Fight Aging!

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Contents

• Arguing for an Expansion of the Hallmarks of Aging
• Germline Stem Cells in Ovaries and Female Reproductive Aging
• Much Yet to Establish Regarding the Role of Regulatory T Cells in Immune System Aging
• The Hevolution Foundation Plans to Fund Aging Research and the Longevity Industry
• The Benefits of Exercise as the Results of Hormesis
• More Evidence Against Herpesvirus Infection as a Meaningful Contribution to Alzheimer's Disease
• Fat Tissue Changes With Age to Become Less Functional and More Harmful
• Inflammatory Proteins in Extracellular Vesicles Correlate with Mortality
• Using the Peripheral Nervous System as a Source of Cells for Central Nervous System Regeneration
• Profiling the Work of VitaDAO in Funding Aging Research and Development
• Bacteriophages as a Class of Vector for Future Targeted Senolytics
• Lesser Physical Function in Old Age Correlates with a Greater Cardiovascular Disease Risk
• A Discussion of Present Drug Development to Target Senescent Cells
• Targeting Senescent Cells to Better Address Cancer and Consequences of Cancer Therapy
• Calorie Restriction Suppresses Generation of Immune Cells via Changes to the Gut Microbiome

Arguing for an Expansion of the Hallmarks of Aging
https://www.fightaging.org/archives/2022/09/arguing-for-an-expansion-of-the-hallmarks-of-aging/

The hallmarks of aging form a catalog of largely better studied changes in cells and tissues considered relevant, and possibly more important, in the onset and development of age-related degeneration and disease. This is not the same thing as a list of causes of aging. A few of the hallmarks mostly likely are or include deeper causes of aging, or close to causes of aging. The hallmarks do overlap with the SENS description of aging as a set of root causes, forms of molecular damage that result from the normal operation of a youthful metabolism. Since the hallmarks of aging are not, and are not intended to be a list of causes of aging, it is always possible to argue for an expansion, particularly since the hallmarks as they stand omit a number of line items that are not as well studied, but still probably important. Equally, once started on an expansion of the hallmarks, where does one stop?

We might ask ourselves: what use is a taxonomy of aging? To my eyes, the best thing that a taxonomy can achieve is to focus research and development efforts in directions that are more likely to produce meaningful gains in health and longevity. It isn't clear that the hallmarks of aging will achieve that goal, given that the primary issue in the treatment of aging lies in identifying mechanisms that are more rather than less likely to produce large effect sizes when used as a basis for anti-aging therapies. Picking a prevalent aspect of aging is no guarantee of success in this regard. Many quite prominent aspects of aging are far removed from the causes of aging (in the SENS view, at least), and treating them will most likely have little effect on overall health because the underlying causes will continue forward untouched, producing many other problems.

The SENS advocates had the right idea, "let's just talk about root causes", which produces a limited list. Whereas if less constrained, to "important things about aging that we're looking into", then there is potentially no end to the list, and no guidance as to whether any given hallmark is a good target for intervention. Certainly the hallmarks of aging look more relevant to the field today as the 14 items suggested in the open access conference report below, rather than the original 9 items, but then a decade from now they will look more relevant as 26 items, well on their way to becoming a poor guide to strategy in the treatment of aging as a medical condition.

New hallmarks of ageing: A 2022 Copenhagen ageing meeting summary

The definition of nine cellular and molecular hallmarks of ageing in 2013 provided a contextual framework to guide future ageing research. These hallmarks comprise: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Recently, these hallmarks have been criticized for being insufficient in serving as a causative paradigm of ageing. Importantly though, they have recently been shown to map to age-related diseases. To address this and to explore potential new hallmarks, a research symposium "New Hallmarks of Ageing" was held in Copenhagen (Denmark) on the 22nd of March 2022, focusing on novel findings and the recontextualization of the nine hallmarks of ageing. This included the discussion of new advances and the future of the field of ageing research.

The panel stressed the importance of progress in the field, as ageing is the primary risk factor of many major human diseases. It was highlighted that increasing average lifespan over the last decades is one of the most remarkable human accomplishments, but that this success has led to a different, challenging problem, namely the ever-increasing number of chronically ill patients suffering from age-related diseases, and the resulting toll on individuals and society. Understanding the mechanisms of the ageing process will therefore be pivotal to treat the root cause of multiple age-related diseases. The panellists emphasised that only taking a limited number of defined hallmarks into account might also halt progress on processes relevant to ageing but not currently defined as hallmarks. The panellists thereby discussed the inclusion of new hallmarks to the current list.

1) Compromised autophagy is observed in numerous ageing conditions including neurodegeneration and immunosenescence. Importantly activation of autophagy can increase mouse lifespan, and even improve immune response to vaccination in older humans by overcoming immunosenescence. While originally considered under hallmark 'altered proteostasis', autophagy regulates a number of other hallmarks of ageing such as DNA repair and nutrient sensing/metabolism, and hence it was proposed to be categorised as an integrative hallmark.

2) Dysregulation of RNA processing has been noted in human ageing population studies while interventions that appear to reverse senescent phenotypes act at least in part by restoring youthful patterns of splicing factor expression. Similarly, alternative polyadenylation of mRNAs, already known to contribute to cancer, is altered with ageing and may contribute to senescence. Such changes in RNA processing add an additional layer of gene expression control over those of genome integrity, transcriptional efficacy and epigenetic regulation that are already known to change during biological ageing.

3) Microbiome disturbances: recent advances in next generation sequencing technologies have allowed the identification of notable changes in the gut microbiome with age, pointing in particular to shifts in microbial populations and loss of species diversity. Together with age-associated loss of structural integrity of the gut and other barriers (e.g. blood brain barrier), this shift in microbial populations can drive inflammation.

4) Altered mechanical properties applies both to cells and to the extracellular milieu. For example, fibroblast senescence is accompanied by a major change from a mobilizable pool of actin that can be readily polymerised and depolymerised during cell motility, to stable stress fibres of f-actin anchored through focal adhesions to the substrate, which is particularly marked in cells from patients with premature ageing syndromes and which is likely to impact on cell motility and cell-cell communication. The nucleoskeleton is also altered during ageing, with the nuclear lamina becoming destabilised, with concomitant extrusion of chromatin into the cytoplasm which trigger the SASP in senescence. Finally, extracellular matrix also changes with ageing, which greatly alters cell behaviour. Increased rigidity and loss of elasticity, for example arising through glycation cross-links between collagen molecules, can lead to multiple age-related disease states such as hypertension with concomitant kidney and neurological defects - such cross-linking may contribute to the accelerated ageing seen in patients with diabetes. The field of mechanobiology and its intersection with ageing is thus very promising in terms of 'rejuvenation'.

5) Inflammation: Inflammageing, age-dependent chronic inflammation, is implicated in a wide range of age-related diseases. Ageing correlates with high, levels of inflammatory mediators in the blood, such as IL-1, IL-6, C-reactive protein, IFNα, and several others. Originally inflammation was considered part of the hallmark 'altered intercellular communication', however it could be considered on its own merit, due to its large contribution to the ageing process and its cross-play with other hallmarks such as cellular senescence and the newly proposed gut microbiota.

Germline Stem Cells in Ovaries and Female Reproductive Aging
https://www.fightaging.org/archives/2022/09/germline-stem-cells-in-ovaries-and-female-reproductive-aging/

In today's open access paper, researchers discuss the evidence for the existence of germline stem cells in the ovaries, responsible for maintaining fertility in the usual manner of stem cells, by generating daughter cells that replace losses and ensure function. Is ovarian aging, leading into age-related infertility, much accelerated over the aging of other organs in our species because this stem cell population loses function more rapidly than those in other tissues? That is a reasonable hypothesis, and some of the possible mechanisms are discussed. That ovaries are a hypoxic environment to begin with, and that supply of oxygen and nutrients does tend to decline with age for a range of reasons, is one of the more intriguing ideas.

A number of groups, including a few biotech startups in the growing longevity industry, appear to believe that ovarian aging is a good place to start on the development of the next generation of regenerative medicine, deploying more sophisticated approaches to either replace stem cell populations or rejuvenate existing populations and their damaged niches. In part this is because such therapies would be targeted to people who are not very old, are more robust and resilient. In part it is because the understanding of ovarian tissue and cell function has reached a tipping point: we are past the point at which researchers have constructed artificial ovaries and demonstrated that they are functional following transplantation into mice, for example. Techniques that succeed in restoring ovarian function could generalize to other stem cell populations. This may or may not come to pass, depending on how much of a special case ovarian aging turns out to be, but we can hope.

Female germline stem cells: aging and anti-aging

The underlying mechanisms for the aging of the ovary are still poorly understood, partially because it is a complex biological process in which many factors interact internally and externally. Compared with the "evergreen" male testes, female ovaries in advanced age women are more like "rotten root of old tree". What makes this big difference? The researchers believe that the female germline stem cells (FGSCs) aging directly determines the ovarian aging. In physiological conditions, when women reach their advanced age, the stem cells in their ovaries are exhausted, they face menopause and symptoms of hypoestrogenism, while males enjoy their old age life without dramatic decline of their testes function. They still have the ability to father as long as their spouses are young enough.

Whether mammal's ovaries have FGSCs to supplement the original follicle pool after birth has been debated for nearly one century. Now, however, scientists have isolated cells that could be subcultured in vitro and express the both stem and germ cell-specific protein markers in mice, adult mice, rats, and human ovarian tissue cortex respectively. Using a variety of methods, including stem cell culture and expansion, stem cell transplantation, genetic modification and gene editing, in vivo cell lineage tracking, the researchers confirmed existence of FGSCs in the postnatal ovaries in a variety of mammals, including humans, even old women ovarian surface epithelium, and observed that FGSCs had the ability to direct differentiation into eggs, continuously replenish follicle pools, and restore progeny to infertile model. FGSCs with GFP were transplanted into infertile mice, and both mature follicles with GFP and offspring with GFP were is covered obtained, which provided the most direct evidence of FGSCs existence.

Accumulating evidence suggest the FGSCs niche is the key link to ovarian failure. The FGSCs niche might be more important than aging of FGSCs themselves. The niche of ovaries in mammals maybe includes follicular membrane-stromal cells, granulosa cells, extracellular matrix, blood vessels, immune system-related cells and cytokines. Transplanting niche cells (mainly refer to Sertoli or mesenchymal cells) can regenerate the non-functional gonads, and this approach has resulted in the birth of fertile offspring in mice. The stem cell niche, combined with exogenous microenvironment alterations, such as changes from oxygen tension, temperature, hormones or cytokines from blood supplement, results in restricted self-renewal, senescence, skewed differentiation and compromised regeneration.

In the exogenous microenvironment, special focus has to be placed on the role of hypoxia in inducing and accelerating stem cell aging. Hypoxia, the unbalance between oxygen supply and demand, is the primary culprit of oxidative stress and chronic inflammation. Unfortunately, ovary is a deeply hypoxic organ due to it's unique structure and cell composition. On the one hand, with the growth and progression of follicular oocytes and the proliferation and division of granulosa cells, the oxygen demand gradually increases. On the other hand, continuous ovulation results in the increase of fibrous connective tissue and the significant reduction of blood vessels in the ovary, which leads to the decrease of oxygen supply in the ovary, and the decrease of blood vessels and blood supply in the ovary with the increase of age. In addition, chronic, low-grade inflammatory response caused by repeated ovulation and the accompanying oxidative stress aggravate the imbalance between supply and demand, resulting in low oxygen concentration in the ovary. This may be the important reason that the speed of ovarian aging should be faster than other organs.

In summary, exploring the mechanism of FGSCs aging is helpful in solving female infertility fundamentally in clinical practice. Rebuilding niches of FGSCs, regulation of immune dysfunction, anti-inflammation, and oxidative stress remission are expected to restore or replenish FGSCs, ultimately to delay ovarian aging.

Much Yet to Establish Regarding the Role of Regulatory T Cells in Immune System Aging
https://www.fightaging.org/archives/2022/09/much-yet-to-establish-regarding-the-role-of-regulatory-t-cells-in-immune-system-aging/

Regulatory T cells, as the name might suggest, are involved in controlling the immune response, particularly damping it down at the point at which it should resolve. They also prevent an inflammatory response from starting when it would be harmful or unnecessary, such as in response to self-antigens. A failure of regulatory T cell function is likely involved in autoimmunity, as well as in the chronic inflammation of aging.

As today's open access paper notes, regulatory T cells may be both harmful and helpful in older individuals, attempting to suppress inappropriate inflammation, but also becoming dysfunctional in ways that both suppress appropriate immune responses to infection and allow autoimmune conditions to arise by failing to suppress the response to self-antigens. Yet all too little of this is certain in the details, and published studies provide a wealth of entirely contradictory evidence. The paper notes studies that report, variously, that immune suppression by regulatory T cells is increased, decreased, or unchanged with age under various circumstances.

How does a class of immune cells responsible for suppressing inflammatory signaling and behavior manage to both over-suppress where inappropriate and under-suppress where inappropriate? Therein lies the question. The immune system is complicated, and no class of T cells is a single monolithic entity. Regulatory T cells have subtypes, while the effects of the surrounding environment on their behavior are just as complicated, situational, and distant from a full understanding as is the case for the rest of the immune system as a whole.

The dark side of Tregs during aging

From a holistic point of view, aging results from the progressive decline of various systems. Among them, the distinctive age-dependent changes in the immune system contribute to the enhanced frailty of the elderly. One of these affects a population of lymphocytes, known as regulatory T cells (Tregs), as accumulating evidence suggest that there is a significant increase in the frequency of these cells in secondary lymphoid organs of aged animals. Although there are still discrepancies in the literature about modifications to their functional properties during aging, mounting evidence suggests a detrimental role for Tregs in the elderly in the context of bacterial and viral infections by suppressing immune responses against non-self-antigens. Interestingly, Tregs seem to also contribute to the reduced effectiveness of immunizations against many pathogens by limiting the production of vaccine-induced protective antibodies

With regard to Treg immunosuppressive activity, there is still an open debate regarding whether these cells have increased or decreased functionality during aging, with evidence for both outcomes. However, there is also evidence from other studies that the suppressive activity of Tregs is not contingent on age, but instead is retained at nearly the same level throughout the lifespan. These studies showed that Tregs from young and aged mice as well as in humans have the same suppressive capacity since they can suppress CD4+ T cell proliferation to the same extent. On the other hand, Tregs from old mice have also been described as being better suppressors than those from young adult animals due to higher IL-10 production.

The most likely reason behind these inconsistencies and conflicting data is that CD25 does not accurately recapitulate Foxp3 expression and Treg activity in aged mice, so it may act as a confounding factor in the interpretation of suppression assays. Another major caveat regarding the use and interpretation of in vitro suppression assays is that they may not be truly representative of in vivo Treg-mediated suppression mechanisms. Results obtained through the use of anti-CD25 antibodies do not allow researchers to discriminate between the suppressive activity of CD4+ and CD8+ Tregs, which have also been reported to increase with age. Results can also be deeply influenced by the responder cells, which may change depending on the cell's age and type, as well as the stimuli they receive, independently of Treg functions. Moreover, the in vivo model used might affect Treg suppression, phenotype, and homing, depending on the unique local inflammatory environment.

Taken together, these conflicting data do not completely explain the simultaneously increased risk of autoimmunity, cancer, and infections observed in the elderly. Therefore, how the intrinsic functions of Tregs change during aging and what the impact of those changes may be remain questions yet to be elucidated.

The Hevolution Foundation Plans to Fund Aging Research and the Longevity Industry
https://www.fightaging.org/archives/2022/09/the-hevolution-foundation-plans-to-fund-aging-research-and-the-longevity-industry/

Funding for aging research and the development of therapies to treat aging as a medical condition used to be hard to come by. It was a fringe field of medicine. But slow years of bootstrapping incremental progress - hard work, patient advocacy, and philanthropy - eventually led to technology demonstrations, such as the rejuvenation of mice with senolytic therapies, that convinced the first large sources of funding to enter the field. That produced further progress, and the start of a longevity industry, enough to convince deeper pockets to participate. That in turn made slowing and reversing aging a viable investment for a growing number of sizable sources of wealth.

History teaches to be cautious about newly announced large investments in the field of aging and longevity, however. Calico launched with much fanfare, hundreds of millions of Google's funds devoted to aging research, but a decade on it seems clear that little will result from this initiative. We might look at Altos Labs, recently launched with 3 billion in funding, as a newer Calico, but with the narrow goal of achieving human rejuvenation via cell reprogramming technologies. Will a narrow focus allow success where a broad focus leads to an organization losing its way? Only time will tell.

So to today's topic, the Hevolution Foundation, which has broadly announced intentions to funnel very large amounts of Saudia Arabian sovereign wealth into aging research and the longevity industry. The organization has started slowly, but we can ask the same sorts of questions as of other large intiatives: will meaningful projects be funded? Much of the longevity industry, and much of aging research, is focused on goals that cannot and will not make much of a difference to the healthy human life span, such as the prevalent calorie restriction mimetics, supplements, and approaches to cellular stress response upregulation. Many of the large investment funds have devoted much of their funding to date to aging-branded efforts that are really just business as usual in medicine and biotech, nothing that offers the possibility to significantly change the shape of a human life.

The most important battle today, with regard to human aging, is over steering funding to projects that are more likely rather than less likely to result in significant rejuvenation. Senolytics, not calorie restriction. Partial reprogramming, not more supplements. And so forth. Until the broad scope of aging research and the longevity industry is significantly focused on rejuvenation, it is hard to be more than cautiously optimistic about any new large-scale venture, no matter how good their rhetoric sounds at the outset.

Hevolution CEO on how to spend 1 billion a year on longevity

"First of all, we are very much about extending healthy life, not just lifespan. I think if you ask anybody, with rare exception, they don't want to live longer for the sake of living longer. 'For the benefit of all' means not only being all-inclusive, but how do you democratise these technologies and discoveries? If we can't scale and democratise discoveries, and how to maximise the impact, then we should question ourselves: why are we doing this? Number one, we need to provide and support the development of the scientific field," says Hevolution's CEO Dr Mehmood Khan, who bemoans the huge gap in funding from governments around the world that goes into aging research compared to diseases like cancer, Alzheimer's, and heart disease (most of which are the consequences of aging). There's a log scale, if not two log scales, difference between the funding that goes into understanding how to keep people healthy on a biological level, versus treating the consequences of it. And that gap needs to be filled."

Another challenge that Khan sees is that most of the funding that is currently available for aging research is very much siloed, both within countries but also within disciplines. "One institute will fund the biology, and another will fund clinical research - it is not integrated together, for a whole variety of reasons. And that all needs to change. The irony is that the largest part of the healthcare budget for all developed countries is age-related diseases. So, we're already paying for the consequences of this ... and it's only getting bigger because our populations are aging."

When setting up Hevolution, Khan strongly felt that, to achieve all of this with the right incentives, the organisation had to be a non-profit. "If we were mandated as a for-profit organisation, then it's going to all be about return on investment back to our investors, and funders, which changes the types of decisions you'll make. To avoid this, you have to create a non-profit organisation, where the mission implementation is about funding science, which has no strings attached. We're not looking for an equity stake or anything like that - just fund the science, regardless of geographic location, for the benefit of all."

"Our vision is that we can invest up to a billion a year, but the question now is how do we get there? The rate-limiting step in this is not the ability to invest or provide scientific research funding, but how to do that responsibly, such that the field can absorb it. This field needs to grow, and part of that is creating a pipeline of good scientific ideas, a pipeline of talent, and then pull that through into where venture comes in and build companies and then grow those companies. Some are already along that spectrum, but the funnel is not large enough, the pipeline is not large enough. So we're starting by funding science but we'll also be announcing our first investments very soon." Khan says that Hevolution's research funding and venture capital investment approaches will run in parallel, although how much of that 1 billion budget is allocated to each is not yet determined.

The Benefits of Exercise as the Results of Hormesis
https://www.fightaging.org/archives/2022/09/the-benefits-of-exercise-as-the-results-of-hormesis/

Exercise modestly slows aging. In humans epidemiological data only allows for the establishment of correlation between physical activity and measures of aging and mortality. Animal data, however, shows that regular exercise modestly slows aging to an extent that improves long-term health, increasing healthspan without extending maximum life span. It is not as impressive as the effects of calorie restriction on life span, but the effects on health along the way are not all that dissimilar in nature.

In today's open access paper, the authors present a view of exercise and aging that is essentially hormetic in nature. They suggest that exercise slows aging because the short-term stresses generated by exercise overlap to some degree with the long-term stresses generated by the aging of tissues, and adaptation to the former grants greater resistance to the latter. This really need not be the case for exercise to slow aging, however. All that is needed is for the stresses of exercise to trigger generally beneficial responses. Or for exercise to correlate with reduced visceral fat burden, or reduced frailty, or reduced overall calorie intake.

Hormesis is used to describe situations in which mild stress and damage can produce a net gain in function by spurring a lasting increase in maintenance, repair, and defensive activities among the cells making up our tissues. Many forms of stress have this effect, such as reduced nutrient intake, exposure to toxins, heat, cold, and so forth. Exercise evidently stresses tissues via increased energy demands and pushes mitochondria to greater activity, generating oxidative stress as a side-effect, which cells must respond to with greater maintenance, but it also produces a range of other stress mechanisms, such as via inflammatory signaling.

Exercise as an Aging Mimetic: A New Perspective on the Mechanisms Behind Exercise as Preventive Medicine Against Age-Related Chronic Disease

Preventive lifestyle strategies such as exercise have emerged as potent, cost-effective means of reducing chronic disease risk. Exercise has a critical role in disease prevention and has been proposed as a form of "medicine". The protective effects of exercise on chronic disease risk are ultimately accumulated over time through physiological adaptations to the stress of exercise. Acute exercise causes widespread physiological disruptions that require a complex, integrated response from the major physiological systems (autonomic, cardiovascular, metabolic, musculoskeletal, etc.) to meet the substantial requirements of human locomotion. Repeated exposure to the physiological disruptions incurred by acute exercise (through exercise training) stimulate physiological adaptations that act to attenuate stress during subsequent exercise bouts. These exercise adaptations provide the foundation through which individuals can adapt and improve their ability to perform physical work (e.g., increase muscular power, endurance, aerobic capacity, etc.) and also prevent development of age-related chronic disease.

Thus, physiologic adaptations to exercise are the latent mechanisms through which exercise acts as medicine and reduces chronic disease risk. Despite seminal work that has identified several key mechanisms underlying the protective effects of exercise, there has yet to be an overarching hypothesis that explains broadly why or how it is that exercise protects against age-related chronic disease. We posit that exercise prevents age-related chronic disease because it acutely elicits physiological responses that mimic physiological changes seen with aging, the greatest contributing risk factor to all chronic disease. Thus, we propose the hypothesis that exercise is "medicine" that protects against age-related chronic diseases because exercise can effectively simulate "aging."

Acute exercise transiently disrupts cardiovascular, musculoskeletal, and brain function and triggers a substantial inflammatory response in a manner that mimics aging/age-related chronic disease. Data indicate that select acute exercise responses may be similar in magnitude to changes seen with an added 10-50 years of aging. The initial insult of the age-mimicking effects of exercise induces beneficial adaptations that serve to attenuate disruption to successive "aging" stimuli (i.e., exercise). Ultimately, these exercise-induced adaptations reduce the subsequent physiological stress incurred from aging and protect against age-related chronic disease. To further examine this hypothesis, future work should more intricately describe the physiological signature of different types/intensities of acute exercise in order to better predict the subsequent adaptation and chronic disease prevention with exercise training in healthy and at-risk populations.

More Evidence Against Herpesvirus Infection as a Meaningful Contribution to Alzheimer's Disease
https://www.fightaging.org/archives/2022/09/more-evidence-against-herpesvirus-infection-as-a-meaningful-contribution-to-alzheimers-disease/

There is a continuing debate over the role of persistent viral infection in the development of neurodegenerative disease. It seems plausible that such infection could increase chronic inflammation, and inflammation in brain tissue is a hallmark of neurodegenerative conditions. Just because the mechanism exists doesn't mean it is the primary, or even important, component of the disease process however. This is ever the challenge in complex age-related diseases, determining which of the many mechanisms in play are in fact those that primarily cause the condition. So there is a back and forth of epidemiological studies in recent years, attempting to settle the role of viral infection, particularly by herpesviruses, in neurodegenerative conditions such as Alzheimer's disease. At present neither side has a convincing advantage in weight of evidence, which suggests that there may be a more complex set of interactions going on under the hood.

The causes of Alzheimer's disease are not fully understood. There are clear associations with the accumulation of abnormal proteins in the brain, beta-amyloid and tau. There is also clear evidence of neuroinflammation, and there appears to be evidence of immune dysfunction in microglia, a type of immune cell found within the brain. One recurring theory is that herpes viruses, which are responsible for cold sores, genital herpes and other infections, might cause Alzheimer's disease.

However, researchers studying 1,009 participants in the Baltimore Longitudinal Study of Aging (BLSA) have found that while symptomatic herpes viruses were associated with neurological and cognitive symptoms, but there was no evidence to support the long-held theory that they are linked to Alzheimer's disease. The participants who were diagnosed with herpes had higher cognitive scores at the beginning of their participation but demonstrated greater longitudinal decreases in attention performance. The study did not find a link between herpes virus infection and the volume of total brain or gray matter, or in areas associated with Alzheimer's disease. Of the total participants, 119 had a record of symptomatic herpes infection. These infections were linked to longitudinal decreases in white matter volume, particularly in the temporal lobe. Being treated with antivirals slowed the declines in occipital white matter.

Fat Tissue Changes With Age to Become Less Functional and More Harmful
https://www.fightaging.org/archives/2022/09/fat-tissue-changes-with-age-to-become-less-functional-and-more-harmful/

People bearing more visceral fat are less healthy as a rule, due to its contribution to inflammation and burden of senescent cells, among other issues. Additionally, however, that fat tissue becomes more harmful with age, as there are changes in its function, as well as the function of other fat deposits in the body. The paper here looks at some of what is known of the functional decline in fat tissue with age.

Adipose tissue undergoes significant anatomical and functional changes with aging, leading to an increased risk of metabolic diseases. Age-related changes in adipose tissue include overall defective adipogenesis, dysfunctional adipokine secretion, inflammation, and impaired ability to produce heat by nonshivering thermogenesis. Thermogenesis in adipose tissue is accomplished by brown and beige adipocytes, which also play a role in regulating energy homeostasis. Brown adipocytes develop prenatally, are found in dedicated depots, and involute in early infancy in humans. In contrast, beige adipocytes arise postnatally in white adipose tissue and persist throughout life, despite being lost with aging.

In recent years, there have been significant advances in the understanding of age-related reduction in thermogenic adipocyte mass and function. Mechanisms underlying such changes are beginning to be delineated. They comprise diminished adipose precursor cell pool size and adipogenic potential, mitochondrial dysfunction, decreased sympathetic signaling, and altered paracrine and endocrine signals. This review presents current evidence from animal models and human studies for the mechanisms underlying thermogenic adipocyte loss and discusses potential strategies targeting brown and beige adipocytes to increase health span and longevity.

Inflammatory Proteins in Extracellular Vesicles Correlate with Mortality
https://www.fightaging.org/archives/2022/09/inflammatory-proteins-in-extracellular-vesicles-correlate-with-mortality/

Here, researchers demonstrate that inflammatory proteins found in extracellular vesicles, used by cells to communicate, are correlated with mortality risk. This is not a surprising result, as the signaling associated with chronic inflammation causes disruption of normal tissue function and cell behavior in many ways. It is an important contributing factor in the progression of age-related degeneration, and the risk of suffering many of the common age-related conditions is strongly correlated with the burden of chronic inflammation. Aiming to minimize age-related inflammation without disrupting immune function is a noteworthy goal for future research and development. Senolytic therapies to remove senescent cells and their pro-inflammatory signaling is a step forward, but other causes of age-related inflammation, such as the DNA debris released by stressed and dying cells, will be harder to deal with.

Even before the COVID-19 pandemic declines in life expectancy in the United States were attributed to increased mortality rates in midlife adults across racial and ethnic groups, indicating a need for markers to identify individuals at risk for early mortality. Extracellular vesicles (EVs) are small, lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids. Given their role as intercellular communicators and potential biomarkers of disease, we explored whether circulating EVs may be markers of mortality in a prospective, racially, and socioeconomically diverse middle-aged cohort.

We isolated plasma EVs from 76 individuals (mean age = 59.6 years) who died within a 5 year period and 76 surviving individuals matched by age, race, and poverty status. There were no significant differences in EV concentration, size, or EV-associated mitochondrial DNA levels associated with mortality. We found that several EV-associated inflammatory proteins including CCL23, CSF-1, CXCL9, GDNF, MCP-1, STAMBP, and 4E-BP1 were significantly associated with mortality. IL-10RB and CDCP1 were more likely to be present in plasma EVs from deceased individuals than in their alive counterparts. Our results suggest that plasma EV-associated inflammatory proteins are promising potential clinical biomarkers of mortality.

Using the Peripheral Nervous System as a Source of Cells for Central Nervous System Regeneration
https://www.fightaging.org/archives/2022/09/using-the-peripheral-nervous-system-as-a-source-of-cells-for-central-nervous-system-regeneration/

It is in principle possible to obtain cells from the peripheral nervous system that may, once cultured and expanded in number, and possibly altered in their behavior via the application of suitable signal molecules, produce regeneration in the brain or other portions of the central nervous system. The peripheral nervous system is more readily accessed than the central nervous system, and this is the big point in favor of searching the periphery of the body for cells that might be useful in areas of the more protected, less accessible inner body.

With a steadily aging population there is an increasing prevalence of neurological disorders. Given the lack of effective treatment strategies and a limited ability for the central nervous system (CNS) to regenerate endogenously, there is a critical need to better understand exogenous strategies for nervous system repair. Stem cell therapy offers a promising approach to promote the repair of neurologic tissue and function, however studies to date have been limited by various factors including challenges in harvesting donor cells from the CNS, ethical concerns regarding use of embryonic or fetal tissue, tumorigenic potential of induced pluripotent stem cells, and immune-mediated rejection of non-autologous cell sources.

Here we review and propose two alternative sources of autologous cells derived from the peripheral nervous system (PNS) for CNS repair: enteric neuronal stem cells (ENSCs) and neural crest-derived Schwann cells found in subcutaneous adipose tissue (termed SAT-NSCs). ENSCs can be successfully isolated from the postnatal enteric nervous system, propagated in vitro, and transplanted successfully into models of CNS injury via both direct intracerebral injection and systemic tail vein injection. Similarly, SAT-NSCs can be readily isolated from both human and mouse adipose tissue and, although not yet utilized in models of CNS injury, have successfully been transplanted and restored function in models of colonic aganglionosis and gastroparesis. These unique sources of PNS-derived autologous cells offer an exciting option for stem cell therapies for the CNS as they have proven neurogenic potential and eliminate concerns around tumorigenic risk, ethical considerations, and immune-mediated rejection.

Profiling the Work of VitaDAO in Funding Aging Research and Development
https://www.fightaging.org/archives/2022/09/profiling-the-work-of-vitadao-in-funding-aging-research-and-development/

A sizable part of the magic of blockchain technologies is the ability of the present ecosystem to materialize significant funding for near any effort that would have struggled to find backers via more traditional approaches. So much money flows through the exchanges and ongoing speculation that any new blockchain connected to that system quickly gains value almost regardless of its merit. That of course enables a lot of fraud. But at the same time, it enables worthwhile exercises such as VitaDAO, an organization that is using its blockchain-derived resources to fund meaningful research and development in the aging field, leading towards means to treating aging as a medical condition. As VitaDAO expands its activities, it is attracting more attention from the research community, always interested in novel means of funding fundamental science.

Like all researchers, Morten Scheibye-Knudsen is constantly looking for ways to fund his research, and he had been considering crowdfunding, when, out of the blue, he was contacted about a new platform under development for resourcing potential therapeutic programs using an online network of like-minded individuals - a so-called DAO, or decentralized autonomous community - who contribute their time or money to projects. In recent years, other DAOs have been emerging in life sciences. Scheibye-Knudsen's project searching for molecules that promote longevity seemed like an ideal program with which to test drive the new platform, which came to be called VitaDAO. Intrigued by this new means of funding, with its unusual community of stakeholders, Scheibye-Knudsen decided to apply. Several mostly academic programs have received funding from VitaDAO in the two years since he joined the group.

VitaDAO is housed on the Swiss web3-powered company Molecule, which in July received its first round of funding with a 12.6 million investment from a set of investors - some, including lead firm NorthPond Ventures, well known in the biotech space. Molecule was launched on a shoestring two years ago to catalyze the assembly of communities of life-science researchers, patients, and other stakeholders into DAOs, with the goal of democratizing and advancing translational research. Molecule's core innovation is a system for sharing intellectual property (IP) through non-fungible tokens (IP-NFTs), which simply turns IP into a digital asset, one with verifiable ownership by virtue of its being on Molecule's blockchain. The aim is to open up siloed research, at the same time enabling DAO members to play roles in advancing research that they care about.

A few weeks prior had marked the first anniversary of VitaDAO, which is Molecule's most advanced DAO. Last year, VitaDao raised more than 10 million through a token sale, 2 million of which, as of late July, has been allotted to funding various projects in geroscience, among them four that forged IP-NFTs. The idea is to provide infrastructure to market research in emerging areas that are underfunded by conventional avenues but show commercial promise - in VitaDAO's case, in geroscience. Should the DAO achieve commercial success with its projects, through a licensing event, partnership or co-development deal that further advances the asset, any financial gains will be plowed back into the platform to fund future generations of research.

Bacteriophages as a Class of Vector for Future Targeted Senolytics
https://www.fightaging.org/archives/2022/09/bacteriophages-as-a-class-of-vector-for-future-targeted-senolytics/

In this open access paper, the authors discuss the merits of bacteriophages to carry therapeutics to specific cell populations, offering targeting of senescent cells as a starting point. While they see bacteriophages as a way to displace existing viral vectors in the long run, clearly this will be a matter of decades from where things stand now, if it comes to pass. It is, nonetheless, an interesting look at a growing area of therapeutic development. Setting aside the question of senescent cells, a better general platform for carrying gene therapies to specific tissues, or throughout the body with high efficiency, is very much needed. Whether lipid nanoparticles, improvements to existing viral vectors, or some other technology such as engineered bacteriophages will satisfy that need at the end of the day is yet to be determined. Work proceeds on all fronts, at various stages of development.

Bacteriophages are viruses that are widespread in the environment because they occur wherever they find a suitable bacterial host to survive and multiply; thus, they are naturally present on and in the human body. Because of their selectivity to specific bacterial species, they are highly specialised in infecting bacteria and fighting bacterial infections. Interestingly, this selectivity is not accompanied by any harmful effects on human cells, which is probably the result of large interspecies differences. For this reason, various studies have used phages and their enzymes as alternatives to antibiotics to address dangerously increasing antibiotic resistance.

Several unique features of bacteriophages include the ability to integrate fragments of an exogenous nucleic acid into their genome and undergo easy chemical modification to display specific targeting and/or imaging ligands on the phage surface; because of such features, they may be used as new forms of modern high-performance vectors for therapeutic compounds and vaccine delivery. Bacteriophages can carry various types of cargo, including oligonucleotides, peptides, antibodies, proteins, carbohydrates, vitamins, drugs, fluorescent dyes, aptamers, siRNA, CRISPR-Cas, large mammalian gene expression cassette, synthetic polymers, photosensitizers, quantum dots and other small nanoparticles. It was demonstrated that the potential of phages as vectors is broadened by their good biocompatibility, homogeneity, thermodynamic stability, high load capacity, efficient self-organisation ability, and scalability.

Moreover, genetic engineering and/or chemical methods may enable the synthesis of a specially designed phage with the ability to target a specific surface marker of a senescent cell. The application of a preparation composed of one type of phages to the patient is called single therapy. As many types of senescent cells characterized by various surface markers are present in different tissues simultaneously, even more beneficial than single therapy, seems to be a combination therapy. Such therapy can be simultaneous and rely on the introduction at the same time of a mixture of several types of phages (so-called phage cocktail) as well as sequential, consisting of the application of different types of phages or their cocktails at fixed intervals.

Lesser Physical Function in Old Age Correlates with a Greater Cardiovascular Disease Risk
https://www.fightaging.org/archives/2022/09/lesser-physical-function-in-old-age-correlates-with-a-greater-cardiovascular-disease-risk/

Better fitness in later life reduces mortality, and the study results here are just one of many examples that demonstrate this correlation, though specifically for cardiovascular disease in this case. While only correlations can be determined from most human data, animal studies make it quite clear that better fitness causes a reduced later life mortality. Maintaining better physical fitness is a good idea for many reasons, and it seems clear that health and longevity will benefit from doing so.

The Atherosclerosis Risk in Communities (ARIC) study, an ongoing community-based cohort enrolled 15,792 participants, ages 45-64 years from 1987-1989, to investigate the causes for atherosclerotic disease (plaque or fatty buildup in the arteries). Yearly and semi-yearly (beginning in 2012) check-ins included phone calls and in-person clinic exams. The present study evaluated health data from ARIC visit 5 (2011-2013; all participants were older than age 65) as a baseline, when the Short Physical Performance Battery (SPPB) test was first collected. The SPPB measured physical function to produce a score according to walking speed, speed of rising from a chair without using your hands, and standing balance.

Researchers analyzed health data for 5,570 adults, average age of 75 from 2011 to 2019. Using SPPB scores, the physical function of the participants was categorized into three groups: low, intermediate, and high, based on their test performance. Researchers examined the association of SPPB scores with future heart attack, stroke, and heart failure, as well as the composite of the three, adjusting for major cardiovascular disease risk factors, such as high blood pressure, smoking, high cholesterol, diabetes, and history of cardiovascular disease.

Among all participants, 13% had low, 30% had intermediate, and 57% had high physical function scores. During the 8 years of the study, there were 930 participants with one or more confirmed cardiovascular events: 386 diagnosed with heart attack, 251 who had a stroke, and 529 heart failure cases. Compared to adults with high physical function scores, those with low physical function scores were 47% more likely to experience at least one cardiovascular disease event, and those with intermediate physical function scores had a 25% higher risk of having at least one cardiovascular disease event. The association between physical function and cardiovascular disease remained after controlling for traditional cardiovascular disease risk factors such as age, high blood pressure, high cholesterol, and diabetes.

A Discussion of Present Drug Development to Target Senescent Cells
https://www.fightaging.org/archives/2022/09/a-discussion-of-present-drug-development-to-target-senescent-cells/

The paper noted here is titled "New Trends in Aging Drug Discovery", but the authors really only discuss the development of senolytics and other classes of treatment that target the burden of senescent cells in aged tissues. Senescent cells are created throughout life, but in youth are cleared quickly by the immune system; with age, the balance between creation and destruction shifts, and the numbers of such cells increase. Lingering senescent cells produce disruptive signaling that changes the behavior of normal cells for the worse and provokes the immune system into chronic inflammation, contributing to age-related disease and mortality.

Research over the past decade has demonstrated that selective elimination of senescent cells (SnCs) extends health and lifespan in animal models and can significantly ameliorate aging-associated diseases; therefore, numerous efforts are invested in the development of senolytics that target molecular pathways underlying senescence to selectively kill SnCs. In this sense, resistance to apoptosis is a key characteristic feature of SnCs and inhibition of pro-survival and anti-apoptotic regulators is the most common strategy for the development of means to remove senescent cells.

The removal or modulation of SnCs by senotherapeutic drugs has become an attractive approach to prevent, delay, and even revert many of the chronic age-associated disorders and to extend healthspan. Senotherapeutic compounds can be divided into senolytics, which selectively promote the death of SnCs or induce senolysis, and senomorphics that suppress markers of senescence, in particular the senescence-associated secretory phenotype (SASP), to cause senostasis and prevent the detrimental cell-extrinsic effects of SnCs. Here we detail the most profoundly characterized small molecules and their mechanism of action in the context of the diseases in which they have been studied.

Aging is commonly regarded as an inevitable part of the life cycle; however, current research suggests that it may not be the inexorable process we consider it at the present moment. Actually, obtained results with different models indicate that (i) cells become senescent as time passes; (ii) SnCs have altered functions, which eventually lead to aging-related diseases; (iii) aged cells are different from young cells and these differences can be exploited for specific targeting; (iv) senescent cell removal or rejuvenation strategies involve improvements in aging-related pathological states; (v) there exist compounds (that may become drugs in the near future) that, by correcting and modulating cellular senescence can slow down, halt or even reverse aging-related diseases. Globally, these results suggest that aging is a druggable process that can be targeted with the appropriate drugs, similar to other chronic disorders.

Targeting Senescent Cells to Better Address Cancer and Consequences of Cancer Therapy
https://www.fightaging.org/archives/2022/09/targeting-senescent-cells-to-better-address-cancer-and-consequences-of-cancer-therapy/

The goal of cancer therapies is to kill cancerous cells or force those cells into the state of senescence, to shut down their uncontrolled replication. Chemotherapy and radiotherapy do harm non-cancerous cells as well, however, and can create further senescent cells in this way. It is thought that a substantial fraction of the increased mortality and risk of age-related disease seen in cancer survivors is due to the increased burden of senescent cells produced by the treatment of cancer. That is obviously preferential to death by cancer, but it is a concern, with a significant negative impact to remaining life expectancy. With the advent of senolytic therapies capable of selectively destroying senescent cells, it seems likely that this further harm inflicted on cancer patients can be ameliorated, however.

Cellular senescence is an inherent and virtually unavoidable consequence of treatment in patients with cancer. Cancer cell senescence mainly refers to surviving cancer cells that enter stable and durable cell cycle arrest, but can also be triggered in non-malignant cells in various organ systems across the body. Given the complex cell-extrinsic effects that senescent cells can exert in their surroundings, and the fundamental cell-intrinsic rewiring that profoundly alters cellular functionality and can account for stem-like reprogramming, the consequences of senescence are far more complex than those of apoptosis. Thus, managing residual senescent cancer cells as well as the consequences of senescence of non-malignant cells in patients receiving pro-senescent antitumour therapies is a clinical challenge.

Weighing the balance between the 'bright' and 'dark' sides of senescence is difficult, given that tumour-suppressive and tumour-promoting effects linked to senescent cancer cells can coexist in the same patient. Specifically, neither a dependable quantitative assessment of the different contributions that such effects could have on long-term outcome nor marker-based detection and selective targeting of less-desirable senescent cell populations is currently feasible in the clinic. Pharmacological suppression or modulation of the senescence-associated secretory phenotype (SASP) might work to a certain extent, but is unlikely to robustly change tumour fate. By and large, premature cancer cell senescence has acutely beneficial but chronically detrimental ramifications.

Most cytotoxic and cytostatic cancer treatments currently available induce senescence, whether intended or not, as a collateral effect in a certain proportion of the surviving cancer cell population. Thus far, senolysis (that is, senescence-related opportunities to eliminate drug-exposed malignant cells that failed to undergo apoptotic cell death in the first place but contributed to the initial treatment response via proliferative arrest) seems to be the preferred strategy because it seems the only definitive option towards tumour eradication. Although numerous promising candidate senolytics are being identified, some of which have entered clinical trials, prospective results of large-cohort oncology trials remain to be reported. Such studies should provide insights as to whether protection from post-senescent cancer relapse and concurrent elimination of organ function-disabling senescent cells in non-malignant tissues can be established as key objectives of therapeutic senolytic approaches in patients with cancer.

Calorie Restriction Suppresses Generation of Immune Cells via Changes to the Gut Microbiome
https://www.fightaging.org/archives/2022/09/calorie-restriction-suppresses-generation-of-immune-cells-via-changes-to-the-gut-microbiome/

An interesting set of connections are made in this paper, in which researchers show that favorable changes to the gut microbiome produced by the practice of calorie restriction lead to greater butyrate production, generally thought to be a positive change, as butyrate can improve neurogenesis, among other beneficial effects. However butyrate supplementation also suppresses the generation of new immune cells, an outcome also known to be a feature of calorie restriction and fasting. Whether this suppression is outright harmful is an open question; certainly fasting has been shown to help clear damaged immune cells following cancer therapy, to pick one example, and repeated reductions in circulating immune cells may be beneficial in the long term in healthy individuals via partial clearance of problem immune cell populations.

Dietary restriction (DR) is one of the most robust interventions shown to extend health-span and remains on the forefront of anti-aging intervention studies, though conflicting results have been shown on its effect on lifespan both in rodents and primates. The severe inhibitory effects on the lymphoid lineage by DR remains one of its major negative downsides which reduces its overall beneficial effects on organismal health. Yet, the underlying mechanism of how DR suppresses the lymphoid system remains to be explored.

Here, we show that antibiotic ablation of gut microbiota significantly rescued the inhibition of lymphopoiesis by DR. Interestingly, glycolysis in lymphocytes was significantly down-regulated in DR mice and pharmacological inhibition of glycolysis reverted this rescue effect of lymphopoiesis in DR mice with ablated gut microbiota. Furthermore, DR remarkably reconstructed gut microbiota with a significant increase in butyrate-producing bacterial taxa and in expression of But, a key gene involved in butyrate synthesis. Moreover, supplemental butyrate feeding in AL mice suppressed glycolysis in lymphoid cells and mimicked the inhibition of lymphopoiesis in AL mice.

Together, our study reveals that gut microbiota mediates the inhibition on lymphopoiesis via down-regulation of glycolysis under DR conditions, which is associated with increased butyrate-synthesis. Our study uncovered a candidate that could potentially be targeted for ameliorating the negative effects of DR on lymphopoiesis, and therefore may have important implications for the wider application of DR and promoting healthy aging.