consistent with this view, telomere-independent senescence can be controlled by pathways triggered by insults (stress-induced senescence), as well as by other intrinsic signals that occur during embryonic development and tissue repair. Notably, senescence can also be engaged by the hyperactivation of factors, such as RAS, that promote cell growth, a process known as oncogene-induced senescence that may be linked to telomere dysfunction. While the exact connection between senescence and organismal aging is still much debated, it has become increasingly clear that cellular senescence plays a role in some age-related diseases and in tissue degeneration associated with aging.

As senescence and aging are characterized by global cellular and molecular changes, it is fair to expect that splicing control will also be subjected to alterations. The challenge is to determine whether these changes are collateral or direct effects, and how they contribute to senescence and aging. Several reviews have recently presented splicing defects linked to age-associated diseases, such as neurodegenerative disorders and cancer. Given the challenges associated with maintaining homeostasis in cells and tissues subjected to constant internal and external insults, we can anticipate that a subset of mutations and epigenetic changes may alter the expression or activity of spliceosome components and splicing regulatory factors. These changes may, in turn, alter the splicing profile in several transcripts, resulting in a cascade of alterations that may either activate senescence, promote apoptosis, or elicit tumor formation. Although senescence and apoptosis may protect against tumor formation, the gradual accumulation of senescent cells will elicit tissue degeneration and organ dysfunction. While progressive age-related disturbances in homeostasis do indeed correlate with a broad range of alterations in alternative splicing, the current challenge is to determine whether a specific splicing change contributes to the aging phenotype or is simply a consequence with little or no functional impact.

Although we reviewed the impact of selected splice variants on aging, regulatory networks likely coordinate the production of splice variants from different genes to maximize functional outcomes that determine cell fate, and ultimately the aging phenotype. Consistent with this proposition, the activity of p53 in senescence and apoptosis can be modulated by SIRT1 and ING1, in turn affecting ING1 signaling and SIRT1 activity. Extending these relationships to the full repertoire of splice variants for all the components of the extended p53 regulatory network may be required to determine how important is the level of coordination and feedback involved in the production of splice variants contributing to aging. Already, the splicing regulatory proteins SRSF1, SRSF2, SRSF3, and SRSF6 are emerging as central players coordinating multiple splicing decisions in age-relevant and senescent transcripts. To help clarify the contribution of an expanding list of splice variants and regulators associated with aging, it would be useful to combine expression assays with the monitoring of phenotypes like cell growth and the production of senescent markers. Likewise, it would be informative to determine whether and how SASP components produced by senescent cells reprogram the splicing profiles of neighboring cells.

Link: https://doi.org/10.1111/acel.12646

Here, researchers provide evidence for a correlation between the rate of errors in translation, a step in the process by which proteins are produced from their genetic blueprints, and species longevity. Infrequent errors in the creation of proteins may be only a short-lived form of damage, as a low level of defective proteins should be recycled rapidly. It is quite possible that a higher error rate is an evolutionary consequence of short life spans, rather than vice versa. If a species is short-lived because it fills an environmental niche characterized by aggressive predation, for example, then evolution will not tend to produce a large investment in repair and systems integrity. Where such systems did exist in ancestors, they are lost in the absence of selection pressure to maintain them in the face of random mutational change. Still, the correlation is there to consider.

The error catastrophe theory of aging was proposed in the 1960s. According to this model, the aging process results from errors in mRNA translation that reduce the fidelity of the protein-translating enzymes leading to increasingly inaccurate protein synthesis, terminating in functional decline, and, ultimately, the death of the organism. This theory, for the first time, proposed that translation fidelity plays a major role in aging. The error catastrophe theory has been challenged by a number of studies in the 1980s. A major caveat of these studies, however, is that many of them were conducted in vitro following ribosome isolation. As the aging process affects entire cellular networks, isolated proteins or other cellular components may not fully recapitulate this in vivo process.

Experimental models where translation fidelity was experimentally perturbed displayed shortened lifespan and susceptibility to disease. For example, mutations in tRNA genes and tRNA processing enzymes have been linked to various human diseases. These studies underscore the importance of translation fidelity for maintaining organismal health. However, to prove that a process controls aging and longevity, ideally one would have to improve this process and show that it leads to lifespan extension. In the last decade, it was established that modulating the translational machinery can extend lifespan in a variety of organisms. Inhibition of the highly conserved target of rapamycin (TOR) pathway by mutations or chemical inhibitors such as rapamycin results in downregulation of protein synthesis and lifespan extension. The mechanisms explaining the life-extending effects of TOR inhibition are not fully understood, but most evidence points toward preferential translation of specific transcripts involved in stress response, rather than improved fidelity of translation. This leaves an open question whether translation fidelity plays a role in aging, and whether it is possible to improve translation fidelity.

A study by our group showed that the longest lived rodent, the naked mole rat (NMR) has significantly increased translational fidelity in comparison to a short-lived mouse. To examine the role of translational fidelity in aging, we tested whether translational fidelity co-evolved with species maximum lifespan. We examined translation fidelity in rodent species with diverse maximum lifespan ranged from 4 to 32 years. We found a strong correlation between the frequency of mistranslating the first and second codon positions and the maximum lifespan in 16 rodent species. This correlation remained significant after phylogenetic correction by the method of independent contrast, indicating that translation fidelity co-evolved with longevity. The fidelity of mistranslation at the third position and the misreading of a stop codon did not correlate with maximum lifespan, possibly due to the wobble effect at the third codon position, and to extremely low frequency of misreading the stop codon in all species. These results provide evidence that translation fidelity is an important factor in determining species lifespan.

Link: https://doi.org/10.1111/acel.12628

Aubrey de Grey, advocate for radical life extension and originator of the Strategies for Engineered Negligible Senescence (SENS) research programs, has derived a great deal of mileage from his assessment that it is possible to achieve life spans of 1000 years or longer, as illustrated in the brief interview below. Life spans of centuries and longer can be achieved by progress in biotechnology sufficient to bring aging under medical control, but the important point is that this progress doesn't have to happen all at once. For so long as the early rejuvenation therapies are good enough to add a decade or two of healthy life, that gives additional time to improve those therapies and obtain access to greater and more efficient means of rejuvenation. A tipping point of actuarial escape velocity is reached and remaining healthy life spans increase at a faster pace than one year of additional life expectancy with every passing calendar year. For there onwards, life expectancy is no longer limited by aging and disease.

Could Human Beings Live For 1,000 Years?

What have been the major advances at SENS and why haven't life-extension programmes gone mainstream yet?

Over the past two years we've had a slew of breakthrough publications in journals such as Science, Nature Communications and Nucleic Acids Research that reported key advances against the most intractable components of aging. It's no exaggeration to say that in at least a couple of cases we have broken through logjams that have stalled key areas for over 15 years. You may feel that eight years is a long time to be only making such preliminary, step-one breakthroughs, but you'd be wrong - step one is always the hardest, and that is why nearly all research, whether in academia or in industry, is immensely biased towards the low-hanging fruit and against the high-risk high-reward work that is so essential for long-term progress. We exist as an independent foundation for precisely that reason. But, saying that, I must also stress that we are already showing great success in taking enough steps so that our programmes become investable. The atherosclerosis one was the first of, at this point, five start-ups that have emerged from our projects - covering conditions as diverse as macular degeneration, senescent cells, amyloid in the heart, and organ transplantation.

What are the key therapies that will create a 1,000-year-old human?

It's critical to understand, and yet it's almost universally overlooked, that my prediction of such long lifespans for people who are already alive divides into two phases. The first phase consists of the therapies that SENS Research Foundation is working on right now, along with parallel initiatives that have achieved sufficient traction that we don't need to be their engine room anymore; most importantly, a variety of stem-cell therapies. The other ones are also one or another kind of damage repair or obviation - removing waste products, rendering mutations harmless, restoring elasticity. They combine to restore the molecular, cellular structure and composition of the middle-aged (or older) body, and thereby its function (both mental and physical), to how it was as a young adult.

But that's only the first phase and I have always stressed that I don't anticipate more than about 30 years of additional life arising from it. That's a lot when compared to anything we can do today, but it's not four digits. My prediction of four digits comes from the second phase, which arises from the critical fact that phase one buys time. If you're 60 and you get a therapy that makes you biologically 30, then, yes, you will be biologically 60 again by the time you're chronologically 90. Sure enough, the therapies won't really work any more, because the damage that has made you biologically 60 again is, by definition, the more difficult damage, the damage that the therapies don't repair. But this is 30 years on, and that's an insanely long time in any technology, including medical technology. So, when you're 90 you will have access not just to the same therapies that you had 30 years ago, but to improved ones that can repair a whole bunch of the damage that the first-generation ones couldn't. So they will work. They still won't be 100 percent perfect, but they won't need to be; they will just need to be good enough to 're-rejuvenate' you so that you won't be biologically 60 for the third time until you're chronologically 150 or whatever. And so on.

What is more important in reducing aging: medical therapies, drugs, or lifestyle changes?

I'm all for lifestyle optimisation, but you have phrased your question as a comparison and, for sure, the answer is that lifestyle optimisation can only, ever, make a very small difference - a year or two - to how long we stay healthy and thereby to how long we live. Now, medicines and drugs that we have today are equally modest in their effects, and that's why people die today at ages only slightly older than their parents. But within the next couple of decades we have, I believe, a very good chance to change that scenario completely.

Is anyone testing your therapies at the moment on humans?

Sure, but only a subset of them. Some of the easiest components of SENS are already in clinical trials, such as stem cells for Parkinson's disease. Others, including ones spun out from SENS Research Foundation's research, may get there within a year or two. But some are probably 10-15 years out still. Those ones are just as critical as the easier ones, so we are working as hard as we can to accelerate them, but we're devastatingly limited in that regard by shortage of funds.

Since the aging research community was quite hostile towards discussions of life extension up until comparatively recently, it took an outsider to point out the obvious: that it seemed plausible to achieve rejuvenation by repairing the molecular damage that appears to cause aging, and given even initially modest rejuvenation, the inevitable outcome would be actuarial escape velocity and life spans that stretched off into the far distance. It has to be said that there are advocates in the community these days who are quite uncomfortable with discussions of radical life extension of decades and centuries: but it is very, very important to put it on the table. Many of the strongest supporters in the early days of rejuvenation research were drawn to SENS by the prospect of greatly extending life spans, and by the first reasonable, plausible program that offered the potential to achieve this goal.

Further, consider that the aging research community now includes a great many people willing to argue for and work on approaches that might add a couple of years of additional life. Like the Longevity Dividend folk, they put forward grand proposals for large-scale funding, but only aim to extend human life expectancy by 5 or 10 years by 2030 or 2040, and explicitly deny any interest in extending maximum life spans. These unambitious goals are to be achieved through approaches such as calorie restriction mimetics, autophagy enhancement, or other metabolic tinkering. This is weak medicine, and if it is the only argument being put forward to the public, then we have already lost. There is no real difference between achieving nothing and achieving the Longevity Dividend; we all still age and die on roughly the same schedule.

If billions are to be spent and the careers of thousands of researchers devoted to this field, then let it be in pursuit of technologies that have the chance of bringing an end to aging. Let the goal be to build rejuvenation therapies that can in principle prevent and reverse the causes of degeneration, not just slow it down a little. The bottom line is that we must advocate for rejuvenation research and radical life extension if we want to benefit from meaningful results in our lifetimes. If we don't carry this flag forward, then we either end up with the Longevity Dividend or nothing, and our lives end in pain and decline in the same way and on the same schedule as those of our ancestors, with the sole difference being that we turned our backs on the opportunity that they never had.

Prior to a few years ago, senescent cells were a research backwater, and this state of affairs persisted for far too long given the evidence for their importance in degenerative aging. As a result, the standard assays for the presence of cellular senescence are going on twenty years old, an eternity in biotechnology development. The current thinking on senescent cells in the now revitalized field is that these methods are too crude, and that there are likely many varieties of senescence with significant differences from one another. While it is perfectly possible to build viable senolytic therapies today, producing benefits to health and longevity by selectively destroying at least some of the burden of senescent cells in old individuals, better and more comprehensive second generation therapies will require a correspondingly improved understanding of cellular senescence as a phenomenon - and certainly better assays for quantifying the presence of these cells.

Senescent cells accumulate with age, and can cause or contribute to several degenerative diseases of aging. These effects might stem from the fact that senescent cells cannot divide and therefore cannot create new cells to maintain tissue homeostasis. However, as senescent cells generally comprise a minority of cells within even very old tissues, it is more likely that senescent cells drive age-related disease cells via signaling effects. Indeed, senescent cells secrete a myriad of inflammatory cytokines, chemokines, proteases, and growth factors, the senescence-associated secretory phenotype (SASP), that can have potent effects on tissue microenvironments and thus drive age-related pathologies by mechanisms that extend beyond the loss of proliferative potential.

Traditional gene expression analyses that compare transcriptional profiles of cell populations are limited because they measure average of gene expression levels across the entire population. For example, two populations of 5000 cells each might show a twofold difference in the mRNA level of a particular gene, but this change could result from every cell expressing twice as much mRNA, or from a single cell expressing 5000 times more of that mRNA. The difference between these possibilities could have enormous phenotypic consequences in the context of a tissue. Single-cell approaches offer advantages over population studies because they can distinguish between these types of scenarios. Single-cell analyses also require fewer cells and therefore can be used to interrogate the phenotypes of rare cells, such as senescent cells produced during organismal aging.

To assess the contributions of individual senescent cells to known senescent phenotypes, we conducted quantitative PCR analyses of single quiescent and senescent cells from cultured populations of human fibroblasts. From these analyses, we find that (i) virtually all senescent cells display a gene expression signature that distinguishes them from their quiescent counterparts; (ii) nonetheless, the expression of most genes is more variable in senescent cells compared to quiescent cells; and (iii) there are correlations among genes expressed by senescent cells, including those encoding SASP factors, that localize in genomic clusters. Together, the data demonstrate that senescent phenotypes are more variable than the transcriptional profiles of cell populations previously suggested.

Identifying senescent cells at the single-cell level is an important technological step for future studies, especially in human tissues. While transgenic mouse models now allow senescent cells to be identified and isolated from mouse tissues, identifying senescent cells in human tissues remains difficult. Our findings emphasize the risk of using a single biomarker to identify senescent cells, whether in culture or in vivo. We recommend using several markers - in our own studies, for example, we tend to use combinations of SA-Bgal activity, loss of LMNB1 expression, HMGB1 relocalization, p16INK4a and/or p21WAF1 expressions, and the expression of strongly upregulated SASP factors. As many inducers of senescence (e.g., telomere attrition, ionizing radiation, bleomycin, and oncogene activation) ultimately induce a DNA damage response, it is likely that many of the factors identified in this study are common to several senescence inducers.

Link: https://doi.org/10.1111/acel.12632

It is becoming clear that the behavior of varieties of macrophage immune cells (including the microglia resident in the central nervous system) is important in regeneration, and may be one of the key distinguishing differences between mammalian species with limited regenerative capacity and proficient regenerators such as salamanders and zebrafish, capable of regrowing lost organs. It is too early to say whether it is possible or plausible in the near future to produce salamander-like regenerative in humans, but adjusting macrophage behavior appears quite promising based on the human research to date. The results noted here tie this macrophage-based approach to enhanced regeneration in mammals to the mechanisms of regeneration in zebrafish, adding more evidence to suggest that it is a good direction for continued research and development.

Researchers report evidence that zebrafishes' natural ability to regenerate their eyes' retinal tissue can be accelerated by controlling the fishes' immune systems. Because evolution likely conserved this mechanism of regenerative potential in other animals, the new findings may one day advance efforts to combat degenerative eye disease damage in humans. Both human and zebrafish eyes contain Müller glia, an 'inducible' stem cell type that gives zebrafish their remarkable regenerative abilities. The researchers found evidence that microglia, a cell type found in most vertebrae innate immune systems, affect the Müller glia's regenerative response and can be harnessed to accelerate the growth of new tissue in the retina. For the study, researchers created a model of the human degenerative retinal disease, retinitis pigmentosa, in zebrafish by incorporating a gene for a specialized enzyme into the rod cells of the fish retina. The enzyme has the novel ability to convert a chemical, metronidazole, into a toxin, which allows researchers to selectively kill the cells expressing it.

After initiating photoreceptor loss in the fish retinas, the researchers monitored the immune system's response by tracking the activity of three types of fluorescently labeled immune cells in and around the eye: neutrophils, microglia and peripheral macrophages. They found that neutrophils, the type of immune cells that are typically the first responders to tissue injury, were largely unresponsive to photoreceptor death. They also observed that the peripheral macrophages sensed the injury, but were unable to penetrate the blood-retinal barrier to access the dying cells. Microglia were the only cells the researchers saw that were able to both respond to the injury and reach the injured cells.

Building on the evidence that microglia were in play during injury, the researchers conducted tests in zebrafish with the specialized enzyme incorporated into both rod cells and microglial cells, removing both cell types to ask what role microglia play during regeneration. They found that when microglia were also lost, Müller glia showed almost no regenerative activity after three days of recovery, compared with approximately 75 percent regeneration in the control population. They then used an anti-inflammatory drug, dexamethasone to see if they could speed up regeneration in the zebrafish retinal tissue. Microglia come in two forms - M1, which is associated with inflammation; and M2, which is associated with repair. The researchers believed that by triggering the microglia to transition from phase 1 to phase 2 more quickly by using the drug, they could improve the zebrafishes' regenerative capabilities.

After using the enzyme to cause rod cell death in the fish, the researchers added the anti-inflammatory drug to the water to reduce microglia reactivity. The researchers saw a 30 percent increase in retinal regeneration at day 4 of recovery compared with controls. The researchers hope that by harnessing the ability to improve regeneration in zebrafish, they can better understand how to induce regeneration in human eyes, which share many of the same mechanisms for controlling regenerative potential.

Link: http://www.hopkinsmedicine.org/news/media/releases/immune_system_found_to_control_eye_tissue_renewal_in_zebrafish

Today, I thought I'd point out a few varied publications from the epidemiology research community. They have nothing much in common beyond being interesting and of relevance to the broader understanding of how aging progresses at the present time. The first addresses a common theme in recent years, which is to provide arguments against the misconception that excess weight is in any way beneficial in older age; the second adds data to the debate over whether there is in fact a physical, genetic basis for the correlation observed between intelligence and life expectancy; the third might be taken as an essay-length complaint about the state of the data and methodologies used to assess the degree to which longevity is inherited.

Epidemiology has a long history: if you trace back a great deal of today's aging research far enough, you'll eventually arrive at a starting point consisting of observations of large numbers of humans. Only in more recent decades has it become the case that lines of medical research relevant to aging can spring forth from examining the biochemistry of a few individuals, or of other species. Prior to the development of the tools of modern biotechnology, researchers had to start with the search for patterns in the demographics of life, disease, and death. That approach to medicine still continues today, of course, but it is slowly becoming divorced from those parts of the field that will make the greatest difference to the future of health and longevity.

Epidemiology can tell us things about how aging progresses in the absence of effective means to treat it. It can help to identify the difference between better and worse lifestyle choices, or find bearers of common genetic variants that somewhat improve resistance to the consequences of age-related cell and tissue damage. But epidemiology has nothing to say about the future of rejuvenation therapies: as a field it looks backwards, not forwards. It is the construction of a description of things as they are and were, not as they will be. Treatments capable of repairing the damage that causes aging will change the whole of the picture, and tomorrow will look nothing like today.

Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants

For older groups, being overweight [body mass index (BMI): 25 to 30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to 25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life. This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD). This study followed 130,473 UK Biobank participants aged 60-69 years (baseline 2006-2010) for 8.3 years (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group.

Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects. However, among normal-weight subjects, mortality increased for those with a higher WHR (hazard ratio: 1.33) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (hazard ratio: 1.41) and greatly increased CAD incidence compared with being normal weight with a lower WHR. Thus for healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.

Childhood intelligence in relation to major causes of death in 68 year follow-up: prospective population study

Findings from prospective cohort studies based on populations from Australia, Sweden, Denmark, the US, and the UK indicate that higher cognitive ability (intelligence) measured with standard tests in childhood or early adulthood is related to a lower risk of total mortality by mid to late adulthood. The association is evident in men and women; is incremental across the full range of ability scores; and does not seem to be confounded by socioeconomic status of origin or perinatal factors.

Several hypotheses have been proposed to explain associations between intelligence and later risk of mortality. The suggested causal mechanisms put forward, in which cognitive ability is the exposure and disease or death the outcome, include mediation by adverse or protective health behaviours in adulthood (such as smoking, physical activity), disease management and health literacy, and adult socioeconomic status (which could, for example, indicate occupational hazards). Recent evidence of a genetic contribution to the association between general cognitive ability and longevity, however, might support a system integrity theory that posits a "latent trait of optimal bodily functioning" proximally indicated by both cognitive test performance and disease biomarkers. None of these possibilities are mutually exclusive.

We investigated the magnitudes of the association between childhood intelligence and all major causes of death, using a whole year of birth population followed up to older age, therefore capturing sufficient numbers of cases for each outcome. All individuals born in Scotland in 1936 and registered at school in Scotland in 1947 were targeted for tracing and subsequent data linkage to death certificates. For most endpoints, higher childhood intelligence was associated with a lower risk of cause specific death. Risk of death related to lifetime respiratory disease was two thirds lower in the top performing 10th for childhood intelligence versus the bottom 10th. Furthermore for deaths from coronary heart disease, stroke, smoking related cancers, digestive diseases, and external causes, risk of mortality was halved for those in the highest versus lowest 10th of intelligence. The risk of dementia related mortality and deaths by suicide were reduced by at least a third in the highest performing quarter of intelligence test score versus the lowest quarter.

Historical demography and longevity genetics: back to the future

In the literature, the familial component of human longevity has been investigated using survival to extreme age and age at death as phenotypes of survival. The former actually refers to longevity whereas the latter refers to individual or population based lifespan. Both definitions are often used in the context of longevity research which is confusing and incorrect. Another complication is that most studies exclude infant and child mortality by applying a lower limit age threshold when considering the lifespan of a population or group of individuals. Unfortunately, there is no consensus on the age threshold for longevity studies. As a result of both the inconsistent use of terminology and different lower and upper limit age thresholds, the comparison of longevity studies is generally problematic. We will refer to longevity as survival into extreme old ages whereas lifespan refers to age at death related measures.

Progress in longevity research is also hampered by the fact that longevity is likely dependent on an interplay between combinations of multiple genes and environmental factors which makes it difficult to separate environmental from genetic influences. In fact, environmental influences likely moderate genetic effects on longevity. Several genealogical studies have attempted to estimate the heritability of lifespan and longevity. These studies can be divided into two categories based on the type of data they used; (1) twin data and (2) pedigree data. Unlike animal studies in a lab setting, the effects of the environment on longevity in human studies cannot be controlled. In twins at least the variation in early environment is minimized as compared to other family based studies. In all cases, heritability estimates and the effect of specific gene variants on lifespan and longevity depends on the populations studied and their past and present environmental conditions.

It can be concluded from study results that the heritability of lifespan is between 0.01 and 0.27 in the population at large. The large variation in the heritability estimates indicates a prominent role for differential environmental influences on the estimates. Studies showing that siblings of centenarians and longevous sib-pairs have a high probability to also become a centenarian or longevous, respectively, and studies, which show that longevous parents have a high probability to bear longevous offspring, provide indications that the heritability of longevity may be higher than that of lifespan.

However, the heritability of longevity has only been investigated once in a twin study design, though of limited sample size. In addition, the heritability of longevity has been investigated more often in pedigree studies but the studies raise several questions about their design, sample size, and generalizability. Establishing the heritability of longevity is necessary for case definitions in genetic studies focused on gene mapping. Hence, researchers' attention should shift from lifespan to longevity and the heritability of longevity should be estimated in an appropriate design with a sufficiently large sample.

Cardiac syndrome X has the standard risk factors for cardiovascular disease, which is to say age of the individual and degree of excess fat tissue carried by the individual. It is a comparatively poorly understood variety of structural alteration and failure of blood vessels, however. The risk factors are well known, but the biochemistry is yet to be mapped in full. Here, researchers shed more light onto what is taking place under the hood.

"Older obese patients and sometimes women who suffer heart failure go to the cardiac catheterization lab and the cardiologist finds nothing that would explain their heart failure. They have normal large blood vessels in the heart still the heart failure has developed." What isn't readily seen with these routine exams is the thickened walls that can hinder dilation of the small capillaries fed by these bigger vessels, a condition called coronary microvascular dysfunction, or cardiac syndrome X.

In patients and animal models, who are both older and obese, researchers have found a key dynamic in the dysfunction is an enzyme called ADAM17, which is involved in a huge variety of functions like releasing growth factors as we develop, but also implicated in diseases from Alzheimer's to arthritis. ADAM17 levels increase in obesity while levels of its natural inhibitor, the protein caveolin-1, decrease with age, enabling the perfect storm. ADAM17 was discovered 20 years ago for its ability to cut and release previously inactive tumor necrosis factor, or TNF, from the cell membrane. TNF is a major promoter of inflammation that also directly impacts the function of the endothelial cells that line blood vessels. The scientist found that ADAM17 cleaves TNF from fat, releasing it into the bloodstream where it preferentially targets the heart. The bottom line: the walls of the hair-sized microvasculature become thicker, less elastic, less able to dilate and to properly sustain the heart.

The research team found ADAM17 highly expressed in fat and even higher in the blood vessels of aged human fat. The protein level was increased in younger mice on a high-fat diet, but the significant increase in its activity came with age and fat. In humans, they saw the ability of the tiny vessels to dilate significantly reduced in those ages 69 and older and further reduced in older individuals - males and females - who also were obese. They found ADAM17 present in the fat of young and old mice on high-fat diets compared to normals, but it was only significantly active in the older mice on a high-fat diet. When they looked at younger and older obese patients, again much like the mice, they found high levels of expression of ADAM17 in the lining of blood vessel walls. When they transplanted fat from aged obese mice to younger mice, it increased circulating levels of proinflammatory factors and impaired dilation of the coronary microvasculature. "It basically mimicked the old vascular phenotype in the young animals."

The researchers have started to look at antibodies that would directly target and ideally reduce levels of ADAM17 in the face of aged fat and at least delay development of small vessel disease. They further think a similar process may happen in the brains of older obese individuals, so have ongoing studies of how microvascular disease can lead to Alzheimer's in these individuals. The researchers note that young, obese individuals could help themselves avoid this and likely other diseases like diabetes, by losing weight while they are young.

Link: http://jagwire.augusta.edu/archives/45733

Researchers here demonstrate that reducing the levels of circulating insulin in mice extends life by 10% or so in the best scenario they tested. Insulin, insulin-like growth factor 1 (IGF-1), and growth hormone are all closely linked in their interactions, a well-studied area of metabolism that is connected to the pace of aging through its influence on most of the fundamental activities of cells. Adjusting metabolism to slow aging isn't a promising path forward, however. We can already see the likely bounds of the possible in the known effects of exercise, diet, and calorie restriction, as well as in some human lineages with similar loss of function mutations to those created in long-lived genetically engineered mouse lineages. Slowing down the accumulation of cell and tissue damage can only modestly slow aging. If we want more than that, we must look instead to therapies that repair and reverse this damage so as to produce rejuvenation.

As insulin and Igf1 share nearly identical downstream signaling pathways in mammals, and act in part via hybrid insulin/Igf1 heterodimer receptors that can bind to either ligand, the relative functions of these two ligands have not been completely delineated. Many studies have focused on Igf1 as the primary ligand which mediates the lifespan-altering effects through this signaling cascade in mammals, but the impact of directly altering insulin levels on longevity had not been evaluated.

Insulin resistance is a common feature of mammalian aging and a risk factor for numerous age-related diseases. Although this suggests that reducing insulin signaling could be detrimental for mammalian healthspan, it is important to consider that conventionally defined insulin resistance (i.e., impaired insulin-stimulated glucose disposal) is not a generalized reduction of all insulin signaling. Instead, some insulin-regulated processes are maintained at normal capacity in the "insulin resistant" state, while others are downregulated. Moreover, circulating levels of the insulin ligand are elevated with insulin resistance. The commonly accepted paradigm posits that insulin levels rise as a compensatory response to prevent hyperglycemia when there is insufficient insulin-stimulated glucose uptake. However, causality between the closely associated conditions of systemic insulin resistance and insulin hypersecretion has remained controversial, and it has been suggested that hyperinsulinemia could be an early, primary cause of insulin resistance, obesity, and eventually type 2 diabetes. Genetic loss-of-function experiments targeting insulin itself present an ideal opportunity to disentangle hyperinsulinemia from insulin resistance and to evaluate the lifelong effects of limiting endogenous insulin production and secretion.

To determine how moderately lowering the insulin ligand would affect late-life glucose homeostasis and longevity in mammals, we compared mice with either full or partial expression of the ancestral insulin gene Ins2. Since altering insulin gene dosage does not affect circulating insulin levels in all contexts, we used a mouse model in which the rodent-specific insulin gene (Ins1) was fully inactivated to prevent compensatory Ins1 expression. We designed our experiment to evaluate these animals in the context of two distinct diets (diet A: moderate-energy diet; diet B: high-energy diet). Remarkably, we found that across both diets, mice with reduced circulating insulin levels had improved insulin sensitivity with advanced age and exhibited lifespan extension without changing Igf1 levels. These results suggest a causal contribution for hyperinsulinemia in age-dependent insulin resistance and point to the modest suppression of insulin as a safe and attainable strategy for extending lifespan.

Link: http://dx.doi.org/10.1016/j.celrep.2017.06.048

Today, an update on the Vascular Tissue Challenge arrived in my in-box. It's been a year or so since the Methuselah Foundation and NASA jointly announced the Vascular Tissue Challenge, conducted as a part of the foundation's New Organ initiative. The challenge is a $500,000 research prize intended to draw greater attention to - and investment in - efforts that aim to surmount the greatest present roadblock in the field of tissue engineering: how to build tissues that contain the capillary networks required to sustain them. Natural tissues are packed with capillaries, hundreds passing through every square millimeter examined in cross-section. Reproducing this complexity in artificially grown tissues has proven to be very difficult. Yet other complex aspects of tissue growth have been solved: in the past few years, researchers have demonstrated themselves able to produce near fully functional organ tissues of many varieties. Unfortunately, since capillary networks are not yet a part of this picture, such solid tissue sections are limited in size to a few millimeters in their broadest dimension.

The goal of the New Organ initiative is the construction of patient-matched organs, as needed, from cell samples. To build any sizable tissue requires a life-like vascular network; there is no way around that. Given the impressive progress to date in every other aspect of tissue engineering required, however, it is fair to say that if the research community had a reliable solution for production of integrated blood vessel networks, then manufactured human organs would be only a few years distant. Thus initiatives like the Vascular Tissue Challenge are important; the creation of microscale blood vessel networks is the fulcrum for this field of medical research and development. Solve this challenge, and the first engineered organs are close.

Last June, the Methuselah Foundation and NASA officially launched the Vascular Tissue Challenge (VTC) at the White House Organ Summit, hosted by the Office of Science and Technology Policy. The VTC includes a $500,000 prize purse from NASA for the first teams that can successfully create 1cm or thicker vascularized tissues that remain functional and alive for more than 30 days. Along with this is the Center for the Advancement of Science in Space's (CASIS) "Innovations in Space Award," providing an additional $200,000 to support a research opportunity on board the International Space Station's National Laboratory. With the one year mark just behind us, we thought it was fitting to check in with the teams and see how they're doing. There's been a lot happening to advance these amazing bioengineering technologies over the last 12 months!

Since launching the Vascular Tissue Challenge, seven research organizations officially signed on to pursue the challenge of creating the thick, vascularized tissues required to win the $700,000 in awards along with the opportunity to pursue further research using the microgravity environment onboard the International Space Station. Each team is pursuing a different approach to creating vascularized tissues, and each has their own unique strategies and hurdles ahead. Here is a quick snapshot of what some of the teams have been doing and what they are planning for their next steps toward winning the Challenge before the sunset of the award at the end of 2019.

iTEAMS, Stanford University

Over the past year, iTEAMS has proposed and proved an integrated multi-scale, multi-modular system approach to overcome the challenges and tradeoff in functional vasculature requirements between major vascular lasting perfusion and capillary rapid sprouting and extensive coverage for diffusion. The former requires a slowly degradable biomaterial for sustained perfusion and the latter requires a fast biodegradable biomaterial for rapid sprouting and diffusion. The next steps being pursued are an optimization of perusable channel pathways, biomaterial candidates, and fabrication parameters. A critical upcoming milestone is to demonstrate functional microvasculature at a large scale for a long term in vitro. Team iTEAMS is working towards conducting their Vascular Tissue Challenge trials in 2018.

BioPrinter, Florida Institute of Technology

The team have developed a self-contained bioprinting system that is being used to generate tissue samples with high resolution and cell viability. They plan to use this printer to develop a sacrificial technique of bioprinting channels within a tissue sample. These channels will be used for the exchange of nutrients to cells needed to maintain viable tissue for an extended period of time. Currently, research is being conducted with various concentrations of bioink to obtain values that will result in high quality bioprinted tissue samples. In parallel, research on sacrificial techniques to create channels for nutrient flow is being conducted. The team anticipates that an official trial for the Vascular Tissue Challenge to be initiated in 2018.

Flow, Maize, and Blue, University of Michigan

The team has built a perfusion bioreactor that it is currently optimizing for customized tissue engineered vascular networks. The team hope to accomplish long-term perfusion of these vascular networks in the next 6 months with an official Vascular Tissue Challenge trial occurring sometime after that research is completed.

Techshot

Last summer, Techshot began formal efforts toward winning the Vascular Tissue Challenge by 3D printing biological materials and adult stem cells into vascular and cardiac structures on board a Zero Gravity Corporation aircraft. Test structures were printed during cycles of both zero G and high G forces, permitting evaluation of low viscosity, biological material printing in multiple gravity environments. As expected, the cycles of microgravity facilitated layer-by-layer printing of 3D structures with very low viscosities (these materials become puddles if printed on the ground). The team's next large step forward is a "Tissue Cassette" experiment that will be conducted this summer. Building upon last summer's work, Techshot will bioprint larger cardiac and vascular structures within a specialized container, a bioreactor they refer to as a "Tissue Cassette". This Tissue Cassette will not only provide an appropriate environment for culturing the 3D printed structure, it will impart physical and electrical cues to accelerate cell growth and tissue development. The bioreactor will also permit perfusion of the 3D bioprinted structure to further support cell growth in the larger printed volume.

The planned experiments will start by bioprinting identical sets of cardiac and vascular structures with an initial print size of 20mm x 30mm x 10mm. One set will stay on the ground. The second set will be loaded into a Techshot ADSEP system and launched to the International Space Station aboard SpaceX Cargo Dragon (CRS-12) on August 1, 2017. These experiments will provide insight into bioprinted cell behavior in microgravity and the associated differences in tissue development. This will provide a preliminary test of the technology Techshot plans to use for their Vascular Tissue Challenge trials that they expect to conduct after getting these results back.

Team Penn State, Pennsylvania State University

The team has made substantial progress with their research on micro-vascularization in engineered islets. In addition, the team has scaled up tissue constructs to a sub-cm^3 level and are working on expanding to the cm^3 level for the VTC trial. They have demonstrated viable vascularization with mouse cells and are currently conducting research to overcome technical issues with the co-culture of stem cell-derived human beta cells and microvascular endothelial cells. Finalizing the research to reach vascularization with these cells at the cm^3 level is the next critical step for this team, which they expect to take them into 2018 before conducting their final trials for the VTC.

Team WFIRM Bioprinting, Wake Forest University

During the past year, the WFIRM Bioprinting Team was focusing on the development of tissue-specific bioink systems that could mimic the microenvironments of each target tissues. The team assumes that these tissue-specific bioink systems can enhance the cell-cell and cell-matrix interactions that can accelerate tissue maturation/formation and functions. Up next in the team's research is to combine microvasculature created by endothelial cells with tissue-specific printed constructs. They plan to investigate the effects of endothelialized microvasculature on cell viability and tissue-specific functions of the tissue-specific printed constructs. It is not yet clear when the team's VTC trials will start, more will be known after their next research projects are completed.

Team Vital Organs, Rice University

At Rice University, Team Vital Organs is continuing to build out their 3D printing technology, characterizing the precision, cell viability and activity, designing assays for tissue assessment, and designing proper vascular architectures for complete tissue integration. Perfusion systems are complicated, but the team has a new large incubator that can now accommodate their proposed perfusion systems for the VTC. They are now working on validating long-term sterility and measurements from longitudinal assays. The team is looking forward to finishing these feasibility studies and putting together an official trial to win the Vascular Tissue Challenge within the next year.

Researchers here discuss a new cellular approach to building a biomarker of aging, a way to assess the biological age of an individual. In the SENS view of aging as accumulated molecular damage and its secondary consequences, such a biomarker must reflect the current load of damage present in an individual: people with more damage are older and suffer greater degeneration. The true value of a good biomarker of biological age is that it can be used to significantly speed up research and development, in that it will allow potential rejuvenation therapies to be assessed for their ability to turn back aging far more rapidly, cost-effectively, and accurately than is presently the case.

Sure, you know how old you are, but what about your cells? Are they the same age? Are they older, younger? Why does it matter? A team of researchers is reporting progress in developing a method to accurately determine the functional age of cells, a step that could eventually help clinicians evaluate and recommend ways to delay some health effects of aging and potentially improve other treatments, including skin graft matching and predicting prospects for wound healing.

The researchers devised a system that can consider a wide array of cellular and molecular factors in one comprehensive aging study. These results show that the biophysical qualities of cells, such as cell movements and structural features, make better measures of functional age than other factors, including cell secretions and cell energy. The team examined dermal cells from just underneath the surface of the skin taken from both males and females between the ages of 2 to 96 years. The researchers hoped to build a system that through computational analysis could take the measure of various factors of cellular and molecular functions. From that information, they hoped to determine the biological age of individuals more accurately using their cells, in contrast to previous studies, which makes use of gross physiology, or examining cellular mechanisms such as DNA methylation.

Researchers trying to understand aging have up to now focused on factors such as tissue and organ function and on molecular-level studies of genetics and epigenetics, meaning heritable traits that are not traced to DNA. However, the level in between, the cells, have received relatively little attention. This research was meant to correct for that omission by considering also the biophysical attributes of cells, including such factors as the cells' ability to move, maintain flexibility and structure. This focus emerges from the understanding that changes associated with aging at the physiological level such as diminished lung capacity, grip strength and mean pressure in the arteries "tend to be secondary to changes in the cells themselves, thus advocating the value of cell-based technologies to assess biological age." For example, older cells are more rigid and do not move as well as younger cells, which most likely contributes to the slower wound healing commonly seen in older people.

From the analysis, researchers were able to stratify individuals' samples into three groups: those whose cells roughly reflected their chronological age, those whose cells were functionally older, and those whose cells were functionally younger. The results also showed that the so-called biophysical factors of cells determined a more accurate measure of age relative to biomolecular factors such as cell secretions, cell energy, and the organization of DNA. The more accurate system could eventually enable clinicians to see aging in the cells before the person experiences age-related health decline. This in turn could allow doctors to recommend treatments or changes in life habits, such as exercise or diet changes.

Link: http://releases.jhu.edu/2017/07/11/method-determines-cell-age-more-accurately-could-help-elderly-patients/

If only all popular science articles were this good. The author here manages to accurately capture the state and uncertainties of heterochronic parabiosis research, which involves the transfer of blood between animals of different ages in search of factors that might be impacting tissue functions, either positively in youth or negatively in old age. From the results to date, I'd say that parabiosis is somewhat analogous in scope and likely impact to, say, research surrounding a class of drugs that modestly slow aging in mice. I'd not expect to see significantly better or worse advances in the treatment of aging resulting from this part of the field than from the development of mTOR inhibitors such as rapamycin. From my point of view it is an interesting area of science, but not the path ahead to rejuvenation.

Research into parabiosis can be technically challenging, and had more or less died out by the late 1970s. These days, though, it is back in the news - for a string of recent discoveries have suggested that previous generations of researchers were on to something. The blood of young animals, it seems, may be able to ameliorate at least some of the effects of ageing. In 2005, research joined the circulatory systems of mice aged between two and three months with members of the same strain that were 19-26 months old. That is roughly equivalent to hooking a 20-year-old human up to a septuagenarian. After five weeks, the researchers deliberately injured the older mice's muscles. Usually, old animals heal far less effectively from such injuries than young ones do. But these mice healed almost as well as a set of young control animals. The young blood had a similar effect on liver cells, too, doubling or tripling their proliferation rate in older animals.

Since then, a torrent of papers have shown matching improvements elsewhere in the body. No one has yet replicated the finding that young blood makes superannuated mice live longer. But it can help repair damaged spinal cords. It can encourage the formation of new neurons in mouse brains. It can help rejuvenate their pancreases. The walls of mouse hearts get thicker as the animals age; young blood can reverse that process as well. The effects work backwards, too. Old blood can impair neuron growth in young brains and decrepify youthful muscles. Finding out exactly what is happening is tricky. The working theory is that chemical signals in young blood are doing something to stem cells in older animals. Stem cells are special cells kept in reserve as means to repair and regrow damaged tissue. Like every other part of the body, they wear out as an animal ages. But something in the youngsters' blood seems to restore their ability to proliferate and encourages them to repair damage with the same vigour as those belonging to a younger animal would. In all probability, it is not one thing at all, but dozens or hundreds of hormones, signalling proteins and the like, working together. Researchers have been comparing the chemical composition of old and young blood, searching for those chemicals that show the biggest changes in level between the two.

Even with a list of targets, working out what is going on is hard. Blood is complicated stuff, and the tools available to analyse it are far from perfect. In 2014 a group suggested GDF-11 as a possible rejuvenating factor. The following year another team said that they were unable to replicate those results. They claimed the original test was sensitive to proteins besides GDF-11, messing up the results. The original team replied within months that, no, it was in fact the new test that was flawed, because it was itself picking up extra proteins. And there, at the moment, the matter stands. There are further possible explanations for parabiotic rejuvenation besides blood chemistry. One is that older animals may also benefit from having their blood scrubbed by young kidneys and livers, which mere blood transfusion would not offer. A 2016 paper described blood exchanges that were done in short bursts (thus eliminating the possibility of such scrubbing) and reported rejuvenating effects, but ones that were not as widespread as those obtained by full-on parabiosis. Another idea is that cells from the young animal, rather than chemicals in its blood, could be doing some of the work. The mechanisms by which parabiosis operates, then, are foggy.

Link: https://www.economist.com/news/science-and-technology/21724967-might-be-true-people-too