Fight Aging! Newsletter, July 24th 2017

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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."

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.

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."

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.

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.

"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.