The correlation between socioeconomic status and life expectancy is well established, a part of a web of connections that include intelligence, education, lifestyle choices, use of medical services, air pollution, and wealth. Why does a higher socioeconomic status add a few years to life expectancy? That is the question, and in formulating a reasonable hypothesis it is always interesting to find groups that buck the trend. Here, for example, researchers examine a population in which low socioeconomic status individuals live for longer than is the case in the general population. I can't say that the focus on community by the researchers is much of an answer, however, as it only raises exactly the same question, one step removed from socioeconomic status: what exactly about community affects life span?

Almshouses provide affordable community housing for local people in housing need. They are generally designed around a courtyard to provide a 'community spirit', that is synonymous with the almshouse movement. They offer independent living but provide friendship and support when needed. Analysing up to 100 years' worth of residents' records from various almshouses in England, the research suggests that living in these communities can reduce the negative impact on health and social wellbeing which is commonly experienced by the older population in lower socioeconomic groups, particularly those individuals who are living in isolation.

The results are very encouraging. Residents in almshouses in England receive a longevity boost relative to people of the same socioeconomic group from the wider population. The best-performing almshouses in the study so far have shown a longevity boost which increases life expectancy to that of a life in the second-highest socioeconomic quintile - a remarkable outcome. As an example, the authors estimate that a 73-year-old male entering an almshouse such as The Charterhouse today would receive a longevity boost of 2.4 years (an extra 15% of future lifetime at the point of joining) compared to his peers from the same socioeconomic group, and 0.7 years when compared to an average 73-year-old from the general population. This longevity boost could be due to both the strong sense of community and social belonging within almshouses which lead to better physical and mental health. Enhanced wellbeing helps to mitigate loneliness which is endemic in older age groups.

Link: https://www.eurekalert.org/news-releases/990288

The APOE4 variant gene is robustly linked to an increased risk of Alzheimer's disease. Separately, Alzheimer's disease has a clear inflammatory component, to the point at which some groups hypothesize that chronic inflammation is the important driving mechanism of the condition. Here, researchers report on evidence linking the APOE4 variant to greater induction of inflammation related to the presence of amyloid-β aggregates in the brain.

Alzheimer's disease is characterised by the accumulation of plaques of the amyloid-β protein, chronic inflammation and impaired neuronal function in the brain. The most significant genetic risk factor for the disease is apoE4, a variant of apolipoprotein E, which is known for, among other things, advancing the onset of the disease. While more than half of all individuals with Alzheimer's disease carry this variant, the exact effect of apoE4 on the development of the disease has remained unknown.

A new study identified a more accurate link between the apoE4 gene and the part of the human body's immune system that underlies, among other things, Alzheimer's disease. This is known as the complement system, and it contributes to the destruction of foreign cells and easily triggers inflammatory responses in the body. "We found that apoE4 poorly binds factor H, a regulatory factor of immunity. The factor H molecule is crucial in preventing complement-mediated inflammation. Usually, apoE binds factor H to the amyloid-β aggregates in the brain, thus reducing local inflammation. But apoE4 does not. This results in the accumulation of harmful amyloid-β aggregates and inflammation in the brain."

Link: https://www.helsinki.fi/en/news/brain/new-information-development-alzheimers-disease-study-reveals-possible-cause-inflammation

As often mentioned here, cells and living organisms are built out of an enormous array of very complex subsystems, and those very complex subsystems are prone to dysfunction over the course of aging. As soon as any one part of a subsystem is sufficiently impacted by the mechanisms of aging to run awry, the whole subsystem starts to run awry. An army of scientists ten times the size of the one we have now would take a century to catalog every last important detail of the way in which aging causes disarray.

These mechanisms are all interesting in their own right, and the goal of science is full understanding. But the sheer scope of such a project is precisely why we should not focus on increased understanding of the fine details of the progression of aging as the primary near future path to the production of therapies. Instead, we should focus on attempting to repair and reverse the well-known mechanisms of aging, and then observe the outcomes. That is the practical path to longer, healthier lives over the course of the near future of the next few decades.

As an example of a complex system that may run awry with age for reasons that are poorly understood and have the look of being quite interesting, researchers here discuss whether or not there exists a form of stress response focused on maintaining the integrity of the cell cytoskeleton. That the upregulation of some associated regulatory proteins can increase life span in short-lived species is suggestive. One might also consider that disruption of the cytoskeleton, as in progeria, produces a dramatic shortening of life span and general dysfunction of cells and tissues. Stress responses in general have proven to be a reliable source of ways to modestly slow aging in short lived species, but not so great at extending life in long-lived species; it remains to be seen as to how a cytoskeletal stress response behaves.

More than a loading control: actin regulation in aging

Organelle-specific stress responses have evolved to preserve homeostatic function of each specialized organelle compartment within eukaryotic cells. These include the cytosolic heat shock response (HSR) and the unfolded protein responses of the mitochondria (UPRmt) and endoplasmic reticulum (UPRER), all of which contribute to homeostatic function of their designated organelle and have implications in longevity.

Despite major efforts in this field, the machineries dictating homeostatic function of the actin cytoskeleton during stress and aging are poorly understood. The actin cytoskeleton is a complex, dynamic network of protein filaments that provide structural support and shape to cells and has been implicated in many physiological age-related changes. For example, in multiple model systems, cytoskeletal form and function has been shown to decline with age, which can directly impact nutrient sensing and aging in S. cerevisiae and thermotolerance and longevity in C. elegans. Mechanistic function of the cytoskeleton is also important in mammalian systems, as dysfunctions in actin are implicated in age-associated diseases, such as Alzheimer's Disease (AD).

Despite the implications of the actin cytoskeleton contributing to aging physiology and disease, little is known about actin regulation throughout an organism's lifespan. To date, there are two known "master" regulators of actin function: heat shock transcription factor-1 (HSF-1), and serum response factor 1 (SRF1). Therefore, to identify additional conserved regulators of the actin cytoskeleton, we performed an unbiased, cross-species screen. A number of targets were identified from the consecutive screens; however, bet-1 was the only gene that showed correlations with lifespan in C. elegans. Specifically, bet-1 knockdown resulted in shortened lifespan, while overexpression was sufficient to drive longevity. bet-1 is a conserved (BRD4 in mammals) double bromodomain protein recognized for its role in cell fate determination with some links to actin function.

On a physiological level, our study found that BET-1 drives organismal health and longevity by promoting stability of muscle and intestinal actin, which maintained muscle motility and gut barrier function at advanced age. While our study did not identify mechanistically how BET-1 promotes actin health, transcriptome analysis revealed that overexpression of bet-1 induces expression of actin regulatory genes. Moreover, the increased stability of actin is required for the beneficial effects of bet-1 overexpression on organismal health and longevity.

It is worth investigating whether a true "actin cytoskeletal stress response" (ACSR) exists whereby in response to stress, actin integrity can be maintained as a mechanism to drive resilience and organismal health. An exciting area of research can be to investigate whether a BET-1/BRD4 driven ACSR - possibly in coordination with other stress regulators - can drive overall stress resilience and longevity.

That vaccinations decline in effectiveness with advancing age is only one of countless ways in which the underlying mechanisms of aging collectively harm health and resilience in later life. If the urge to improve vaccination efficacy in older individuals turns out to be a major contribution to driving greater investment in the development of means of rejuvenation, therapies that target the causes of aging, then the benefits will extend far beyond this narrow goal.

Despite the availability of flu vaccines formulated to better protect older adults, older adults remain disproportionally at-risk for severe infection, flu-associated disability, and death. However, vaccination remains the most effective way to prevent infectious diseases and reduce severity of infections. Fortunately, the vast amount of research aimed to understand the hallmarks of aging have opened many doors to improve flu vaccine responses in individuals 65 years and older, potentially without the need to reformulate the vaccines themselves. Targeting aging as a whole, rather than specific age-related deficits, is likely more suited to improve the highly coordinated responses to vaccination and improve overall immunological resilience in older adults.

It is important to acknowledge age-related immune changes as a hurdle that requires continued attention and investigation for future vaccine clinical trials. Alternative vaccine platforms for flu, such as mRNA-based vaccines, may be able to overcome some age-related immune deficits, while also providing improved production time and increased subtype inclusion to increase overall vaccine efficacy regardless of changes in predominantly circulating strains. Further, pre-vaccination treatments that target the hallmarks of aging may be a novel approach to improve flu vaccination responses with aging that don't require any vaccine formulation changes. Overall, flu vaccine efficacy is integral to protecting older adults from excessive morbidity and mortality. Alternative vaccination strategies and pre-vaccination interventions that better address aging physiology likely can improve immunological resilience and overall protection in at-risk older adults.

Link: https://doi.org/10.1186/s12979-023-00348-6

Microglia are innate immune cells of the central nervous system, similar to macrophages elsewhere in the body. These cells become more inflammatory and dysfunctional with age, and this is implicated in the onset and progression of neurodegenerative conditions. Chronic inflammation is disruptive of tissue function, and in the brain is connected with a range of pathological mechanisms. Here, researchers discuss the loss of autophagy and related mitochondrial quality control characteristic of age, and how this might affect microglia. Inflammation and mitochondrial dysfunction are connected, one of the many ways in which age-related decline can provoke chronic, unresolved inflammation in tissues throughout the body.

Microglia, characterized by responding to damage, regulating the secretion of soluble inflammatory mediators, and engulfing specific segments in the central nervous system (CNS), function as key immune cells in the CNS. Emerging evidence suggests that microglia coordinate the inflammatory responses in CNS system and play a pivotal role in the pathogenesis of age-related neurodegenerative diseases (NDDs). Remarkably, microglia autophagy participates in the regulation of subcellular substances, which includes the degradation of misfolded proteins and other harmful constituents produced by neurons. Therefore, microglia autophagy regulates neuronal homeostasis maintenance and process of neuroinflammation.

Here, we provide an overview of the relationship between microglia autophagy and NDDs. The onset and progression of NDDs are associated with the accumulation of abnormal substances in the nervous system. Recent studies revealed that microglia autophagy removes harmful substances and abnormal aggregates produced by neurons in the nervous system and acts as a neuroprotective agent, which can help treat NDDs or control their progression. Meantime, manipulation of microglia autophagy also interrupts neuroinflammation in NDDs, maintain a state of equilibrium, and prevent disease progression. Therefore, the balance between microglia autophagy and neuroinflammation is of critical importance in NDDs.

Noticeably, potential drugs such as kaempferol, melatonin, and spermidine have been shown to balance microglia autophagy and neuroinflammation in NDDs. However, the mechanisms of interaction between microglia autophagy and neurons have not been sufficiently elucidated, such as how microglia autophagy remove toxic substances produced by neurons or glial cells or how microglia autophagy counteract abnormal neuronal death. More in-depth studies remain to be completed in this area.

Link: https://doi.org/10.3389/fnagi.2022.1100133

Rapamycin is arguably the best of the many calorie restriction mimetic small molecules, treatments that can provoke some of the sweeping, favorable metabolic and cellular changes produced by a reduction in calorie intake. The data showing a modest slowing of aging in mice with rapamycin treatment is robust and well replicated, albeit only producing a 5-10% extension of life span, much less than has been shown to be possible via forms of calorie restriction. Like calorie restriction, rapamycin upregulates the cellular housekeeping process of autophagy, but there is much more going on under the hood for both of these interventions.

Is rapamycin better than exercise for longevity? In mice, yes. In humans, who knows? No-one has yet devoted the time and funding to completing a robust clinical trial of rapamycin aimed at evaluating late life health and life expectancy, though the PEARL trial, funded by philanthropic donations, is a step in the right direction. Another step one can take at lesser cost than a clinical trial is to survey some of the many people who are taking rapamycin in the hopes that it will slow aging. Thus we have today's open access paper. While self-reported data is of generally poor quality, for all the obvious reasons (and perhaps especially so in this context!), it is sometimes possible to learn from it, given a large enough study population. The one thing I'd be inclined to take at face value is the reporting on side-effects, for example.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Rapamycin (sirolimus) is an FDA-approved drug with immune-modulating and growth-inhibitory properties. Preclinical studies have shown that rapamycin extends lifespan and healthspan metrics in yeast, invertebrates, and rodents. Several physicians are now prescribing rapamycin off-label as a preventative therapy to maintain healthspan. Thus far, however, there is limited data available on side effects or efficacy associated with use of rapamycin in this context. To begin to address this gap in knowledge, we collected data from 333 adults with a history of off-label use of rapamycin by survey. Similar data were also collected from 172 adults who had never used rapamycin.

Rapamycin users generally reported perceived improvements in quality of life since beginning off-label use of rapamycin. Ratios of greater than 3:1 in agreement were observed for self-reported improvements in health, happiness, brain function, feelings of youthfulness, confidence, calmness, anxiety, and generalized aches and pains. Interestingly, greater than fivefold more rapamycin users agreed with the comment that "family/friends have commented that I look good" than disagreed, suggesting that these perceived self-benefits may also be apparent to others.

Rapamycin use by organ transplant patients is associated with a long list of potential side effects. Interestingly, among survey respondents, only mouth sores was significantly more prevalent in rapamycin users compared to non-users. The lack of apparent side effects associated with off-label rapamycin use here is also consistent with prior reports that once weekly administration of 5mg of the rapamycin derivative everolimus has side effects comparable to placebo among healthy older adults.

This study has several limitations that make the data less reliable than what would be obtained from a double-blind, randomized clinical trial. The self-reported nature of the data and the possibility of unintended bias in the participant pool reduce confidence that these results would be recapitulated in a larger, more heterogenous population. In particular, we cannot rule out the possibility that the population of rapamycin users is self-selected against people who started taking rapamycin and stopped because of negative experiences; however, we attempted to recruit as broadly as possible to include such individuals both through social media and through direct recruitment of prior patients who had been prescribed rapamycin in the past.

It is also possible that individuals taking rapamycin off-label are more likely to practice healthy lifestyle habits or take other substances that could confound this analysis. We attempted to evaluate this and found no major differences between groups. Indeed, both rapamycin users and non-users in this study appear to be atypical in that they report higher rates of exercise and healthy dietary habits, lower body mass index, and lower rates of alcohol consumption and tobacco use, relative to the general population. It is possible that potential benefits and side effects from off-label rapamycin use would be different in a less healthy population.

Complex systems that require different cell types to interact in intricate ways are found everywhere in the body, and these systems become dysfunctional with age. If all of the moving parts must perform correctly, then the system is vulnerable. It will start to fail the moment that any one of those component parts is sufficiently affected by the growing damage and signaling changes characteristic of aging. Here find an example of this point in the behavior of the germinal centers that form in well-trafficked locations such as lymph nodes, where immune cells can meet and exchange information. These germinal centers cease to efficiently function with age, reducing the effectiveness of the immune response, and researchers here identify the proximate cause of the problem.

After a vaccination our immune system reacts by creating specialised structures called germinal centres that produce the immune cells (B cells) that provide long-term protection through the production of antibodies. The correct function of the germinal centre response requires the coordination of cellular interactions across time and space. Germinal centres are made up of two distinct regions - the light zone and dark zone, with some cells located in specific areas, and others which move between the zones. B cells are shaped by their interactions in first the dark zone and then in the light zone.

Researchers were able to show that changes to key interactors of B cells in the light zone of the germinal centre, T follicular helper (Tfh) cells, and also to light-zone specific cells called follicular dendritic cells (FDCs), were at the heart of the diminished vaccination response. "In this study we looked at what was happening to different cell types in the germinal centre, particularly the structure and organisation of the germinal centre across its two functionally distinct zones, to try and understand what causes the reduced germinal centre response with age. What we found is that the T follicular helper cells aren't where they should be and as a result, antibody-producing cells lose essential selection cues. Surprisingly we also uncovered an unknown role for T follicular helper cells in supporting the expansion of follicular dendritic cells in the light zone after vaccination."

Having identified the dependencies between the cell types, the researchers used genetically modified mice to control the location of Tfh cells in the germinal centre, demonstrating that the defective FDC response was caused by loss of Tfh from the light zone. Importantly, they were also able to correct the defective FDC response and boost the germinal centre response in aged mice by providing T cells that could correctly colocalize with FDCs using CXCR5 upregulation.

Link: https://www.babraham.ac.uk/news/2023/05/lost-immune-cells

Researchers are discovering new senolytic drugs at a fairly steady pace. These compounds can selectively destroy senescent cells, though their efficacy varies widely, both generally and by origin and tissue of senescent cell. It requires the destruction of a sizable fraction of the burden of senescent cells in aged tissues to produce the rapid, sizable rejuvenation observed in mice treated with the best of the senolytics discovered to date. Senolytics that clear only a small fraction of lingering senescent cells are far less interesting.

The study noted here is an example of the sort of early stage discovery taking place in this part of the field, with researchers presenting in vitro data only on their drug of interest. Animal data arrives later, if at all: evidence of efficacy in destroying senescent cells in a cell culture often fails to translate to efficacy in destroying senescent cells in a living mammal.

The accumulation of senescent cells has an important role in the phenotypical changes observed in ageing and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated.

Given the involvement of histone deacetylases (HDACs and the PI3K pathway in senescence, we hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53. Consistent with this, CUDC-907 showed senolytic properties in different cell models of stress-induced senescence.

Our results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, our results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved.

Link: https://doi.org/10.18632/aging.204616

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Contents

• Reviewing the Complexity of Immunosenescence
• Reviewing mTOR Inhibition as a Pharmacological Strategy to Modestly Slow Aging
• Less Sleep and a Longer Life, a Desirable Mutation
• Cellular Senescence in Skin as an Early Sign of Aging
• Rejuvenation of the Gut Microbiome as a Strategy to Improve Late Life Cognitive Function
• Decline in Vascular Function Correlates with Decline in Physical Function
• THBD Signaling as a Novel Target for Senolytic Drugs
• Towards SIRT6 Upregulation as a Calorie Restriction Mimetic Strategy
• Skeletal Age as an Alternative Way to Present the Mortality Risk Following Fracture Due to Osteoporosis
• Sufficient Physical Activity Correlates With a Halving of the Risk of Influenza Mortality
• Innate Immune Regulation in Life Extension via Calorie Restriction
• Triglyceride Depletion Mimics Calorie Restriction in Old Muscles
• Exercise Reduces the Risk of Parkinson's Disease
• Long Term Exercise Improves Neurogenesis and Memory Function in Mice
• Hunger Extends Life in Flies Independently of Calorie Intake

Reviewing the Complexity of Immunosenescence
https://www.fightaging.org/archives/2023/05/reviewing-the-complexity-of-immunosenescence/

The immune system becomes more inflammatory and less competent with advancing age, undergoing sweeping changes in immune cell characteristics and relative population sizes. The cells, structures, and processes that produce immune cells similarly undergo significant changes. Taken together, this is called immunosenescence, though many researchers choose to break out the inflammatory component of dysfunction into its own category, calling it inflammaging. One of the most important goals for the research community is to find ways to improve immune function in older people.

Evidently, the decline of the immune system is an important aspect of aging. It produces many directly, obviously harmful consequences. The inability to defend against infectious disease leads to a tremendous death toll in older individuals, largely resulting from common infectious agents such as influenza, diseases that younger people can shrug off. Similarly, the ability to clear precancerous and senescent cells is also much reduced, driving the increased risk of cancer on the one hand, and the growing number of lingering senescent cells on the other. There are many more subtle issues, more poorly researched, however, in which aged immune cells play a harmful role, contributing to age-related disease and dysfunction in specific organs.

Immunosenescence: molecular mechanisms and diseases

Immunosenescence is a complex process that involves organ reorganization and numerous regulatory processes at the cellular level. As a result, immune system function decreases, leading to an inadequate response to infections or vaccines in elderly individuals. Although the full extent of the biological changes is unknown, several characteristic changes are typically observed such as thymic involution, hematopoietic stem cell (HSC) dysfunctions, disrupted naïve/memory ratio in T cells and B cells, inflammaging, accumulation of senescent cells, impaired new antigen response, mitochondrial dysfunction, genomic instability, and stress responses. Identifying hallmarks and characteristics associated with immunosenescence is crucial for exploring its impact and significance, particularly in age-related diseases.

Thymic involution plays a vital role in the imbalance of immune cell proportions, particularly for T cells. Thymic tissue can be divided into epithelial tissue and nonepithelial perivascular space without thymopoiesis. As the thymus atrophies, the epithelial spaces gradually disappear, and the perivascular space gradually fills the elderly thymus, leading to a decrease in naïve T cells, an increase in peripheral late-differentiated memory T cells, and diminished migration of naïve T cells to the periphery. According to recent studies, thymic rejuvenation does not restore diversity, and we agree that thymic degeneration does not perfectly explain the decline in T-cell receptor (TCR) diversity in humans.

One of the hallmarks of immunosenescence is "inflammaging," which refers to a systemic state of chronic low-grade inflammation characterized by upregulated blood inflammatory markers and is considered the central pillar of aging. The accumulation of damaged macromolecules is responsible for inflammaging, and endogenous host-derived cell debris is the source of chronic tissue damage. Cellular senescence is central to the inflammaging process. Senescent cells exhibit a distinctive senescence-associated secretory phenotype (SASP), leading to the inflammaging phenotype. Cellular senescence has been hotly debated as a driver of immunosenescence.

As the immune system ages, metabolism undergoes changes that involve increased glycolysis, mitochondrial dysfunction, and reactive oxygen species (ROS). These features of immunosenescence are strongly related to high morbidity and mortality from age-associated diseases such as cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, metabolic diseases, and cancers in older patients. As the incidence of these disorders exponentially increases later in life, common cellular and molecular mechanisms likely contribute to their development. In this context, it is crucial to examine the molecular mechanisms, altered immune cell pool, and regulatory signaling impact on immunosenescence and age-related diseases.

Reviewing mTOR Inhibition as a Pharmacological Strategy to Modestly Slow Aging
https://www.fightaging.org/archives/2023/05/reviewing-mtor-inhibition-as-a-pharmacological-strategy-to-modestly-slow-aging/

It is arguably the case that we should look at small molecule mTOR inhibitors, such as rapamycin and its descendant rapalog compounds, as the most effective of the calorie restriction mimetic approaches developed to date. The practice of calorie restriction, eating as much as 40% fewer calories while still obtaining optimal levels of micronutrients, produces sweeping changes to metabolism. Some of these, such as increased autophagy and other forms of cellular housekeeping, appear to be beneficial to long-term health. Keeping cells more free of damage leads to a slowing of aging.

In mice, that slowing of aging can lead to as much as a 40% extension of life span via calorie restriction. Rapamycin, on the other hand, managed a 5% to 10% extension of life span in the very rigorous Interventions Testing Program studies. This illustrates one of the issues with calorie restriction mimetic treatments, which is that they only capture a fraction of the beneficial metabolic change produced by calorie restriction, and are therefore considerably less effective.

The other issue is that the practice of calorie restriction certainly doesn't produce a 40% extension of life span in humans; that would be quite evident, and have been well known since antiquity. Long-lived mammals exhibit very similar short-term metabolic changes and improved measures of health in comparison to short-lived mammals when undergoing calorie restriction, but long-term effects on life span are much more muted.

It seems plausible that many of the metabolic changes caused by calorie restriction in short-lived species became permanent in the course of evolving longer life spans. Thus humans, one of the more long-lived mammals, likely gain only a few years from the practice of calorie restriction. This might lead one to the reasonable conclusion that calorie restriction mimetics are not the way forward to greatly improve late life health in humans. Nonetheless, there is considerable appetite and funding for this line of research and development.

Targeting the biology of aging with mTOR inhibitors

mTOR is an evolutionarily conserved serine-threonine protein kinase found in diverse species including mice and humans. The mTOR kinase forms the catalytic core of two distinct protein complexes, mTORC1 and mTORC2, each of which are composed of shared as well as unique protein subunits and phosphorylate different substrates. mTORC1 is regulated by a wide range of nutrients and hormonal cues, most notably by the availability of amino acids, but also glucose, oxygen, and cholesterol. mTORC1 activity drives a wide variety of anabolic processes, as well autophagy, through phosphorylation of substrates.

Beginning 20 years ago, researchers discovered a role for mTORC1 signaling in the aging process. Studies in yeast, worms, and flies found that genetic inhibition of mTORC1 or signaling pathways downstream of mTORC1 extends lifespan. These results quite logically spurred substantial interest in the possibility that a potent chemical inhibitor of mTORC1, rapamycin, could extend lifespan. This was indeed the case, and there are now numerous studies showing that rapamycin can extend the lifespan not only of model organisms including yeast, worms, and flies but also of both wild-type mice and in many disease models. In this review, we will discuss the results of these studies, as well as the possible mechanism by which reduced mTORC1 signaling via both dietary and pharmacological means may improve healthspan.

There is rapidly growing interest in using mTOR inhibitors to promote healthy aging and to treat, delay or reverse numerous age-related diseases. While there is incredibly strong preclinical evidence in mice that rapamycin can extend lifespan and healthspan, excitement about rapamycin has outpaced rigorous evidence that rapalogs are both safe and efficacious for diseases of aging in humans. There are many unanswered questions from the trials that have been conducted thus far, but a few general lessons can be taken from the clinical trials of mTOR inhibitors that have been performed thus far. In both humans and mice, treatment with low or intermittent doses of rapamycin or everolimus or treatment of mice with the mTORC1-selective inhibitor DL001, is much better tolerated than the high doses of mTOR inhibitors currently approved for organ transplant and oncology indications, with fewer metabolic side effects and less immunosuppression. In addition, low doses of mTOR inhibitors have been shown to have some beneficial effects on the function of aging human organ systems, in particular, the immune system.

There remains much work ahead to bring mTOR inhibitors into the clinic for age-related conditions and many open questions remain. While the safety profile of low-dose rapamycin and rapalogs in humans appears promising, the long-term safety and efficacy of low-dose regimens remain to be determined. A much better understanding is needed of the specific dose and duration of mTOR inhibitors that both maximize efficacy and minimize risk. In humans, higher doses (for example, 3 mg per day) of mTOR inhibitors such as everolimus inhibit T cell function and are therefore are used to suppress immune-mediated organ transplant rejection in patients. By contrast, a sixfold lower dose of everolimus for 6 weeks was associated with improved immune function as assessed by vaccination response. Thus, both dose and duration may contribute to whether mTOR inhibition has positive or negative effects on healthy aging, but, generally speaking, the lower the dose of a drug, the fewer expected side effects.

Over the next 5 years, we expect results from a rapidly expanding list of human clinical trials as well as work in canines and non-human primates to shed light on the viability of mTOR inhibition as a therapy for aging-related conditions. New mTORC1-specific molecules may help to widen the therapeutic window for rapalogs, limiting undesirable side effects resulting in whole or in part from inhibition of mTORC2. Collectively, we expect that researchers will soon be able to determine whether clinicians can safely and effectively bring mTOR inhibitors to the geriatric bedside.

Less Sleep and a Longer Life, a Desirable Mutation
https://www.fightaging.org/archives/2023/05/less-sleep-and-a-longer-life-a-desirable-mutation/

A person who sleeps six hours rather than eight hours every day, give or take, is effectively gaining a bonus 12.5% additional time spent alive and active. From that perspective, there isn't all that much difference between being able to sleep two hours less every night throughout life, without consequences, and being able to live for the better part of an additional decade in good health. There are mutations that produce this effect in humans, other mammals, and lower animals such as flies, and at least one of them does so without any apparent negative side-effects.

Today's open access paper offers an exploration of one of these mutations, a small alteration in DEC2, which not only reduces the need for sleep, thereby granting additional subjective life span, but is also found to extend actual life span in flies. The size of the effect is larger than many of the calorie restriction mimetic compounds explored in recent years. Interestingly, the authors here argue that reduced need for sleep is more a reflection of increased robustness and health resulting from this mutation than any independent, top-down alteration of the regulation of sleep.

A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila

One of the most well-studied examples of natural short sleepers in the human population are individuals with rare genetic mutations in the dec2 gene. Dec2 is a transcriptional repressor that, in mammals, is recruited to the prepro-orexin promoter and represses the expression of orexin, a neuropeptide that promotes wakefulness. A single point mutation in dec2 (dec2P384R) inhibits the ability of Dec2 to bind the prepro-orexin promoter, resulting in increased orexin expression. Consequently, wakefulness increases, and individuals sleep on average 6hrs/day instead of 8hrs/day.

Intriguingly, these natural short sleepers do not appear to exhibit any phenotypes typically associated with chronic sleep deprivation, and expression of the dec2P384R mutation in mice suppresses neurodegeneration. Thus, it has been suggested that individuals harboring the dec2P384R mutation may employ compensatory mechanisms that allow them to thrive with chronic sleep loss. However, whether the dec2P384R mutation directly confers global health benefits has not yet been tested experimentally in any system.

In this study, we used a Drosophila model to understand the role of the dec2P384R mutation on animal health and elucidate the mechanisms driving these physiological changes. We found that the expression of the mammalian dec2P384R transgene in fly sleep neurons was sufficient to mimic the short sleep phenotype observed in mammals. Remarkably, dec2P384Rmutants lived significantly longer with improved health despite sleeping less. In particular, dec2P384R mutants were more stress resistant and displayed improved mitochondrial fitness in flight muscles. Differential gene expression analyses went on to reveal several altered transcriptional pathways related to stress response, including detoxification and xenobiotic stress pathways, that we demonstrate collectively contribute to the increased lifespan and improved health of dec2P384R mutants.

Finally, we provide evidence that the short sleep phenotype observed in dec2P384R mutants may be a result of their improved health rather than altered core sleep programs. Taken together, our results highlight the dec2P384R mutation as a novel pro-longevity factor and suggest a link between pro-health pathways and reduced sleep pressure.

Cellular Senescence in Skin as an Early Sign of Aging
https://www.fightaging.org/archives/2023/05/cellular-senescence-in-skin-as-an-early-sign-of-aging/

While no-one likes to be reminded of it, there are clear, albeit minor signs of aging that arise in as young a stage of life as the 20s to 30s. These early manifestations of aging are very poorly understood; perhaps understandably, near all research into mechanisms of aging is focused on late life pathology and its causes. Thus we are left with a very unsatisfactory understanding of what exactly is going in early adult life that makes a mid-30s adult physiologically different from an immediately post-development teenager.

In today's open access commentary, researchers report on evidence implicating senescent cells in these differences, at least in skin, and this is quite interesting. Present understanding holds that the accumulation of senescent cells in later life is most likely driven by immune dysfunction that impairs the timely clearance of newly created senescent cells. A similar immune-driven slowdown in clearance in the 20s and 30s, as described here, is unexpected.

Immune dysfunction over the course of life is thought to proceed along much the same lines as cancer risk, because of the role of the immune system in suppressing precancerous lesions. Risk of cancer doesn't start to meaningfully increase until the 50s and on. Still, it is also clear that the gut microbiome begins to change in the 30s as well, and there also the immune system is implicated, as immune cells are responsible for gardening the gut microbiome, destroying problematic microbes. We might speculate that these recent discoveries are setting the stage for the realization that early immune aging both exists and is a driver of the comparatively small changes in physiology that take place in the 20s and 30s.

Changes of senescent cell accumulation and removal in skin tissue with ageing

Senescent cells are known to secrete various inflammatory cytokines (known as the senescence-associated secretory phenotype factors: SASP factors) and adversely affect surrounding tissues. Senolytic drugs that selectively induce the death of senescent cells are under development. We reported that skin inherently possesses mechanisms to remove senescent cells. In the epidermis, this is achieved by the binding of JAG1, a Notch ligand expressed on adjacent non-senescent keratinocytes, to Notch1 receptors expressed by senescent keratinocytes, which promotes the exclusion of senescent cells from the basal layer by inducing differentiation. Meanwhile, in the dermis, senescent cells are phagocytosed by macrophages through recognition by the phosphatidyl serine (PS) receptor STAB1. However, since ageing is associated with the accumulation of senescent cells in skin tissue, it is hypothesized that this accumulation is preceded by a decline in the ability to remove them.

Here, we tested this hypothesis by analysing in detail the changes in the number of senescent cells and the ability of them to be removed from the skin with ageing. Marginal skin tissues at the time of surgery were collected from patients who had provided informed consent. Paraffin-embedded sections prepared from the unexposed skin tissue were subjected to immunostaining with the major senescent cell marker p16INK4A to analyse the number of senescent cells. To characterize the ability for senescent cells to be removed from the skin, the expression of JAG1 in the epidermal keratinocytes and STAB1 in macrophages was analysed. The results confirmed that senescent cell accumulation was increased with age in both epidermis and dermis. We also found that the ability to remove senescent cells decreased with age.

In addition, it was observed that while the accumulation of senescent cells was detected after 30s, the removal capacity began to decrease at 20s. Although there was a delay of the age at which senescent cell accumulation starts after the onset of declining of senescent cell removal ability, there appears to be a correlation across all ages between the removal ability and the accumulation of senescent cells. The reason of the decline in the senescent cell removal function in the 20s, before senescent cells accumulate, is still a mystery. We believe that environmental factors such UV radiation, reactive oxygen species, and exposure to SASP factors released by transiently senescent cells in young age may have an impact on the function of senescent cell removal. Future plans for this research include a closer look at these factors and the techniques for enhancing the efficiency of senescent cell removal.

Rejuvenation of the Gut Microbiome as a Strategy to Improve Late Life Cognitive Function
https://www.fightaging.org/archives/2023/05/rejuvenation-of-the-gut-microbiome-as-a-strategy-to-improve-late-life-cognitive-function/

The aging of the brain is driven by many factors. Animal studies have demonstrated that the composition of the gut microbiome is one such factor. With age, the balance of microbial populations shifts to favor harmful, inflammatory microbes at the expense of helpful microbial species that produce metabolites necessary for tissue function. Chronic inflammation is a feature of many age-related conditions, neurodegenerative conditions particularly, and the aging gut microbiome contributes to that inflammatory state. Further, the microbiome generates metabolites such as butyrate that support neurogenesis, the creation of new neurons necessary for learning and memory function. Butyrate production falls with advancing age as the microbiome changes.

Fecal microbiota transplant from a young animal to an old animal has been demonstrated to produce a lasting rejuvenation of the gut microbiome, restoring a more youthful balance of populations. In some studies this has resulted in extended life span, in others improved physical and cognitive function. It is a comparatively simple procedure that is already used in a limited way in human medicine, as a treatment for C. difficile infection. It can be carried out width considerably less expense and medical support than the use of the FDA approved procedure, of course. Services like Human Microbes sell screened stool samples from young donors. Further, the measurement of gut microbiome composition and function, a way to clearly and accurately assess outcomes following fecal microbiota transplant, is available via low cost commercial services.

The use of fecal microbiota transplants from young individuals is promising, cost-effective, easy to conduct, and easy to assess as a self-experimenter in the present environment. The procedure should undergo broad clinical testing as a treatment to improve late-life health, but both academia and industry tend to be very slow to undertake clinical trials for a low-cost existing treatment that cannot be effectively patented and monopolized. Given that, setting up one or more low cost clinical trials of fecal microbiota transplant in a few hundred individuals would be a good project for a philanthropic initiative, a way to accelerate the adoption of a way to improve health in a lasting way for hundreds of millions of older people.

The gut microbiota is an emerging target for improving brain health during ageing

While the impact of ageing on the mammalian and human gut microbiome is well established, the impact of the gut microbiota on brain ageing has only recently been investigated, and relies dominantly on preclinical evidence and association analysis derived from small clinical trials. Studies utilising fecal microbiota transplantation (FMT) have demonstrated that the gut microbiota from aged individuals has the capacity to hinder cognitive performance and neurobiological phenotypes when transferred to younger individuals. For instance, transplanting microbes from aged and diseased models to young mice has been shown to impair learning, memory, and neuroplasticity in recipient young mice. Furthermore, young mice who received gut microbiota from aged donors suffered increased rates of mortality following ischemic stroke, along with increased levels of pro-inflammatory plasma cytokines and impaired motor strength. Conversely, aged mice who were colonised with the microbiota from young donor mice had increased survival and improved recovery post-stroke, demonstrating the functional differences between microbiota derived from young or aged individuals in influencing brain recovery following trauma.

Fascinatingly, the gut microbiota from young mice appears to harness properties that enable it to rejuvenate aspects of brain ageing when transferred into aged mice. Two studies recently confirmed similar findings, wherein FMT from young mice to aged mice improved ageing-related deficits in memory and learning ability. Microbiota from young mice restored age-related changes in peripheral and hippocampal immune responses and reversed age-related alterations in hippocampal transcriptional profiles and metabolites suggesting potential mechanisms by which the gut microbiota from young mice improve cognitive performance by modulating immune and metabolic pathways. In this regard, the microbially-derived metabolite δ-valerobetaine, which is increased in aged mice and humans, was shown to directly impair learning and memory abilities, and was reduced in aged mice following FMT from young donor mice. Relatedly, other gut microbiota-derived metabolites which are linked to age-related shifts in the gut microbiota and are increased in aged humans indicate that specific microbially-derived metabolites can impair cognitive abilities during ageing.

As the causal relationships between the gut microbiota and host brain ageing become increasingly clear, it is critical to continue to investigate whether microbiota-targeted therapeutics hold the potential to ameliorate the effects of ageing onto the brain. Several approaches to altering the gut microbiota, including medical interventions such as FMT and antibiotics, as well as lifestyle choices such as diet including probiotics, prebiotics, Mediterranean diet, and intermittent fasting, and exercise, may hold the key to the fountain of brain youth.

Decline in Vascular Function Correlates with Decline in Physical Function
https://www.fightaging.org/archives/2023/05/decline-in-vascular-function-correlates-with-decline-in-physical-function/

The vasculature becomes increasingly dysfunctional with age in a number of different ways, from loss of capillary density to tissue stiffening and issues with smooth muscle function that lead to raised blood pressure, as well as the development of endothelial inflammation and atherosclerotic lesions that lead to heart attack or stroke. It isn't surprising to find that even simple measures of vascular aging, such as raised blood pressure, correlate fairly well with other aspects of aging, such as declines in physical function.

Approximately 10% of older adults have muscle weakness and diminished physical function that leads to adverse health outcomes and physical disability. A new study showed that vascular measures are associated with grip strength in cross-sectional analyses and change in gait speed (a measure of physical function) in longitudinal analyses. This is one of the first community-based studies to comprehensively examine relations of aortic stiffness and vascular function with age-related decline in physical function. Higher aortic stiffness was associated with loss of physical function over ~11 years.

Blood flow declines with aging, in part due to arterial stiffening. Consequent dysfunction in blood vessel dynamics may contribute to organ pathology and declines in muscle mass. The current study utilized data from a large cohort of 2,498 relatively healthy men and women and extends previous investigations by utilizing a longitudinal study design. The majority of previously published studies have utilized cross-sectional study designs with modest sample sizes. The authors believe that future studies should evaluate whether interventions that target vascular health may reduce age-related declines in physical function.

THBD Signaling as a Novel Target for Senolytic Drugs
https://www.fightaging.org/archives/2023/05/thbd-signaling-as-a-novel-target-for-senolytic-drugs/

Researchers here show that THBD signaling inhibition is an approach to selectively destroy senescent cells. There is an approved drug that can do this, vorapaxar, though at first glance its safety profile looks worse than that of dasatinib, the only senolytic so far proven to clear senescent cells in humans. One might wonder how much of vorapaxar's successes in clinical trials are due to clearance of senescent cells versus other mechanisms.

As is the case in many lines of research into cellular senescence, the focus here is on fibrosis, a progressive failure of tissue maintenance in which scar-like deposits form to disrupt tissue structure and function. Senescent cells are implicated in this process, and clearance of senescent cells has been shown to reverse fibrosis in a number of different organs and animal models.

Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis.

Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability.

Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.

Towards SIRT6 Upregulation as a Calorie Restriction Mimetic Strategy
https://www.fightaging.org/archives/2023/05/towards-sirt6-upregulation-as-a-calorie-restriction-mimetic-strategy/

Researchers have in recent years expressed a growing interest in the role of sirtuin 6 (SIRT6) in the mechanisms of calorie restriction and improved function that occurs in response to mild stress. Many forms of stress, such as lowered levels of nutrients, produce benefits via upregulation of cellular maintenance processes such as autophagy.

That said, it is unclear as to whether calorie restriction mimetic therapies will prove to be all that interesting as a class of therapy in humans, as calorie restriction only produces significant gains in life span in short-lived species. While scientists are far from a full accounting of how exactly the sweeping metabolic changes induced by calorie restriction lead to slowed aging, it is reasonable to think that long-lived species are long-lived precisely because many of the important changes induced by calorie restriction in short-lived species such as mice are already activated all of the time in long-lived species such as our own. Thus calorie restriction increases mouse life span by 40%, but it certainly doesn't do that in humans.

US-Israeli startup SIRTLab is focused on the development of therapeutics that boost levels of a key protein called sirtuin 6 (SIRT6), which is heavily implicated in longevity. It appears that high levels of SIRT6 also boosts physical performance and improves memory and cognitive function, even in young mice. By generating mice with overexpression of SIRT6, researchers have demonstrated average lifespan extension of 30%, and positive impacts on frailty. But, while the longevity and healthspan benefits of SIRT6 are well-known, no one has yet developed a therapeutic way to increase SIRT6 levels.

Of course, therapeutic approaches that have worked in animal models don't always translate into results in humans, but SIRTLab believes that SIRT6 expression has a good chance of delivering on its promising results in mice. SIRTLab has created a SIRT6-focused therapeutic platform, with multiple approaches to increasing SIRT6 levels in cells. "We have developed four different ways to therapeutically target SIRT6 production: messenger RNA (mRNA), small molecules, adeno-associated viruses (AAVs), and antagonists for microRNAs that control SIRT6 levels. There are different benefits to each approach, and it's even possible that a treatment could use a combination of two or more. We've seen in our experiments that our mRNA therapeutic boosts cellular levels of SIRT6 by 20 times, which is very exciting." The company hopes to commence its first human trials in 2024, after it completes toxicity studies this year.

Skeletal Age as an Alternative Way to Present the Mortality Risk Following Fracture Due to Osteoporosis
https://www.fightaging.org/archives/2023/05/skeletal-age-as-an-alternative-way-to-present-the-mortality-risk-following-fracture-due-to-osteoporosis/

Bone mineral density decreases with age, a growing imbalance between the activity of osteoblasts (depositing bone) and osteoclasts (breaking down bone). This leads eventually to meaningful risk of fracture and osteoporosis. Suffering bone injury due to bone weakness in later life is a spiral downwards into debilitating incapacity, and comes with a significantly raised risk of mortality. Here, researchers run the numbers to present the increased mortality risk following fracture as an adjustment to skeletal age, in the hope of increasing the use of existing therapies for osteoporosis.

Osteoporosis is a 'silent disease' which often has no immediate symptoms but gradually weakens bones and makes them more likely to break. A bone fracture caused by osteoporosis in people over the age of 50 is linked to long-term health decline and in some cases, even early death. However, poor communication of the mortality risk to patients has led to a low uptake of treatment, resulting in a crisis of osteoporosis management. The impact of a fracture on life expectancy is typically conveyed to patients and the public in terms of probability (how likely something is to occur) or the relative risk of death compared to other groups. However, statements such as "Your risk of death over the next 10 years is 5% if you have suffered from a bone fracture" can be difficult to comprehend and can lead to patients underestimating the gravity of the risk.

With the aim of devising a new way of conveying risks to patients, researchers analyzed the relationship between fracture and lifespan in over 1.6 million individuals who were 50 years of age or older. The findings showed that one fracture was associated with losing up to 7 years of life, depending on gender, age and fracture site. Based on this finding, researchers proposed the idea of 'skeletal age' as a new metric for quantifying the impact of a fracture on life expectancy. Skeletal age is the sum of the chronological age of a patient and the estimated number of years of life lost following a fracture. For example, a 60-year-old man with a hip fracture is predicted to lose an estimated 6 years of life, resulting in a skeletal age of around 66. Therefore, this individual has the same life expectancy as a 66-year-old person that has not experienced a fracture.

Skeletal age can also be used to quantify the benefit of osteoporosis treatments. Some approved treatments substantially reduce the likelihood of post-fracture death and translating this into skeletal age could help communicate this to patients. For instance, telling patients that "This treatment will reduce your skeletal age by 2 years" is easier to understand than "This treatment will reduce your risk of death by 25%".

Sufficient Physical Activity Correlates With a Halving of the Risk of Influenza Mortality
https://www.fightaging.org/archives/2023/05/sufficient-physical-activity-correlates-with-a-halving-of-the-risk-of-influenza-mortality/

Analysis of a large epidemiological database here shows that sufficient exercise correlates with a halving of the risk of mortality due to influenza. Like many other studies, it also shows that too much exercise may be harmful, actually increasing the risk of mortality. While correlation does not imply causation, there is plenty of evidence for physical fitness and physical activity to reduce impacts of aging related to immune function. Alternative explanations revolve around the tendency of more robust individuals to conduct more exercise, while also tending to be more resilient independently of the effects of exercise.

A nationally representative sample of US adults (aged ≥18 years) who participated in the National Health Interview Survey from 1998 to 2018 were followed for mortality through 2019. Participants were classified as meeting both physical activity guidelines if they reported ≥150 minutes/week of moderate-intensity equivalent aerobic physical activity and ≥2 episodes/week of muscle-strengthening activity. Participants were also classified into five volume-based categories of self-reported aerobic and muscle-strengthening activity.

Among 577,909 participants followed for a median of 9.23 years, 1,516 influenza and pneumonia deaths were recorded. Compared with participants meeting neither guideline, those meeting both guidelines had 48% lower adjusted risk of influenza and pneumonia mortality. Relative to no aerobic activity, 10-149, 150-300, 301-600 and greater than 600 minutes/week were associated with lower risk (by 21%, 41%, 50% and 41%). Relative to fewer than 2 episodes/week of muscle-strengthening activity, 2 episodes/week was associated with 47% lower risk.

At the opposite end, we found that ≥7 muscle-strengthening activity episodes/week was associated with an increased risk. A J-shaped dose-response between muscle-strengthening activity and all-cause mortality has been observed elsewhere. While beyond the scope of this study, plausible explanations range from inaccurate responses (such as reporting occupational physical activity, which may not confer the same protective effect as leisure-time physical activity) to haemodynamic ramifications of frequent, high-intensity activity.

Innate Immune Regulation in Life Extension via Calorie Restriction
https://www.fightaging.org/archives/2023/05/innate-immune-regulation-in-life-extension-via-calorie-restriction/

The primary challenge in understanding how calorie restriction slows aging and extends life is that it changes near everything in the operation of cellular metabolism. Finding the important differences is a matter of searching for the needle in the haystack. The most compelling evidence to date points to increased autophagy as the important determinant, greater effort made by cells to repair damage, maintain function, and recycle components. It remains likely that other mechanisms are also important, however. Here, researchers focus on regulation of the innate immune system in response to a reduced calorie intake; they are working with nematodes, but many of the noteworthy aspects of calorie restriction are much the same across all species.

Dietary restriction (DR) is a practically effective and reproducible nutritional intervention that extends lifespan in many organisms. Many studies have shown that DR improves immune function, and immune signaling components are required for DR-induced lifespan extension. These results support the idea that the immune system acts as an important mechanism for DR-induced longevity. Recently, analysis of genes that regulate aging or immune response in animal models, including C. elegans, Drosophila, mice, and even humans, has revealed that aging and immunity are controlled by the same signaling pathways, such as TOR/S6K signaling pathway, pleiotropically. DR-induced longevity is also associated with the modulation of the TOR/S6K signaling pathway. Thus, these results suggest that the immune function may be closely associated with aging regulation through DR.

In this study, we found that the F-box gene fbxc-58 is a downstream effector of the S6K signaling pathway, and that it regulates both pathogen resistance and aging in C. elegans. Furthermore, fbxc-58 is necessary for the effects of DR on lifespan extension. F-box protein acts as a modular E3 ubiquitin ligase adaptor protein, and the ubiquitin-dependent mechanisms have been shown to determine lifespan in response to DR or modulate the innate immune response. Therefore, we suggest that gaining insights into the detailed mechanistic aspects of fbxc-58 signaling pathway could elucidate the conserved signaling mechanism that links innate immunity and DR-induced healthy aging in animals.

Further, DR prevents or reduces the burden of age-related diseases or disabilities. Especially, in an aging and sedentary society, sarcopenia, an age-associated muscle disease, is beginning to be recognized as an acute disease condition. Although an effective sarcopenia treatment regime has not yet been identified, nutritional intervention is considered an effective method of preventing sarcopenia. In this study, we found that DR prevents muscle aging via fbxc-58 in C. elegans. fbxc-58 is essential for DR-mediated alleviation of the age-associated decline in muscle activity and protection of mitochondrial network in body wall muscle. Thus, we propose that investigating the molecular mechanism of action of F-box proteins, including fbxc-58, in DR will shed light on means to prevent sarcopenia and offer a potentially practical means of encouraging healthy aging via DR.

Triglyceride Depletion Mimics Calorie Restriction in Old Muscles
https://www.fightaging.org/archives/2023/05/triglyceride-depletion-mimics-calorie-restriction-in-old-muscles/

Researchers here observe that triglyceride depletion in very aged muscles produces benefits, looking much like a form of calorie restriction that improves cell metabolism. This work was carried out in killifish, a highly regenerative species, so it remains to be seen as to whether a similar process operates in mammals, or whether it is in any way interesting or novel as a basis for therapy. Finding modest benefits in very late life is a poor alternative to focusing instead on methods of rejuvenation.

Sarcopenia, the age-related decline in muscle function, places a considerable burden on health-care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish - an extremely short-lived vertebrate - revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an "early-life" state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span.

In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life-like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long-lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.

Exercise Reduces the Risk of Parkinson's Disease
https://www.fightaging.org/archives/2023/05/exercise-reduces-the-risk-of-parkinsons-disease/

Maintaining physical fitness remains one of the most proven approaches to modestly slow the progression of aging. The large study noted here provides an example of the long-term benefits of exercise. The scientists observe a reduction in Parkinson's disease incidence in more active individuals. This is a pattern observed in near all age-related conditions, a good argument for putting in the time and effort needed to remain physically fit and active as one moves into later life.

The study included 95,354 female participants, mostly teachers, with an average age of 49 who did not have Parkinson's disease at the start of the study. Researchers followed participants for three decades during which 1,074 participants developed Parkinson's disease. Over the course of the study, participants completed up to six questionnaires about types and amounts of physical activity. Researchers assigned each activity a score based on the metabolic equivalent of a task (METs), a way to quantify energy expenditure. For each activity, METs were multiplied by their frequency and duration to obtain a physical activity score of METs-hours per week. For example, a more intense form of exercise like cycling was six METs, while less intense forms of exercise such as walking and cleaning were three METs. The average physical activity level for participants was 45 METs-hours per week at the start of the study.

Participants were divided into four equal groups of just over 24,000 people each. At the start of the study, those in the highest group had an average physical activity score of 71 METs-hours per week. Those in the lowest group had an average score of 27 METs-hours per week. Among the participants in the highest exercise group, there were 246 cases of Parkinson's disease or 0.55 cases per 1,000 person-years compared to 286 cases or 0.73 per 1,000 person-years among participants in the lowest exercise group.

After adjusting for factors such as place of residence, age of first period and menopausal status, and smoking, researchers found those in the highest exercise group had a 25% lower rate of developing Parkinson's disease than those in the lowest exercise group when physical activity was assessed up to 10 years before diagnosis. The association remained when physical activity was assessed up to 15 or 20 years before diagnosis. Results were similar after adjusting for diet or medical conditions such as high blood pressure, diabetes, and cardiovascular disease. Researchers also found that 10 years before diagnosis, physical activity declined at a faster rate in those with Parkinson's disease than in those without, likely due to early symptoms of Parkinson's disease.

Long Term Exercise Improves Neurogenesis and Memory Function in Mice
https://www.fightaging.org/archives/2023/05/long-term-exercise-improves-neurogenesis-and-memory-function-in-mice/

Exercise is demonstrated to improve memory function, both immediately in the short-term, and over the long term of regular exercise and improved physical fitness. Exercise is also known to improve measures of neurogenesis, the creation of new neurons and integration into existing neural networks in the brain. This process is essential to learning and memory. Researchers here investigate the effects of exercise on neurogenesis in mice by labeling neurons in order to determine the contribution of adult neurogenesis to neural networks in the areas of the brain important to memory.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear if adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity.

To address this issue we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in 2-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing 'old' new neurons. We identified and quantified the direct afferent inputs to the adult-born neurons within the hippocampus and (sub)cortical areas.

Here we show that long-term running substantially modifies the network of the neurons generated in young adult mice upon middle-age. Exercise increases input from hippocampal interneurons onto 'old' adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of 'old' new neurons, born during early adulthood, within a network that is important for memory function during aging.

Hunger Extends Life in Flies Independently of Calorie Intake
https://www.fightaging.org/archives/2023/05/hunger-extends-life-in-flies-independently-of-calorie-intake/

Calorie restriction is the practice of eating fewer calories while still obtaining an optimal intake of micronutrients. In recent years work in flies has expanded the understanding of how perception of food and regulation of hunger interacts with the health benefits and slowed aging that result from calorie restriction. Allowing flies to scent food removes the benefits of a lowered calorie intake, for example.

Here, researchers generate a lineage of flies that can be induced to be constantly hungry, and they find that this produces similar benefits to calorie restriction even while the flies eat more than their unmodified peers. Relatedly, work on various different forms of calorie restriction in mammals suggests that time spent hungry is the common denominator leading to slowed aging and improved health; the signaling related to hunger is an important determinant of altered cell behavior, perhaps, not just the present availability of nutrients to any given cell.

Researchers induced hunger in flies in several ways. The first was to alter the amount of branched-chain amino acids, or BCAAs, in a test snack food and later allow the flies to freely feed on a buffet of yeast or sugar food. Flies fed the low-BCAA snack consumed more yeast than sugar in the buffet than did the flies fed the high-BCAA snack. This kind of preference for yeast over sugar is one indicator of need-based hunger. The researchers note that this behavior wasn't due to the calorie content of the low-BCAA snack; in fact, these flies consumed more food and more total calories. When flies ate a low-BCAA diet for life, they also lived significantly longer than flies fed high-BCAA diets.

To look at hunger apart from dietary composition, researchers used a unique technique, activating neurons associated with the hunger drive in flies using exposure to red light, using a technique called optogenetics. These flies consumed twice as much food than did flies who were not exposed to the light stimulus. The red-light activated flies also lived significantly longer than flies used as a control. What's more, the team was able to map the molecular mechanics of hunger to changes in the epigenome of the neurons involved - and to identify that neurons responded to the presence or absence of a specific BCAA, isoleucine, in the diet. These changes can affect how much of specific genes are expressed in the brains of flies and, consequently, their feeding behavior and aging.

The aging of the brain is driven by many factors. Animal studies have demonstrated that the composition of the gut microbiome is one such factor. With age, the balance of microbial populations shifts to favor harmful, inflammatory microbes at the expense of helpful microbial species that produce metabolites necessary for tissue function. Chronic inflammation is a feature of many age-related conditions, neurodegenerative conditions particularly, and the aging gut microbiome contributes to that inflammatory state. Further, the microbiome generates metabolites such as butyrate that support neurogenesis, the creation of new neurons necessary for learning and memory function. Butyrate production falls with advancing age as the microbiome changes.

Fecal microbiota transplant from a young animal to an old animal has been demonstrated to produce a lasting rejuvenation of the gut microbiome, restoring a more youthful balance of populations. In some studies this has resulted in extended life span, in others improved physical and cognitive function. It is a comparatively simple procedure that is already used in a limited way in human medicine, as a treatment for C. difficile infection. It can be carried out width considerably less expense and medical support than the use of the FDA approved procedure, of course. Services like Human Microbes sell screened stool samples from young donors. Further, the measurement of gut microbiome composition and function, a way to clearly and accurately assess outcomes following fecal microbiota transplant, is available via low cost commercial services.

The use of fecal microbiota transplants from young individuals is promising, cost-effective, easy to conduct, and easy to assess as a self-experimenter in the present environment. The procedure should undergo broad clinical testing as a treatment to improve late-life health, but both academia and industry tend to be very slow to undertake clinical trials for a low-cost existing treatment that cannot be effectively patented and monopolized. Given that, setting up one or more low cost clinical trials of fecal microbiota transplant in a few hundred individuals would be a good project for a philanthropic initiative, a way to accelerate the adoption of a way to improve health in a lasting way for hundreds of millions of older people.

The gut microbiota is an emerging target for improving brain health during ageing

While the impact of ageing on the mammalian and human gut microbiome is well established, the impact of the gut microbiota on brain ageing has only recently been investigated, and relies dominantly on preclinical evidence and association analysis derived from small clinical trials. Studies utilising fecal microbiota transplantation (FMT) have demonstrated that the gut microbiota from aged individuals has the capacity to hinder cognitive performance and neurobiological phenotypes when transferred to younger individuals. For instance, transplanting microbes from aged and diseased models to young mice has been shown to impair learning, memory, and neuroplasticity in recipient young mice. Furthermore, young mice who received gut microbiota from aged donors suffered increased rates of mortality following ischemic stroke, along with increased levels of pro-inflammatory plasma cytokines and impaired motor strength. Conversely, aged mice who were colonised with the microbiota from young donor mice had increased survival and improved recovery post-stroke, demonstrating the functional differences between microbiota derived from young or aged individuals in influencing brain recovery following trauma.

Fascinatingly, the gut microbiota from young mice appears to harness properties that enable it to rejuvenate aspects of brain ageing when transferred into aged mice. Two studies recently confirmed similar findings, wherein FMT from young mice to aged mice improved ageing-related deficits in memory and learning ability. Microbiota from young mice restored age-related changes in peripheral and hippocampal immune responses and reversed age-related alterations in hippocampal transcriptional profiles and metabolites suggesting potential mechanisms by which the gut microbiota from young mice improve cognitive performance by modulating immune and metabolic pathways. In this regard, the microbially-derived metabolite δ-valerobetaine, which is increased in aged mice and humans, was shown to directly impair learning and memory abilities, and was reduced in aged mice following FMT from young donor mice. Relatedly, other gut microbiota-derived metabolites which are linked to age-related shifts in the gut microbiota and are increased in aged humans indicate that specific microbially-derived metabolites can impair cognitive abilities during ageing.

As the causal relationships between the gut microbiota and host brain ageing become increasingly clear, it is critical to continue to investigate whether microbiota-targeted therapeutics hold the potential to ameliorate the effects of ageing onto the brain. Several approaches to altering the gut microbiota, including medical interventions such as FMT and antibiotics, as well as lifestyle choices such as diet including probiotics, prebiotics, Mediterranean diet, and intermittent fasting, and exercise, may hold the key to the fountain of brain youth.

Calorie restriction is the practice of eating fewer calories while still obtaining an optimal intake of micronutrients. In recent years work in flies has expanded the understanding of how perception of food and regulation of hunger interacts with the health benefits and slowed aging that result from calorie restriction. Allowing flies to scent food removes the benefits of a lowered calorie intake, for example.

Here, researchers generate a lineage of flies that can be induced to be constantly hungry, and they find that this produces similar benefits to calorie restriction even while the flies eat more than their unmodified peers. Relatedly, work on various different forms of calorie restriction in mammals suggests that time spent hungry is the common denominator leading to slowed aging and improved health; the signaling related to hunger is an important determinant of altered cell behavior, perhaps, not just the present availability of nutrients to any given cell.

Researchers induced hunger in flies in several ways. The first was to alter the amount of branched-chain amino acids, or BCAAs, in a test snack food and later allow the flies to freely feed on a buffet of yeast or sugar food. Flies fed the low-BCAA snack consumed more yeast than sugar in the buffet than did the flies fed the high-BCAA snack. This kind of preference for yeast over sugar is one indicator of need-based hunger. The researchers note that this behavior wasn't due to the calorie content of the low-BCAA snack; in fact, these flies consumed more food and more total calories. When flies ate a low-BCAA diet for life, they also lived significantly longer than flies fed high-BCAA diets.

To look at hunger apart from dietary composition, researchers used a unique technique, activating neurons associated with the hunger drive in flies using exposure to red light, using a technique called optogenetics. These flies consumed twice as much food than did flies who were not exposed to the light stimulus. The red-light activated flies also lived significantly longer than flies used as a control. What's more, the team was able to map the molecular mechanics of hunger to changes in the epigenome of the neurons involved - and to identify that neurons responded to the presence or absence of a specific BCAA, isoleucine, in the diet. These changes can affect how much of specific genes are expressed in the brains of flies and, consequently, their feeding behavior and aging.

Link: https://www.michiganmedicine.org/health-lab/feeling-hunger-itself-may-slow-aging-flies

Exercise is demonstrated to improve memory function, both immediately in the short-term, and over the long term of regular exercise and improved physical fitness. Exercise is also known to improve measures of neurogenesis, the creation of new neurons and integration into existing neural networks in the brain. This process is essential to learning and memory. Researchers here investigate the effects of exercise on neurogenesis in mice by labeling neurons in order to determine the contribution of adult neurogenesis to neural networks in the areas of the brain important to memory.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear if adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity.

To address this issue we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in 2-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing 'old' new neurons. We identified and quantified the direct afferent inputs to the adult-born neurons within the hippocampus and (sub)cortical areas.

Here we show that long-term running substantially modifies the network of the neurons generated in young adult mice upon middle-age. Exercise increases input from hippocampal interneurons onto 'old' adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of 'old' new neurons, born during early adulthood, within a network that is important for memory function during aging.

Link: https://doi.org/10.1523/ENEURO.0084-23.2023

While no-one likes to be reminded of it, there are clear, albeit minor signs of aging that arise in as young a stage of life as the late 20s and early 30s. These early manifestations of aging are very poorly understood; perhaps understandably, near all research into mechanisms of aging is focused on late life pathology and its causes. Thus we are left with a very unsatisfactory understanding of what exactly is going in early adult life that makes a mid-30s adult physiologically different from an immediately post-development teenager.

In today's open access commentary, researchers report on evidence implicating senescent cells in these differences, at least in skin, and this is quite interesting. Present understanding holds that the accumulation of senescent cells in later life is most likely driven by immune dysfunction that impairs the timely clearance of newly created senescent cells. A similar immune-driven slowdown in clearance in the 20s and 30s, as described here, is unexpected.

Immune dysfunction over the course of life is thought to proceed along much the same lines as cancer risk, because of the role of the immune system in suppressing precancerous lesions. Risk of cancer doesn't start to meaningfully increase until the 50s and on. Still, it is also clear that the gut microbiome begins to change in the 30s as well, and there also the immune system is implicated, as immune cells are responsible for gardening the gut microbiome, destroying problematic microbes. We might speculate that these recent discoveries are setting the stage for the realization that early immune aging both exists and is a driver of the comparatively small changes in physiology that take place in the 20s and 30s.

Changes of senescent cell accumulation and removal in skin tissue with ageing

Senescent cells are known to secrete various inflammatory cytokines (known as the senescence-associated secretory phenotype factors: SASP factors) and adversely affect surrounding tissues. Senolytic drugs that selectively induce the death of senescent cells are under development. We reported that skin inherently possesses mechanisms to remove senescent cells. In the epidermis, this is achieved by the binding of JAG1, a Notch ligand expressed on adjacent non-senescent keratinocytes, to Notch1 receptors expressed by senescent keratinocytes, which promotes the exclusion of senescent cells from the basal layer by inducing differentiation. Meanwhile, in the dermis, senescent cells are phagocytosed by macrophages through recognition by the phosphatidyl serine (PS) receptor STAB1. However, since ageing is associated with the accumulation of senescent cells in skin tissue, it is hypothesized that this accumulation is preceded by a decline in the ability to remove them.

Here, we tested this hypothesis by analysing in detail the changes in the number of senescent cells and the ability of them to be removed from the skin with ageing. Marginal skin tissues at the time of surgery were collected from patients who had provided informed consent. Paraffin-embedded sections prepared from the unexposed skin tissue were subjected to immunostaining with the major senescent cell marker p16INK4A to analyse the number of senescent cells. To characterize the ability for senescent cells to be removed from the skin, the expression of JAG1 in the epidermal keratinocytes and STAB1 in macrophages was analysed. The results confirmed that senescent cell accumulation was increased with age in both epidermis and dermis. We also found that the ability to remove senescent cells decreased with age.

In addition, it was observed that while the accumulation of senescent cells was detected after 30s, the removal capacity began to decrease at 20s. Although there was a delay of the age at which senescent cell accumulation starts after the onset of declining of senescent cell removal ability, there appears to be a correlation across all ages between the removal ability and the accumulation of senescent cells. The reason of the decline in the senescent cell removal function in the 20s, before senescent cells accumulate, is still a mystery. We believe that environmental factors such UV radiation, reactive oxygen species, and exposure to SASP factors released by transiently senescent cells in young age may have an impact on the function of senescent cell removal. Future plans for this research include a closer look at these factors and the techniques for enhancing the efficiency of senescent cell removal.

Maintaining physical fitness remains one of the most proven approaches to modestly slow the progression of aging. The large study noted here provides an example of the long-term benefits of exercise. The scientists observe a reduction in Parkinson's disease incidence in more active individuals. This is a pattern observed in near all age-related conditions, a good argument for putting in the time and effort needed to remain physically fit and active as one moves into later life.

The study included 95,354 female participants, mostly teachers, with an average age of 49 who did not have Parkinson's disease at the start of the study. Researchers followed participants for three decades during which 1,074 participants developed Parkinson's disease. Over the course of the study, participants completed up to six questionnaires about types and amounts of physical activity. Researchers assigned each activity a score based on the metabolic equivalent of a task (METs), a way to quantify energy expenditure. For each activity, METs were multiplied by their frequency and duration to obtain a physical activity score of METs-hours per week. For example, a more intense form of exercise like cycling was six METs, while less intense forms of exercise such as walking and cleaning were three METs. The average physical activity level for participants was 45 METs-hours per week at the start of the study.

Participants were divided into four equal groups of just over 24,000 people each. At the start of the study, those in the highest group had an average physical activity score of 71 METs-hours per week. Those in the lowest group had an average score of 27 METs-hours per week. Among the participants in the highest exercise group, there were 246 cases of Parkinson's disease or 0.55 cases per 1,000 person-years compared to 286 cases or 0.73 per 1,000 person-years among participants in the lowest exercise group.

After adjusting for factors such as place of residence, age of first period and menopausal status, and smoking, researchers found those in the highest exercise group had a 25% lower rate of developing Parkinson's disease than those in the lowest exercise group when physical activity was assessed up to 10 years before diagnosis. The association remained when physical activity was assessed up to 15 or 20 years before diagnosis. Results were similar after adjusting for diet or medical conditions such as high blood pressure, diabetes, and cardiovascular disease. Researchers also found that 10 years before diagnosis, physical activity declined at a faster rate in those with Parkinson's disease than in those without, likely due to early symptoms of Parkinson's disease.

Link: https://www.aan.com/PressRoom/Home/PressRelease/5086

Researchers here observe that triglyceride depletion in very aged muscles produces benefits, looking much like a form of calorie restriction that improves cell metabolism. This work was carried out in killifish, a highly regenerative species, so it remains to be seen as to whether a similar process operates in mammals, or whether it is in any way interesting or novel as a basis for therapy. Finding modest benefits in very late life is a poor alternative to focusing instead on methods of rejuvenation.

Sarcopenia, the age-related decline in muscle function, places a considerable burden on health-care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish - an extremely short-lived vertebrate - revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an "early-life" state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span.

In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life-like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long-lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.

Link: https://doi.org/10.1111/acel.13862

A person who sleeps six hours rather than eight hours every day, give or take, is effectively gaining a bonus 12.5% additional time spent alive and active. From that perspective, there isn't all that much difference between being able to sleep two hours less every night throughout life, without consequences, and being able to live for the better part of an additional decade in good health. There are mutations that produce this effect in humans, other mammals, and lower animals such as flies, and at least one of them does so without any apparent negative side-effects.

Today's open access paper offers an exploration of one of these mutations, a small alteration in DEC2, which not only reduces the need for sleep, thereby granting additional subjective life span, but is also found to extend actual life span in flies. The size of the effect is larger than many of the calorie restriction mimetic compounds explored in recent years. Interestingly, the authors here argue that reduced need for sleep is more a reflection of increased robustness and health resulting from this mutation than any independent, top-down alteration of the regulation of sleep.

A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila

One of the most well-studied examples of natural short sleepers in the human population are individuals with rare genetic mutations in the dec2 gene. Dec2 is a transcriptional repressor that, in mammals, is recruited to the prepro-orexin promoter and represses the expression of orexin, a neuropeptide that promotes wakefulness. A single point mutation in dec2 (dec2P384R) inhibits the ability of Dec2 to bind the prepro-orexin promoter, resulting in increased orexin expression. Consequently, wakefulness increases, and individuals sleep on average 6hrs/day instead of 8hrs/day.

Intriguingly, these natural short sleepers do not appear to exhibit any phenotypes typically associated with chronic sleep deprivation, and expression of the dec2P384R mutation in mice suppresses neurodegeneration. Thus, it has been suggested that individuals harboring the dec2P384R mutation may employ compensatory mechanisms that allow them to thrive with chronic sleep loss. However, whether the dec2P384R mutation directly confers global health benefits has not yet been tested experimentally in any system.

In this study, we used a Drosophila model to understand the role of the dec2P384R mutation on animal health and elucidate the mechanisms driving these physiological changes. We found that the expression of the mammalian dec2P384R transgene in fly sleep neurons was sufficient to mimic the short sleep phenotype observed in mammals. Remarkably, dec2P384Rmutants lived significantly longer with improved health despite sleeping less. In particular, dec2P384R mutants were more stress resistant and displayed improved mitochondrial fitness in flight muscles. Differential gene expression analyses further revealed several altered transcriptional pathways related to stress response, including detoxification and xenobiotic stress pathways, that we demonstrate collectively contribute to the increased lifespan and improved health of dec2P384R mutants.

Finally, we provide evidence that the short sleep phenotype observed in dec2P384R mutants may be a result of their improved health rather than altered core sleep programs. Taken together, our results highlight the dec2P384R mutation as a novel pro-longevity factor and suggest a link between pro-health pathways and reduced sleep pressure.

The primary challenge in understanding how calorie restriction slows aging and extends life is that it changes near everything in the operation of cellular metabolism. Finding the important differences is a matter of searching for the needle in the haystack. The most compelling evidence to date points to increased autophagy as the important determinant, greater effort made by cells to repair damage, maintain function, and recycle components. It remains likely that other mechanisms are also important, however. Here, researchers focus on regulation of the innate immune system in response to a reduced calorie intake; they are working with nematodes, but many of the noteworthy aspects of calorie restriction are much the same across all species.

Dietary restriction (DR) is a practically effective and reproducible nutritional intervention that extends lifespan in many organisms. Many studies have shown that DR improves immune function, and immune signaling components are required for DR-induced lifespan extension. These results support the idea that the immune system acts as an important mechanism for DR-induced longevity. Recently, analysis of genes that regulate aging or immune response in animal models, including C. elegans, Drosophila, mice, and even humans, has revealed that aging and immunity are controlled by the same signaling pathways, such as TOR/S6K signaling pathway, pleiotropically. DR-induced longevity is also associated with the modulation of the TOR/S6K signaling pathway. Thus, these results suggest that the immune function may be closely associated with aging regulation through DR.

In this study, we found that the F-box gene fbxc-58 is a downstream effector of the S6K signaling pathway, and that it regulates both pathogen resistance and aging in C. elegans. Furthermore, fbxc-58 is necessary for the effects of DR on lifespan extension. F-box protein acts as a modular E3 ubiquitin ligase adaptor protein, and the ubiquitin-dependent mechanisms have been shown to determine lifespan in response to DR or modulate the innate immune response. Therefore, we suggest that gaining insights into the detailed mechanistic aspects of fbxc-58 signaling pathway could elucidate the conserved signaling mechanism that links innate immunity and DR-induced healthy aging in animals.

Further, DR prevents or reduces the burden of age-related diseases or disabilities. Especially, in an aging and sedentary society, sarcopenia, an age-associated muscle disease, is beginning to be recognized as an acute disease condition. Although an effective sarcopenia treatment regime has not yet been identified, nutritional intervention is considered an effective method of preventing sarcopenia. In this study, we found that DR prevents muscle aging via fbxc-58 in C. elegans. fbxc-58 is essential for DR-mediated alleviation of the age-associated decline in muscle activity and protection of mitochondrial network in body wall muscle. Thus, we propose that investigating the molecular mechanism of action of F-box proteins, including fbxc-58, in DR will shed light on means to prevent sarcopenia and offer a potentially practical means of encouraging healthy aging via DR.

Link: https://doi.org/10.18632/aging.204477

Analysis of a large epidemiological database here shows that sufficient exercise correlates with a halving of the risk of mortality due to influenza. Like many other studies, it also shows that too much exercise may be harmful, actually increasing the risk of mortality. While correlation does not imply causation, there is plenty of evidence for physical fitness and physical activity to reduce impacts of aging related to immune function. Alternative explanations revolve around the tendency of more robust individuals to conduct more exercise, while also tending to be more resilient independently of the effects of exercise.

A nationally representative sample of US adults (aged ≥18 years) who participated in the National Health Interview Survey from 1998 to 2018 were followed for mortality through 2019. Participants were classified as meeting both physical activity guidelines if they reported ≥150 minutes/week of moderate-intensity equivalent aerobic physical activity and ≥2 episodes/week of muscle-strengthening activity. Participants were also classified into five volume-based categories of self-reported aerobic and muscle-strengthening activity.

Among 577,909 participants followed for a median of 9.23 years, 1,516 influenza and pneumonia deaths were recorded. Compared with participants meeting neither guideline, those meeting both guidelines had 48% lower adjusted risk of influenza and pneumonia mortality. Relative to no aerobic activity, 10-149, 150-300, 301-600 and greater than 600 minutes/week were associated with lower risk (by 21%, 41%, 50% and 41%). Relative to fewer than 2 episodes/week of muscle-strengthening activity, 2 episodes/week was associated with 47% lower risk.

At the opposite end, we found that ≥7 muscle-strengthening activity episodes/week was associated with an increased risk. A J-shaped dose-response between muscle-strengthening activity and all-cause mortality has been observed elsewhere. While beyond the scope of this study, plausible explanations range from inaccurate responses (such as reporting occupational physical activity, which may not confer the same protective effect as leisure-time physical activity) to haemodynamic ramifications of frequent, high-intensity activity.

Link: https://doi.org/10.1136/bjsports-2022-106644

It is arguably the case that we should look at small molecule mTOR inhibitors, such as rapamycin and its descendant rapalog compounds, as the most effective of the calorie restriction mimetic approaches developed to date. The practice of calorie restriction, eating as much as 40% fewer calories while still obtaining optimal levels of micronutrients, produces sweeping changes to metabolism. Some of these, such as increased autophagy and other forms of cellular housekeeping, appear to be beneficial to long-term health. Keeping cells more free of damage leads to a slowing of aging.

In mice, that slowing of aging can lead to as much as a 40% extension of life span via calorie restriction. Rapamycin, on the other hand, managed a 5% to 10% extension of life span in the very rigorous Interventions Testing Program studies. This illustrates one of the issues with calorie restriction mimetic treatments, which is that they only capture a fraction of the beneficial metabolic change produced by calorie restriction, and are therefore considerably less effective.

The other issue is that the practice of calorie restriction certainly doesn't produce a 40% extension of life span in humans; that would be quite evident, and have been well known since antiquity. Long-lived mammals exhibit very similar short-term metabolic changes and improved measures of health in comparison to short-lived mammals when undergoing calorie restriction, but long-term effects on life span are much more muted.

It seems plausible that many of the metabolic changes caused by calorie restriction in short-lived species became permanent in the course of evolving longer life spans. Thus humans, one of the more long-lived mammals, likely gain only a few years from the practice of calorie restriction. This might lead one to the reasonable conclusion that calorie restriction mimetics are not the way forward to greatly improve late life health in humans. Nonetheless, there is considerable appetite and funding for this line of research and development.

Targeting the biology of aging with mTOR inhibitors

mTOR is an evolutionarily conserved serine-threonine protein kinase found in diverse species including mice and humans. The mTOR kinase forms the catalytic core of two distinct protein complexes, mTORC1 and mTORC2, each of which are composed of shared as well as unique protein subunits and phosphorylate different substrates. mTORC1 is regulated by a wide range of nutrients and hormonal cues, most notably by the availability of amino acids, but also glucose, oxygen, and cholesterol. mTORC1 activity drives a wide variety of anabolic processes, as well autophagy, through phosphorylation of substrates.

Beginning 20 years ago, researchers discovered a role for mTORC1 signaling in the aging process. Studies in yeast, worms, and flies found that genetic inhibition of mTORC1 or signaling pathways downstream of mTORC1 extends lifespan. These results quite logically spurred substantial interest in the possibility that a potent chemical inhibitor of mTORC1, rapamycin, could extend lifespan. This was indeed the case, and there are now numerous studies showing that rapamycin can extend the lifespan not only of model organisms including yeast, worms, and flies but also of both wild-type mice and in many disease models. In this review, we will discuss the results of these studies, as well as the possible mechanism by which reduced mTORC1 signaling via both dietary and pharmacological means may improve healthspan.

There is rapidly growing interest in using mTOR inhibitors to promote healthy aging and to treat, delay or reverse numerous age-related diseases. While there is incredibly strong preclinical evidence in mice that rapamycin can extend lifespan and healthspan, excitement about rapamycin has outpaced rigorous evidence that rapalogs are both safe and efficacious for diseases of aging in humans. There are many unanswered questions from the trials that have been conducted thus far, but a few general lessons can be taken from the clinical trials of mTOR inhibitors that have been performed thus far. In both humans and mice, treatment with low or intermittent doses of rapamycin or everolimus or treatment of mice with the mTORC1-selective inhibitor DL001, is much better tolerated than the high doses of mTOR inhibitors currently approved for organ transplant and oncology indications, with fewer metabolic side effects and less immunosuppression. In addition, low doses of mTOR inhibitors have been shown to have some beneficial effects on the function of aging human organ systems, in particular, the immune system.

There remains much work ahead to bring mTOR inhibitors into the clinic for age-related conditions and many open questions remain. While the safety profile of low-dose rapamycin and rapalogs in humans appears promising, the long-term safety and efficacy of low-dose regimens remain to be determined. A much better understanding is needed of the specific dose and duration of mTOR inhibitors that both maximize efficacy and minimize risk. In humans, higher doses (for example, 3 mg per day) of mTOR inhibitors such as everolimus inhibit T cell function and are therefore are used to suppress immune-mediated organ transplant rejection in patients. By contrast, a sixfold lower dose of everolimus for 6 weeks was associated with improved immune function as assessed by vaccination response. Thus, both dose and duration may contribute to whether mTOR inhibition has positive or negative effects on healthy aging, but, generally speaking, the lower the dose of a drug, the fewer expected side effects.

Over the next 5 years, we expect results from a rapidly expanding list of human clinical trials as well as work in canines and non-human primates to shed light on the viability of mTOR inhibition as a therapy for aging-related conditions. New mTORC1-specific molecules may help to widen the therapeutic window for rapalogs, limiting undesirable side effects resulting in whole or in part from inhibition of mTORC2. Collectively, we expect that researchers will soon be able to determine whether clinicians can safely and effectively bring mTOR inhibitors to the geriatric bedside.

Bone mineral density decreases with age, a growing imbalance between the activity of osteoblasts (depositing bone) and osteoclasts (breaking down bone). This leads eventually to meaningful risk of fracture and osteoporosis. Suffering bone injury due to bone weakness in later life is a spiral downwards into debilitating incapacity, and comes with a significantly raised risk of mortality. Here, researchers run the numbers to present the increased mortality risk following fracture as an adjustment to skeletal age, in the hope of increasing the use of existing therapies for osteoporosis.

Osteoporosis is a 'silent disease' which often has no immediate symptoms but gradually weakens bones and makes them more likely to break. A bone fracture caused by osteoporosis in people over the age of 50 is linked to long-term health decline and in some cases, even early death. However, poor communication of the mortality risk to patients has led to a low uptake of treatment, resulting in a crisis of osteoporosis management. The impact of a fracture on life expectancy is typically conveyed to patients and the public in terms of probability (how likely something is to occur) or the relative risk of death compared to other groups. However, statements such as "Your risk of death over the next 10 years is 5% if you have suffered from a bone fracture" can be difficult to comprehend and can lead to patients underestimating the gravity of the risk.

With the aim of devising a new way of conveying risks to patients, researchers analyzed the relationship between fracture and lifespan in over 1.6 million individuals who were 50 years of age or older. The findings showed that one fracture was associated with losing up to 7 years of life, depending on gender, age and fracture site. Based on this finding, researchers proposed the idea of 'skeletal age' as a new metric for quantifying the impact of a fracture on life expectancy. Skeletal age is the sum of the chronological age of a patient and the estimated number of years of life lost following a fracture. For example, a 60-year-old man with a hip fracture is predicted to lose an estimated 6 years of life, resulting in a skeletal age of around 66. Therefore, this individual has the same life expectancy as a 66-year-old person that has not experienced a fracture.

Skeletal age can also be used to quantify the benefit of osteoporosis treatments. Some approved treatments substantially reduce the likelihood of post-fracture death and translating this into skeletal age could help communicate this to patients. For instance, telling patients that "This treatment will reduce your skeletal age by 2 years" is easier to understand than "This treatment will reduce your risk of death by 25%".

Link: https://doi.org/10.7554/eLife.83888