Fight Aging!

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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.