Fight Aging!

There is a faction within the research and development community who feel that we shouldn't talk about ambitious goals when it comes to human rejuvenation and adding many years to human life spans. They think that the best strategy is to focus on very incremental, modest goals in the treatment of aging. At the present time, that really means calorie restriction mimetic drugs and the like, approaches that are unlikely to be capable of outperforming the effects of good lifestyle choices. This seems like an extension of the old, bad days, in which researchers refused to talk about intervening in the aging process at all. It is optimizing for the ability to raise funds via grant and venture capital, while throwing away any hope of actually achieving meaningful goals. It is a willful relinquishment of the possible.

It is disappointing to see figures with a soapbox, such as Celine Halioua, part of Laura Deming's network, taking this easier road to what will likely be a wasted career, focused on technologies that will have little impact on human life span. That may seem a harsh judgement, but it has to be said. I'm singling out Halioua here only because she caught my attention on this topic today; there are plenty of other people I could point out who are set on a similar path, and with louder rhetoric. The coming decade is a crossroads, at which we collectively vote on whether the longevity industry will turn out to be largely supplement sellers, mTOR inhibitor developers, other metabolic manipulation of stress response mechanisms, and the like, all doing very little to affect longevity, or whether it will be senolytics to clear senescent cells and other SENS-like approaches to damage repair that will produce actual rejuvenation with the chance at adding decades to human life spans at the end of the day. This seems to me an important choice.

It is not hard to predict what will happen in a world in which the only discussions related to the treatment of aging focus on how to very modestly slow the aging process. It is not hard to see what the outcome will be in a world in which the rhetoric on aging is that it is brave and bold to produce technologies that can perform only a fraction as well as the practice of calorie restriction, which itself adds only a few years at most to human life span. The outcome will be that we will all die on much the same schedule as our parents and grandparents. The outcome will be that we will miss the opportunity to build and engage with biotechnologies capable of achieving far greater and more beneficial outcomes. At the large scale and over timeframes of decades, the industries of the world build the visions that are discussed most broadly, not the visions that go unspoken.

What the aging field needs

"I think the most controversial opinion I have from an aging standpoint, and something I'm pretty loud about, is that I think we have moved past the time where this 'immortality,' '1000 year old human,' even '150 year old human' narrative is helpful to the field," Celine Halioua told us. "The idea of an aging drug is completely non-controversial - it's basically a statin for every age related disease - it's a preventative mechanism for the worst diseases that we have. And that fits perfectly with standard pharma really, but it's not seen that way.

"We now have a lot of preclinical, research stage, things that have showed efficacy in non-human models, so we need to quickly develop some subset of them and show if they work or not. And this is really a time when you need to have strategic conservatism. There are set boundaries - you have to deal with regulatory agencies, the FDA, insurance payers, pharma, and you have to raise very sizable funding from people who are going to be turned away by these 1,000 year lifespan claims. And so I'm quite loud about that, because I think it's a trend I see in the aging field where people repeat these things over and over again, and I think it actually pulls back the field."

Halioua feels there's an argument to be made - and it's one with which she agrees - that the audacity of big statements were really critical in the 80s and 90s "when nobody was thinking about this field and nobody was paying attention. But I think we've moved past that time, so that's one of the big things that I want to talk about, and a key driver behind the article."

Taking about longevity and encouraging discussion promotes interest in the field and current research, of course, but as with all opinions, there are assenters and dissenters. "I think I definitely annoyed some people with the strategic conservatism thing. But debate is good - intelligent, data-based debate on these things is only a positive for the field. I'm 100% okay with being proven wrong on any and all of these points. My thesis on writing and putting stuff out there about aging is, if nothing else, it may incite somebody who has a better opinion or more informed opinion to then counter me, and then that gets published, so it really can't hurt."

Epigenetic clocks are correlations identified between physiological age and algorithmic combinations of DNA methylation status at various CpG sites on the genome. Cells constantly change their epigenetic marks, such as DNA methylation, in response to circumstances. Some of those circumstances involve characteristic damage and responses to damage that occur with age, and that are broadly similar between individuals in later life. The clocks thus reflect, to some degree, biological rather than chronological age, the progression of processes of damage rather than time.

It is entirely unclear, and will remain so for some time, as to what exactly is measured by these clocks, however. Which processes of aging drive these epigenetic changes? Without knowing the answer to that question, it is hard to use the clocks to test the efficacy of a potential rejuvenation therapy. Perhaps a clock entirely fails to consider the specific form of damage repaired in a study. There is no practical way to find out other than to run a lot of studies with a lot of different clocks and different potential rejuvenation therapies. Early clocks have interesting and potentially problematic blind spots: the Horvath clock is insensitive to fitness, for example, as demonstrated in twin studies with fit and unfit twin pairs. This is known, and improvements were made. The study noted here demonstrates that the later GrimAge clock is a clear improvement, as it does identify differences in mortality risk between genetically identical twins.

Novel measures of biological aging known as "epigenetic clocks" have been used to assess biological aging process and mortality risk. The major advantage of epigenetic clocks is that they can be utilized to estimate the progress of aging over the life course. Horvath's algorithm was the first widely used epigenetic clock. It was trained against chronological age, and therefore it has been argued that Horvath's DNAmAge estimates may exclude CpGs whose methylation patterns may reflect a deviation of biological age from chronological age. DNAm GrimAge was subsequently developed to predict mortality. It is a combination of DNAm-based surrogate biomarkers for health-related plasma proteins and smoking pack-years as well as sex and chronological age. It is associated with the key "hallmarks of aging," such as mitochondrial dysfunction and cellular senescence.

So far, multiple studies with varying study designs and outcomes have found epigenetic age acceleration - an older DNAm age estimated by epigenetic clocks compared to chronological age - to be associated with increased mortality risk. It has been suggested that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors.

We examined the association of epigenetic age acceleration, defined by Horvath's DNAmAge and DNAm GrimAge, with all-cause mortality within a population-based cohort of 413 Finnish twin sisters. The female participants are twin pairs who share sex, age, and all (monozygotic pairs) or half (dizygotic pairs) of their genetic polymorphisms and most of the intrauterine and childhood environment. This allows us to distinguish the effect of lifestyle and genetic factors on the association of epigenetic aging and mortality.

Our results suggest that DNAm GrimAge outperforms Horvath's DNAmAge in mortality risk prediction. We performed pairwise analysis in which risk for survival as a function of an epigenetic age acceleration was conducted to minimize potential pleiotropic genetic and familial influences on the association between epigenetic aging and mortality. Our genetically controlled analysis suggest that faster epigenetic aging is associated with a higher risk of mortality irrespective of genetic influences. Further, the results indicate that smoking plays an important role in the association between epigenetic aging and mortality. In conclusion, the findings suggest that DNAm GrimAge is a strong predictor of mortality independent of genetic influences.

Link: https://doi.org/10.1186/s13148-021-01112-7

Researchers here report on the identification of MEOX1 as an important regulator of fibrosis. Fibrosis is the inappropriate deposition of collagen in tissue to form scar-like structures that disrupt function, a malfunction of the normal processes of tissue maintenance. Fibrotic diseases often have an inflammatory component, and the presence of senescent cells and their harmful pro-inflammatory, pro-growth signaling has been implicated in the development and progression of fibrosis in aged tissues. Numerous aged organs are characterized by disruptive fibrosis, and this manifestation of aging presently lacks good treatment options. We can hope that senolytic therapies to selectively destroy senescent cells will do well in clinical trials for this sort of condition, but it is always possible that other approaches will be needed.

Fibroblasts are key to normal organ repair and integrity; they're the most abundant cell in connective tissue and congregate at sites of bodily damage or disease. In many cases, their presence is beneficial. They help launch immune responses, mediate inflammation, and rebuild tissue. But in chronic disease, activated fibroblasts can continuously create scar tissue, impeding normal organ function. Researchers knew that in mice with heart disease, blocking a class of proteins known as BET proteins slowed fibrosis and improved heart function, although it wasn't clear which cell type in the heart was being affected. They also knew that BET proteins are needed throughout the body for many important functions, including normal immunity.

Researchers studied mice who developed heart failure, and treated them daily with a BET inhibitor for 1 month. The researchers used single-cell RNA sequencing and single-cell epigenomics to compare heart cells from mice before, during, and after the treatment, and correlate those results with heart function. While the scientists didn't find significant changes to heart muscle cells, they observed that the treatment induced striking changes in cardiac fibroblasts, which represent more than half the cells in the human heart. In particular, the researchers discovered that the gene MEOX1 was highly active in the mice with heart failure and that its levels dramatically dropped when the mice were treated with the BET inhibitor.

The findings point to the precise part of the DNA, regulated by BET, that is responsible for MEOX1 to be turned on in disease states. Using CRISPR genome-editing technology, the scientists showed that deleting this small part of the DNA prevented MEOX1 from being activated, even under stress. The team went on to show that blocking MEOX1 from being switched on had the same effects as a BET inhibitor - it blocks the activation of fibroblasts. The researchers also studied other organs that commonly become fibrotic with disease, and found that cellular stress led to higher levels of MEOX1 in human lung, liver, and kidney fibroblasts. "We hope this discovery provides an avenue to slow down or stop fibrosis in many settings."

Link: https://gladstone.org/news/flipping-molecular-switch-heart-fibrosis

First generation stem cell therapies, such as those using cells derived from fat tissue, have been shown to reduce chronic inflammation. This effect is produced as a result of signaling from the transplanted cells, which near entirely die rather than surviving to integrate into tissues and perform useful work. Improvements to tissue regeneration and function are much less reliably obtained, however. There are no doubt many other effects of stem cell signaling on native cell behavior, a complicated area of research in which progress is slow an incremental.

Researchers here show that stem cell therapy can upregulate the mitochondrial quality control mechanism of mitophagy. This helps to clear out damaged mitochondria more efficiently, and thereby improve cell function. Mitophagy is known to decline with age for a variety of still poorly explored reasons. Mitochondrial function also declines with age, and multiple lines of evidence suggest that faltering mitophagy is a sizable part of that problem. Stem cell therapies are probably not the most efficient way to address failing mitochondrial function with age, but if they can illuminate specific mechanisms that might be targeted by other means, then this is probably helpful.

Adipose-derived stem cells regulate metabolic homeostasis and delay aging by promoting mitophagy

Tissues undergo a process of degeneration as the body ages. Mesenchymal stem cells (MSCs) have been found to have major potential in delaying the aging process in tissues and organs. However, the mechanism underlying the anti-aging effects of MSC is not clear which limits clinical applications. In this study, we used adipose-derived mesenchymal stem cells (ADSCs) to perform anti-aging treatments on senescent cells and progeroid animal models.

Following intervention with ADSCs, replicative senescence was delayed and metabolic homeostasis was transformed from catabolism to anabolism. Metabolomic tests were used to analyze different metabolites. We found that ADSCs acted to accelerate mitophagy which eliminated intracellular reactive oxygen species and improved the quality of mitochondria. These processes acted to regulate the cellular metabolic homeostasis and ultimately delayed the process of aging. Allogeneic stem cell therapy in a Progeria animal model (DNA polymerase gamma (POLG) knockin, mitochondrial dysfunction) also showed that ADSC therapy can improve alopecia and kyphosis by promoting mitophagy.

Our research confirms for the first time that allogeneic stem cell therapy can improve aging-related symbols and phenotypes through mitochondrial quality control. These results are highly significant for the future applications of stem cells in aging-related diseases.

Microglia are innate immune cells of the central nervous system, responsible for clearing harmful molecular waste, tracking down pathogens, and a range of other supporting roles in the function and tissue maintenance of the brain. Unfortunately microglia are known to become dysfunctional with age: notable more inflammatory, and less capable when it comes to clearing protein aggregates such as the amyloid-β associated with Alzheimer's disease. This is thought to be an important contribution to the age-related nature of neurodegenerative conditions. Targeted clearance of senescent microglia has been shown to produce meaningful benefits in mouse models of neurodegeneration, reducing chronic inflammation. Here researchers look at one specific aspect of age-related microglial incapacity, and find that they can override it to improve performance.

Microglia, the innate immune cells of the brain, are essential for maintaining homeostasis and for orchestrating the immune response to pathological stimuli. They are implicated in several neurodegenerative diseases like Alzheimer's and Parkinson's disease. One commonality of these diseases is their strong correlation with aging as the highest risk factor and studying age-related alterations in microglia physiology and associated signaling mechanism is indispensable for a better understanding of age-related pathological mechanisms.

CD22 has been identified as a modifier of microglia phagocytosis in a recent study, but not much is known about the function of CD22 in microglia. Here we show that CD22 surface levels are upregulated in aged versus adult microglia. Furthermore, in the amyloid mouse model PS2APP, amyloid-β-containing microglia also exhibit increased CD22 signal. To assess the impact of CD22 blockage on microglia morphology and dynamics, we have established a protocol to image microglia process motility in acutely prepared brain slices from CX3CR1-GFP reporter mice. We observed a significant reduction of microglial ramification and surveillance capacity in brain slices from aged versus adult mice.

The age-related decrease in surveillance can be restored by antibody-mediated CD22 blockage in aged mice, whereas surveillance in adult mice is not affected by CD22 inhibition. Moreover to complement the results obtained in mice, we show that human iPSC-derived macrophages exhibit an increased phagocytic capacity upon CD22 blockage. Downstream analysis of antibody-mediated CD22 inhibition revealed an influence on BMP and TGFβ associated gene networks. Our results demonstrate CD22 as a broad age-associated modulator of microglia functionality with potential implications for neurodegenerative disorders.

Link: https://doi.org/10.3389/fimmu.2021.684430

Raised levels of senescent cells are found in the liver of patients and animal models exhibiting non-alcoholic fatty liver disease (NAFLD), which progresses to the more serious nonalcoholic steatohepatitis (NASH). These conditions are a consequence of obesity, which is also correlated with a higher burden of senescent cells throughout the body, and particularly in fat deposits. Senescent cells secrete signals that provoke chronic inflammation and disrupt tissue structure and function. They are an important contributing cause of aging and age-related disease. In this sense, we might think of many of the consequences of obesity as literally accelerated aging. In conditions like NAFLD and NASH, however, it is less clear that senescence is a major cause of pathology, versus being a downstream consequence that produces further harms. That will most likely be settled by studies and trials in which animals and patients are given senolytic drugs to clear senescent cells; any major improvement or prevention will argue for an important role for senescent cells in this condition.

Data from studies in rodents and humans have shown that NAFLD is accompanied by an increase in senescent cells in the liver, and that the number of senescent cells is associated with a more advanced disease state. Despite the strong associations between senescence and NAFLD in humans and the work derived from in vitro studies and rodents, it remains to be determined if hepatic senescence is a mere consequence of the metabolic dysregulation and inflammatory phenomena in NAFLD or a causal player in the development of this disease.

Although a causal role of cellular senescence must be further substantiated and subsequently established in humans, this pathophysiological process holds great potential, particularly when bearing in mind that there is currently no effective treatment for NAFLD. Targeting senescence has emerged as an attractive therapeutic target for NAFLD since senescence might be involved in the full spectrum of the disease (i.e. from early steatosis to cirrhosis). Moreover, senolytic drugs can be administrated intermittently, thereby minimising potential toxic effects and increasing adherence in the individual often affected by multiple morbidities and thus treated with multiple medications.

Nevertheless, clinical trials conducted in individuals with NAFLD using senolytics have not been performed. Such trials are needed to better define the benefits and potential risks of these drugs. To increase efficacy and accuracy of these clinical trials, new or composite assays are needed, and development of these assays should be a top priority for the field.

Link: https://doi.org/10.1016/j.jhepr.2021.100301

A sizable enough fraction of T cells of the adaptive immune system become senescent in old age to cause major issues. Senescent cells cease replication and secrete a mix of signals that cause harm in numerous different ways: rousing chronic inflammation; disrupting tissue maintenance and structure; encouraging other cells to become senescent. The cell dynamics of the immune system are quite different from those of tissues. Immune cells are provoked into replication by signals of damage or infection, and enough of that sort of stress over time will have large effects on the number of senescent immune cells.

Somatic cells, such as T cells, can only replicate a set number of times before they reach the Hayflick limit and become senescent or self-destruct. The supply of new T cells is reduced with age, as the thymus, where thymocytes mature into T cells, atrophies. Reduced supply and increased replication stress due to damage, infection, and other disarray in the immune system leads to a growing number of senescent T cells. This is the case in aging, and also the case in conditions such as HIV infection, in which the thymus is damaged and the immune system put under great stress.

In today's open access paper, researchers show that the practice of calorie restriction slows the accumulation of senescent T cells with age. Additionally, clearing these senescent T cells via a suitably targeted therapy also produces similar benefits. A range of other evidence has pointed to senescent and senescent-like subpopulations of T cells that arise with age, and researchers have shown that these cells produce all sorts of problems in later life. This is all the more reason to place a greater emphasis on, firstly, the production of senolytic therapies to destroy these errant cells, and, secondly, on ways to restore a more youthful production of T cells in the bone marrow and thymus.

The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice

Aging is associated with functional decline in the immune system and increases the risk of chronic diseases owing to smoldering inflammation. In the present study, we demonstrated an age-related increase in the accumulation of PD-1+ memory-phenotype T cells that are considered "senescence-associated T cells" in both the visceral adipose tissue and spleen. As caloric restriction is an established intervention scientifically proven to exert anti-aging effects and greatly affects physiological and pathophysiological alterations with advanced age, we evaluated the effect of caloric restriction on the increase in this T-cell subpopulation and glucose tolerance in aged mice.

Long-term caloric restriction significantly decreased the number of PD-1+ memory-phenotype CD4+ and CD8+ T cells in the spleen and visceral adipose tissue, decreased pro-inflammatory M1-type macrophage accumulation in visceral adipose tissue, and improved insulin resistance in aged mice. Furthermore, the immunological depletion of PD-1+ T cells also reduced adipose inflammation and improved insulin resistance in aged mice.

These results indicate that senescence-related T-cell subpopulations are involved in the development of chronic inflammation and insulin resistance in the context of chronological aging and obesity. Thus, long-term caloric restriction and specific deletion of senescence-related T cells are promising interventions to regulate age-related chronic diseases.

Researchers have been arguing for some years now that metformin improves life span via suppression of excessive inflammation. Metformin, it has to be said, has terrible, unreliable, very mixed animal data when it comes to slowing aging. Plus that one human study in diabetic patients in which life expectancy was very modestly increased. So it seems to me that progress in understanding what is going on under the hood is largely of academic interest at this point in time. The effect size is just not large enough to be a medical focus. If suppression of inflammation and extended healthy lives are the goals on the table, then senolytic therapies to clear out senescent cells and their inflammatory signaling look much more promising.

Metformin is a widely prescribed blood sugar-lowering drug. It is often used as an early therapy (in combination with diet and lifestyle changes) for type 2 diabetes. Metformin works by lowering glucose production in the liver, reducing blood glucose levels that, in turn, improve the body's response to insulin. But scientists have also noted that metformin possesses anti-inflammatory properties, though the basis for this activity was not known. Researchers have now identified the molecular mechanism for the anti-inflammatory activity of metformin and, in mouse studies, found that metformin prevents pulmonary or lung inflammation in animals infected with SARS-CoV-2, the virus that causes COVID-19.

But while clinical studies suggested metformin's anti-inflammatory activity, rather than lowering of blood glucose, could be responsible for reduced COVID-19 severity and mortality, none of the studies offered an explanation or prompted large, randomized clinical trials needed for obtaining conclusive answers.

IL-1β, along with IL-6, are small proteins called cytokines that cause inflammation as an early immune response. Their amounts are often highly elevated in persons infected by SARS-CoV-2, creating "cytokine storms" in which the body starts attacking its own cells and tissues. They are signs of an acute immune response gone awry. Production of IL-1β depends on a large protein complex called the inflammasome.

Researchers confirmed that metformin inhibited inflammasome activation and prevented SARS-CoV-2-induced pulmonary inflammation in mice. Cell culture studies using macrophages revealed the underlying mechanism by which metformin exerts its anti-inflammatory activity: reduced production of ATP by mitochondria. ATP is the molecule that mitochondria use to store chemical energy for cells. It is essential to all cellular processes, but blunted ATP production in liver cells is responsible for the glucose lowering effect of metformin.

Lower amounts of ATP in macrophages led to inhibition of mitochondrial DNA synthesis, a critical step in NLRP3 inflammasome activation. Subsequent research found that clearing away damaged mitochondria reduced NLRP3 inflammasome activity and reduced inflammation. "These experiments strongly suggest that improved delivery of metformin into lung macrophages can provide new treatments for severe COVID-19. The findings suggest metformin may have therapeutic potential for treating a variety of neurodegenerative and cardiovascular diseases in which NLRP3 inflammasome activation is a factor. Inhibition of inflammasome activation may also account for the poorly explained anti-aging effect of metformin."

Link: https://www.eurekalert.org/pub_releases/2021-06/uoc--cdd060821.php

It took many years of development and trials for immunotherapies targeting amyloid-β aggregation to successfully clear large amounts of these misfolded protein deposits from the brain. Unfortunately, it appears that this has very little effect on patient outcomes in Alzheimer's disease. It is possible that amyloid-β, while damaging, is only relevant in the early stages of the condition, and becomes unimportant once a feedback loop of inflammation and tau aggregation is underway. Equally, amyloid-β aggregation may turn out to be largely a side-effect of persistent infection or metabolic disruption, while the core disease processes are inflammation and vascular dysfunction. Removal of amyloid-β seems like something that should be accomplished in older people, as there is little debate over its ability to cause mild cognitive impairment, but that is a different topic from its relevance to Alzheimer's disease.

The DIAN-TU study evaluated the effects of two investigational drugs - gantenerumab and solanezumab - in people with a rare, inherited, early-onset form of Alzheimer's known as dominantly inherited Alzheimer's disease or autosomal dominant Alzheimer's disease. Such people are born with a mutation that causes Alzheimer's, and experience declines in memory and thinking skills starting as early as their 30s or 40s.

Over the past few decades, scientists have pieced together the changes that occur as Alzheimer's develops, a process that takes 20 years or more. First, the protein amyloid beta starts forming plaques in the brain. Later, levels of tau and neurofilament light chain rise in the cerebrospinal fluid that surrounds the brain and spinal cord, and the brain begins to shrink. Then, tangles of tau protein form in the brain. Only then do people with the disease start exhibiting signs of memory loss and confusion.

In this study, 52 patients were randomized to gantenerumab, which led to a reduction in the amount of amyloid plaques in the brain, and lowered soluble tau and phospho-tau, and slowed the rise of neurofilament light chain levels in the cerebrospinal fluid. Neurofilament light chain is a marker that reflects neurodegeneration. Overall, gantenerumab's safety profile in this trial was consistent with that from other clinical trials of the investigational medicine, and no new safety issues were identified.

The primary endpoint of the DIAN-TU study was the prevention or slowing of cognitive decline in people who are nearly certain to develop Alzheimer's due to genetic mutations. Neither drug met the primary endpoint, although the study wasn't able to determine effects on thinking and memory in participants who entered the study without symptoms, because they exhibited little to no decline in cognitive function. However, as a secondary endpoint, the study also evaluated the effect of the drugs on molecular and cellular signs of Alzheimer's disease. On these measures, gantenerumab showed potential benefit.

Link: https://medicine.wustl.edu/news/investigational-alzheimers-drug-improves-biomarkers-of-the-disease/

A number of papers in recent years have suggested there to be a link between gum disease (periodontitis) and neurodegeneration. Similarly to the correlation with heart disease, it is thought that the underlying mechanism is raised chronic inflammation deriving from toxins released into the bloodstream by the bacteria that cause gum disease. Some epidemiological data suggests that the effect size is modest at best, however - a 6% increase in risk in one cohort, for example. So is there in fact a meaningful link between inflammatory gum disease and forms of neurodegeneration that are thought to be driven in large part by the chronic inflammation of aging? The hypothesis seems reasonable, but as today's open access paper notes, the evidence to date is just not that great.

This is often the way of things in research into the contributing mechanisms of age-related diseases. Having gingival bacteria release immune-provoking compounds into the bloodstream sounds like something to be avoided, and one can find plenty of evidence for this mechanism to exist. The bacteria are definitely there in the mouth, the immune response to their presence established in various ways. But is it causing enough harm in comparison to all of the other damage and dysfunction of an aged metabolism to be influential outside the local issue of gum disease?

Perhaps, perhaps not; the epidemiological data as it stands isn't enough for a concrete conclusion when taken collectively. This may be a case of where there is smoke there is fire, and better and larger studies would produce conclusive outcomes, but it is hard to say in advance. Nonetheless, it is near universally agreed that maintaining as low a level of chronic inflammation as possible with advancing age is a good idea.

Is There Any Association Between Neurodegenerative Diseases and Periodontitis? A Systematic Review

Some inflammatory diseases, such as periodontitis, might represent a factor that can contribute to central nervous system (CNS) damage. Periodontitis is a multifactorial chronic inflammatory disease that affects the supporting tissues around the teeth, triggered by dysbiotic biofilms that can lead to systemic inflammation. Periodontal disease is one of the most frequent causes of tooth loss, and is highly prevalent in adults affecting about 20-50% of the global population. It can lead to a systemic inflammatory state through mechanisms that include the spread of pro-inflammatory cytokines and/or bacteria located in the oral cavity. Persistent systemic inflammation/infection can cause neuroinflammation in the brain. Considering this possible interaction, the present study aims to systematically review the evidence supporting the association between the presence of some neurodegenerative disease and periodontitis.

From 534 articles found in this systemic review, 12 were included, of which eight were case-control, three were cross-sectional, and one was a cohort, giving a total of 3,460 participants. All studies presented a low risk of bias and reported an association between neurodegenerative disease and periodontitis. The articles showed that the groups with the two concomitant diseases had higher inflammatory markers levels, IgG levels of periodontal bacteria, and/or clinical parameters of periodontitis compared with the isolated conditions. However, the heterogeneity of the studies taken together hindered the accuracy of the evidence and also made impossible the merging of data. Also, it should be highlighted that no cohort study was retrieved regarding the association between periodontal disease and neurodegenerative diseases; therefore, causality cannot be claimed.

Although all the included studies in this review reported an association between neurodegenerative diseases and periodontitis, the level of evidence was classified to be very low, which suggests a cautious interpretation of the results.

The immune system is complex and ages in complex ways, pressed by the lifetime burden of infection and rising levels of molecular damage that trigger many of the same innate immune responses as are produced by invading pathogens. The common innate immune cells known as macrophages play many roles in the body: defense against pathogens; destruction of errant cells; assisting in tissue maintenance and regeneration. Macrophages adopt different phenotypes (M1, M2, and others) depending on the task at hand.

The aging of the macrophage population, and also the analogous microglia of the central nervous system, is not as simple a matter as there being too many angry, inflammatory M1 macrophages and too few regenerative, anti-inflammatory M2 macrophages. There is, however, a sizable amount of evidence to suggest that this growing imbalance towards inflammatory macrophage behavior is a major cause of issues in older individuals. The perspective of this review paper on macrophage aging is a narrow one, focused on skin only, but much of the discussion is applicable to other tissues.

The skin is our largest organ. Its aging reflects both intrinsic (or chronological) and extrinsic (such as radiation and pollution exposure) aging processes at the molecular and phenotypic levels. Skin aging is a process accompanied by changes that alter the local microenvironment, such as weakening of the skin barrier and the accumulation of stressed and senescent cells, both of which foster inflammation through the invasion/release of Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns. The consequences of such an altered microenvironment include the promotion of the senescence-associated secretory phenotype (SASP), compromising tissue renewal and function, altered cellular interactions, and chronic low-grade inflammation. This sterile inflammatory state, termed inflammaging, develops in several organs with advanced age and is associated with persistent inflammation that ultimately exhausts the skin's defense system.

Macrophages (Mφ), a group of heterogeneous and plastic cells, play a central role in tissue homeostasis and repair, as well as host defense. In the skin, Mφ can be found in different layers, being classified as recruited Mφ originating from monocytes following a recruitment process started by tissue injury, or as tissue-resident macrophages (TRM), which are derived from both adult and embryonic progenitors. Mφ may acquire different phenotypes in response to various stimuli. In this sense, based on in vitro assays, Mφ have been divided into two groups based on their polarization phenotypes: M1 and M2. Classically activated Mφ are deemed as M1 and constitute catabolic, proinflammatory cells that are involved in antimicrobial host defense. M2, or alternatively activated Mφ, are anabolic cells with anti-inflammatory and tissue repair properties. However, mainly due to recent advances in single-cell RNA sequencing, it is now clear that such a dichotomy does not accurately represent Mφ in vivo but represents the extremes of a wide range of continuous phenotypes which have been reported.

The aging process has a great impact on Mφ, including alterations in Mφ metabolic and immune function, impacting the Mφ capability of clearance and immunosurveillance, constituting an important aspect of immunosenescence. In fact, old Mφ in a mice model were characterized with a senescent, proinflammatory profile, associated with increased oxidative stress, compromised antioxidant defenses, and impaired function. Mφ are considered as gatekeepers of tissue homeostasis and integrity, constituting primary inflammatory cytokine producers, as well as initiators and regulators of inflammation, and representing one of the main cellular players in adaptive immunity exacerbation and exhaustion during aging. In recognition of the age-related alterations on Mφ function and their importance during skin aging, in this review, we will dissect how aging hallmarks may alter the Mφ phenotype and function and connect these plastic cells with skin inflammaging.

Link: https://doi.org/10.3390/cells10061323

Researchers here present evidence for leukocyte telomere length and a few other less well explored blood biomarkers to correlate with the progression of atherosclerosis and vascular calcification and later mortality. Calcification of blood vessels and the development of fatty atherosclerotic lesions are two distinct processes, but they tend to progress together, most likely because they are both driven to a sizable degree by the presence of chronic inflammation, and related issues such as burden of senescent cells.

Increased oxidative stress, leukocyte telomere length (LTL) shortening, endothelial dysfunction, and lower insulin-like growth factor (IGF)-1 concentrations reflect key molecular mechanisms of aging. We hypothesized that biomarkers representing these pathways are associated with measures of subclinical atherosclerosis and all-cause mortality.

We evaluated 2,314 Framingham Offspring Study participants (mean age 61 years, 55% women) with available biomarkers of aging: LTL, circulating concentrations of IGF-1, asymmetrical dimethylarginine (ADMA), and urinary F2-Isoprostanes indexed to urinary creatinine. We evaluated the association of each biomarker with coronary artery calcium (CAC) and carotid intima-media thickness (IMT).

In multivariable-adjusted linear regression models, higher ADMA levels were associated with higher CAC values. Additionally, shorter LTL and lower IGF-1 values were associated with higher IMT values. During a median follow-up of 15.5 years, 593 subjects died. In multivariable-adjusted Cox regression models, LTL and IGF-1 values were inversely associated with all-cause mortality. F2-Isoprostanes and ADMA values were positively associated with all-cause mortality.

In conclusion, in our prospective community-based study, aging-related biomarkers were associated with measures of subclinical atherosclerosis cross-sectionally and with all-cause mortality prospectively, supporting the concept that these biomarkers may reflect the aging process in community-dwelling adults.

Link: https://doi.org/10.1371/journal.pone.0251308

The Forever Healthy Foundation has been building a database of materials covering presently available options for the treatment of aging, all of which have little available data in comparison to more established areas of medicine. The bias in these materials is towards a very conservative viewpoint, appropriate for physicians, so you will see little to no enthusiasm for forging ahead with use, as the self-experimenters in the longevity community are presently doing. Nonetheless, this provides a convenient repository of information, pulling together references to all of the animal and human data available for the topics under discussion.

The latest article covers the senolytic combination of dasatinib and quercetin, currently in human trials, and with more and better data to back it up than most other approaches. The effects in mice are eye-opening in comparison to anything else yet tried in the field of rejuvenation; quite rapid reversal of many age-related diseases and measures of age-related degeneration. Dasatinib is a chemotherapeutic, and when used continuously produces the usual range of unpleasant, toxic outcomes. When used only very intermittently, as a senolytic, the situation is very different. Still, as pointed out here, there is little data in humans, if one is to be conservative.

Dasatinib and Quercetin Senolytic Therapy

Clinical data on the possible benefits and risks of using dasatinib and quercetin (D+Q) as senolytics is extremely limited. Published results exist from 3 human trials, two in diseased populations and one in healthy subjects. A total of only 8 benefits were documented in these clinical studies. Of the 8 benefits, 5 were actually various measurements of markers of senescence or the SASP, hypothesized to translate to clinically beneficial effects. Only 3 benefits had any direct clinical relevance and they were of low magnitude. Based on the current state of evidence, the beneficial effects of D+Q seem to be extremely limited in humans.

Several more benefits that encompass many organ systems have been reported in preclinical studies. However, the amount of relevant preclinical research is also limited. We identified only 31 preclinical trials related to D+Q as senolytics and the majority of reported benefits occurred exclusively in diseased animals. Only 13 trials included a group of "healthy" animals that were treated with D+Q. Of those 13 trials, only 6 reported a positive effect of D+Q senolytic treatment on aged, otherwise healthy animals as compared to controls.

The main benefits seen in clinical and preclinical trials of D+Q senolytic therapy are: (a) decreased markers of senescent cells in various tissues (clinical and preclinical); (b) increased health span and lifespan (preclinical); (c) improved cognition and cortical blood flow (preclinical); (d) decreased amounts of liver fat (preclinical); (e) improved vasomotor/endothelial function (preclinical); (e) decreased intimal plaque calcification (preclinical). The main risks that have appeared in clinical trials are mostly due to dasatinib. In the two high quality, open-label human pilot senolytic trials there was only one serious adverse event reported (bacterial multifocal pneumonia and pulmonary edema superimposed on the idiopathic pulmonary fibrosis that was the subject of the trial) and no subjects required drug discontinuation.

The 3 clinical trials published to date have all used different protocols (doses, frequency, duration, and repetition). There is no consensus on the optimal treatment protocol. Unfortunately, as of today, there is no single test that is completely sensitive or specific for senescent cells. Generally, a combination of assays is needed to estimate the senescent cell burden in tissue samples. It is unknown if senescent cell abundance in biopsies of skin, adipose tissue, or other tissues, cheek swabs, cells in blood reliably reflect senescent cell abundance overall. Similarly, whether levels of SASP factors or senescence-associated microRNAs in plasma or blood cells reflect senescent cell burden is not clear.

Therefore, until there are more published results showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on the treatment protocol, we will avoid the use of D+Q senolytic therapy.

The accumulation of senescent cells is an important contributing cause of degenerative aging. This is not a recent discovery, enough was known 20 years ago for the first SENS rejuvenation research proposals to prominently feature removal of senescent cells as an approach to treating aging as a medical condition, but it has only become broadly accepted by the research community over the past decade. There has been a considerable growth of interest in cellular senescence, particularly over the last few years as the first (mixed) human data emerged.

There is a something of a land rush underway in the exploration of the biochemistry of senescent cells at the moment, given that every new discovery might lead to potential means of destroying these cells - or perhaps suppressing their harmful signaling in some way - and thus investment, new startup companies to join the growing longevity industry, and potential profit. It remains to be seen which of the many first generation approaches to the selective destruction of senescent cells will win out in the marketplace of medical development, and meanwhile new discoveries are being made by researchers on a fairly regular basis.

Cellular senescence is linked to chronic age-related diseases including atherosclerosis, diabetes, and neurodegeneration. Compared to proliferating cells, senescent cells express distinct subsets of proteins. In this study, we used cultured human diploid fibroblasts rendered senescent through replicative exhaustion or ionizing radiation to identify proteins differentially expressed during senescence. We identified acid ceramidase (ASAH1), a lysosomal enzyme that cleaves ceramide into sphingosine and fatty acid, as being highly elevated in senescent cells. This increase in ASAH1 levels in senescent cells was associated with a rise in the levels of ASAH1 mRNA and a robust increase in ASAH1 protein stability.

Furthermore, silencing ASAH1 in pre-senescent fibroblasts decreased the levels of senescence proteins p16, p21, and p53, and reduced the activity of the senescence-associated β-galactosidase. Interestingly, depletion of ASAH1 in pre-senescent cells sensitized these cells to the senolytics dasatinib and quercetin (D+Q).

Together, our study indicates that ASAH1 promotes senescence, protects senescent cells, and confers resistance against senolytic drugs. Given that inhibiting ASAH1 sensitizes cells towards senolysis, this enzyme represents an attractive therapeutic target in interventions aimed at eliminating senescent cells.

Link: https://doi.org/10.18632/aging.203170

Mechanisms to sense levels of the essential amino acid methionine are one of the more important triggers for the beneficial calorie restriction response in mammals. Since the body doesn't manufacture methionine, it must come from the diet. Either a low calorie diet or a low methionine diet produce broadly similar effects of improved metabolism, health, and longevity, though different in the fine details. Short-lived species, however, have a much larger gain in life span than is the case in longer-lived species. Calorie restriction can make mice live 40% longer, but it certainly doesn't add more than a few years in humans.

Why this is the case, when short-term metabolic responses and benefits appear broadly similar in both short-lived and long-lived mammals, is an open question. In this context, the research here is quite interesting. If background levels of methionine are lower in long-lived species, perhaps the shared trigger mechanisms relating to methionine are less capable of producing sizable effects in long-term health - though again, a detailed understanding of exactly how this happens has yet to be established.

All living organisms use the same 20 amino acids for protein synthesis. Interestingly, the protein compositional content of the sulfur amino acids methionine and cysteine is species-specific and is associated with animal longevity. Thus, long-lived animal species show the lower methionine and cysteine protein content, surely as adaptive response to the low rate of endogenous damage and highly resistant macromolecular components also present in longevous species. Reinforcing these observations, the free tissue methionine content is also lower in diverse long-lived animal species; and the pro-longevity effects of nutritional (methionine restriction, MetR) and pharmacological (metformin) interventions are mediated by changes in methionine metabolism.

In addition to its role in several intracellular processes, methionine is the core of a complex metabolic network which can be divided in three parts: methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Significantly, manipulation of each of these branches affects longevity in diverse experimental animal models. Consequently, available findings point to the metabolism of methionine as a key target to study the molecular adaptive mechanisms underlying differences in animal longevity.

The present study follows a comparative approach to analyse the plasma methionine metabolic profile from 11 mammalian species with a longevity ranging from 3.5 to 120 years. Our findings demonstrate the existence of a species-specific plasma profile for methionine metabolism associated with longevity characterised by: i) reduced methionine, cystathionine and choline; ii) increased non-polar amino acids; iii) reduced succinate and malate; and iv) increased carnitine. Our results support the existence of plasma longevity features that might respond to an optimised energetic metabolism and intracellular structures found in long-lived species.

Link: https://doi.org/10.1038/s42003-021-02254-3

Today's open access paper offers one of a number of different perspectives on the present consensus regarding the causes of individual variance in life expectancy, of differences in species life span, and of changes in human life expectancy over time. Human life expectancy has increased greatly in the modern era, but this is largely due to improved control over infectious disease and other environmental factors that can cause early mortality and long-term health risks. Similarly, individual variance in life span near entirely arises from lifestyle choice and environmental factors. There is a component arising from slowed aging, but this has been an incidental side-effect of improved technologies, medical and otherwise.

The authors of the paper here suggest that life expectancy and mortality data shows that further improvements in the known environmental factors that impact health are unlikely to yield meaningful gains in human life expectancy. The lion's share of possible gains are already claimed, thanks to control of infectious disease and other outcomes of modern technologies. New approaches to age-related degeneration are needed, development programs and therapies that deliberately target the causative mechanisms of aging. Historical data says little about what human life expectancy will look like in the era of widespread use of senolytic treatments and other rejuvenation therapies now under development.

The long lives of primates and the 'invariant rate of ageing' hypothesis

The maximum human life expectancy has increased since the mid-1800s by ~3 months per year. These gains have resulted from shifting the majority of deaths from early to later and later ages, with no evidence of slowing the rate at which mortality increases with age (i.e. the 'rate of ageing'). Further substantial extensions of human longevity will depend on whether it is possible to slow the rate of ageing or otherwise reduce late life mortality. Consequently, the nature of biological constraints on ageing is a central problem in the health sciences and, because of its implications for demographic patterns, is also of long-standing interest in ecology and evolutionary biology.

Across species, rates of ageing are strongly correlated with other aspects of the life history-pre-adult mortality, age at first reproduction, birth rate, metabolic rate and generation time - as well as with morphological traits such as body size and growth rate. These correlations suggest that ageing evolves in concert with a suite of other traits, which may produce constraints on the rate of ageing within species. Indeed, researchers have long hypothesised that the rate of ageing is relatively fixed within species, not only in humans but also other animals.

This 'invariant rate of ageing' hypothesis has received mixed support. Understanding the nature and extent of biological constraints on the rate of ageing and other aspects of age-specific mortality patterns is critical for identifying possible targets of intervention to extend human lifespans, and for understanding the evolutionary forces that have shaped lifespans within and across species. Although no consensus has been reached about the invariant rate of ageing hypothesis, further evidence that biological constraints may shape human ageing comes from the remarkably consistent relationship between life expectancy at birth and lifespan equality in a diverse set of human populations. While life expectancy at birth (a measure of the 'pace' of mortality) describes the average lifespan in a population, lifespan equality (a measure of the 'shape' of mortality) describes the spread in the distribution of ages at death in a population.

To better understand biological constraints on ageing, here we answer two questions. First, is the highly regular linear relationship between life expectancy and lifespan equality in humans also evident in other primates? Second, if so, do biological constraints on ageing underlie this highly regular relationship? We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.

Can we humans slow our own rate of ageing? Our findings support the idea that, in historical population when life expectancies were low, mortality improvements for infants, and in age-independent mortality, were the central contributors to the decades-long trend towards longer human life expectancies and greater lifespan equality. These improvements were largely the result of environmental influences including social, economic, and public health advances. Since the middle of the 20th century, however, declines in the baseline level of adult mortality have very likely played an increasingly important role in industrialised societies. As we show here, improvements in the environment are unlikely to translate into a substantial reduction in the rate of ageing, or in the dramatic increase in lifespan that would result from such a change. It remains to be seen if future advances in medicine can overcome the biological constraints that we have identified here, and achieve what evolution has not.

Numerous forms of cell therapy have been proposed and tested for the treatment of heart failure over the years, from the earliest stem cell therapies to the broader variety of cell types and increasing technical sophistication attempted today. The results here seem promising. Much of the challenge of early efforts was the lack of reliability in outcomes. While first generation stem cell therapies fairly reliably reduce inflammation, they have not delivered on the promise of regeneration. Clinical trials are overly costly in the present system of regulation, and could be run at far less expense absent the regulators, but something like passing a clinical trial with a hundred or more patients is an important milestone to demonstrate reliability. The effect size demonstrated here is modest - a ~20% reduction in cardiac events, with none of the desired structural changes in the heart in evidence - but that is a starting point.

A clinical trial has shown for the first time that heart failure treatments using cells derived from the patient's own bone marrow and heart resulted in improved quality of life and reduced major adverse cardiac events for patients after one year. "This is a very important advance in the field of cell therapy and in the management of heart failure. It suggests that a treatment, given only once, can produce long-term beneficial effects on the quality of life and prognosis of these patients. The results pave the way for a larger, Phase 3 trial of cell therapy in heart failure."

CONCERT-HF evaluated the use of two types of cells - autologous mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs) - alone or in combination, in patients with heart failure caused by chronic ischemic cardiomyopathy, a decrease in heart pumping effectiveness due to heart attacks and a lack of blood getting to the heart. Autologous MSCs are derived from the patient's bone marrow and CPCs are from the patient's heart tissue. Both are known as "autologous" cells because they come from the same patient in whom they are returned for the treatment.

In the study, patients treated with CPC cells alone had a significant 22% reduction in major adverse cardiac events, particularly hospitalization. Patients treated with MSC cells alone and with a combination of both types of cells experienced significantly improved quality of life compared with patients who received no treatment. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups.

Link: https://www.uoflnews.com/section/science-and-tech/uofl-led-clinical-trial-shows-cell-therapy-improves-outcomes-in-heart-failure/

A novel pulsed approach to immunotherapy targeting Alzheimer's disease has been shown to reduce both amyloid-β and tau aggregates in old squirrel monkeys, as well as improve cognitive function. This species offers a potentially less problematic and artificial animal model for the condition, in that aged squirrel monkeys naturally develop amyloid-β aggregates, unlike mice which must be engineered into exhibiting specific features of Alzheimer's pathology. Thus it is hoped that cognitive improvements following therapy in this species will be more likely to also occur in human patients.

Researchers have demonstrated that elderly monkeys had up to 59 percent fewer plaque deposits in their brains after treatment with CpG oligodeoxynucleotides (CpG ODN), compared with untreated animals. These amyloid beta plaques are protein fragments that clump together and clog the junctions between neurons. Brains of treated animals also had a drop in levels of toxic tau. This nerve fiber protein can destroy neighboring tissue when disease-related changes to its chemical structure cause it to catch on other cells.

The investigators say the treatment led to cognitive benefits as well. When presented with a series of puzzles, elderly monkeys given the drug performed similarly to young adult animals and much better than those in their age group that had remained untreated. The treated monkeys also learned new puzzle-solving skills faster than their untreated peers. According to researchers, past treatment efforts targeting the immune system failed because the drugs overstimulated the system, causing dangerous levels of inflammation, which can kill brain cells. "Our new treatment avoids the pitfalls of earlier attempts because it is delivered in cycles, giving the immune system a chance to rest between doses."

A growing body of evidence has implicated the immune system, the set of cells and proteins that defend the body from invading bacteria and viruses, as a contributor to Alzheimer's disease. A subset of immune cells, those within the innate immune system, swallow and clear away debris and toxins from bodily tissues along with invading microbes. Studies have shown that these immune custodians become sluggish as a person ages and fail to clear toxins that cause neurodegeneration.

The new investigation is the first to target the innate immune system with a potential therapy for the disorder in monkeys. The CpG ODN drugs are part of a class of innate immune regulators that quicken these worn out immune custodians. The research team is also the first to use the "pulsing" drug administration technique to avoid excess inflammation, the immune-driven responses like swelling and pain that result from the homing in by immune cells on sites of injury or infection. While necessary to immune defenses and healing, too much inflammation contributes to many disease mechanisms.

Link: https://nyulangone.org/news/new-treatment-stops-progression-alzheimers-disease-monkey-brains

Cells become senescent in response to reaching the Hayflick limit on replication, or to potentially cancerous mutations, or a toxic environment and consequent cell damage, or signaling from other senescent cells. Senescence is nominally an irreversible state. Replication halts and the cell begins secreting pro-inflammatory signals to attract the attention of the immune system. Senescent cells are normally removed via programmed cell death or the actions of cytotoxic immune cells. With age the rate of creation increases and the rate of removal falls, however, leading to a growing number of senescent cells throughout the body. The signaling of that growing number of senescent cells in aged tissues causes chronic inflammation and disrupts tissue maintenance, leading to age-related disease.

What to do about this? Much of the focus of the research community is on senolytic approaches that force senescent cells into apoptosis and self-destruction, or that provoke the immune system into more efficient clearance of senescent cells. These therapies have achieved impressive results in mice, reversing age-related disease and many measures of aging. Some researchers are interested in the reversal of senescence, however: reprogramming cells in ways that overcome the regulatory processes that normally ensure continuation of the senescent state.

Is reversal of senescence a good idea? It seems likely that at least some senescent cells are senescent for a good reason. That they are damaged, and in some cases that damage is potentially cancerous. Reversing senescence may well produce short term gains that are similar to those of senolytic therapies, since in either case the harmful signaling produced by senescent cells is removed. But a significantly raised risk of cancer may be the cost of that approach.

Systems biology for reverse aging

Although partial reprogramming proved that senescent cells can be reverted, early termination of this reprogramming process is known to cause epigenetic dysregulation, resulting in dedifferentiated dysplastic cells such as renal cancer. Therefore, a novel therapeutic strategy without such critical limitations is highly needed. Cellular senescence is caused by complex interactions among biomolecules that govern cell cycle, DNA damage response, energy metabolism, and cytokine secretion. Recent studies showed that cellular senescence, previously considered as an irreversible biological phenomenon, can be reversed, but due to the nature of such complex interactions governing cellular senescence, the mechanism by which cellular senescence can be reversed has not been revealed.

Researchers reconstructed an ensemble of 5000 Boolean network models that can represent senescence, quiescence, and proliferation phenotypes by integrating information from the literature, network databases and phosphoprotein array data of dermal fibroblasts. In their models, cellular senescence is induced by simultaneous activation of DNA damage signal (doxorubicin) and growth signal (IGF-1 plus serum). They identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as the optimal protein target that can safely revert senescence to quiescence while avoiding uncontrolled proliferation, through extensive computer simulation analysis of the ensemble model. PDK1 forms a positive feedback structure along with AKT, IKBKB, and PTEN, that simultaneously control both nuclear factor κB, which controls cytokine secretion, and mTOR, which regulates cell growth.

In order to validate the simulation results, researchers conducted in vitro experiments and confirmed that when PDK1 was inhibited, various markers of cellular senescence are returned to normal and proliferation potential is restored. From wound healing assays and 3D reconstructed skin tissue experiments, they also reaffirmed that the reverted cells are able to respond appropriately to external stimuli. In particular, by observing dermal fibroblast within dermis along with keratinocyte within epidermis, 3D reconstructed skin tissue experiments verified that PDK1 inhibition promotes epidermal renewal and restores skin thickness, resulting in reversal of age-related skin degeneration.

The pituitary gland regulates numerous processes in the body via endocrine signaling. Of particular interest is the relationship between the pituitary gland and the thymus, which appear to influence one another via still poorly understood exchanges of signals. The thymus is of great importance to immune function, but atrophies with age. There is some data to suggest that provoking greater pituary gland activity can reverse that process, at least in mice. Researchers here provide evidence for the age related degeneration of the pituitary gland and its function in the body to be largely the consequence of rising systemic inflammation characteristic of aging. Interestingly, similar conclusions have been drawn for the aging of the thymus.

The pituitary gland is a small, globular gland located underneath the brain that plays a major role in the hormonal system. Due to the central role played by the pituitary, its ageing may contribute to the reduction of hormonal processes and hormone levels in our body - as is the case with menopause, for instance. A new study provides significant insight into the stem cells in the ageing pituitary gland. In 2012, researchers showed that a prompt reaction of stem cells to injury in the gland leads to repair of the tissue, even in adult animals. "As a result of this new study, we now know that stem cells in the pituitary do not lose this regenerative capacity when the organism ages. In fact, the stem cells are only unable to do their job because, over time, the pituitary becomes an 'inflammatory environment' as a result of the chronic inflammation. But as soon as the stem cells are taken out of this environment, they show the same properties as stem cells from a young pituitary."

This insight opens up a number of potential therapeutic avenues: would it be possible to reactivate the pituitary? This wouldn't just involve slowing down hormonal ageing processes, but also repairing the damage caused by a tumour in the pituitary, for example. The study also suggests another interesting avenue: the use of anti-inflammatory drugs to slow down pituitary ageing or rejuvenate an ageing pituitary. "Several studies have shown that anti-inflammatory drugs may have a positive impact on some ageing organs. No research has yet been performed on this effect in relation to the pituitary."

"Mice have a much greater regeneration capacity than humans. They can repair damaged teeth, for instance, while humans have lost this ability over the course of their evolution. Regardless, there are plenty of signs suggesting that pituitary processes in mice and humans are similar, and we have recent evidence to hand that gene expression in the pituitaries of humans and mice is very similar. As such, it is highly likely that the insights we gained in mice will equally apply to humans."

Link: https://nieuws.kuleuven.be/en/content/2021/pnas-main-gland-in-hormone-system-ages-due-to-process-that-can-potentially-be-slowed-down

Fasting produces benefits to health that are meaningful in comparison to the cost of this intervention - it is free, and the health benefits are reliable and repeatable. When it comes to improved metabolism and long-term health benefits, no medical technology is yet established to do better than the practice of intermittent fasting or calorie restriction in people without severe medical conditions. Senolytic therapies should hopefully greatly improve on this performance in older individuals, but that data has yet to emerge. As researchers point out here, fasting is not usually rigorously applied in medical practice. There are groups working on approaches, for example the fasting mimicking diet that is intended to set a standard for how to apply reduced calorie intake as a therapy. But more generally, much work is left to accomplish if fasting is to be integrated into medical practice in the same way as pharmacological approaches have been.

Recently, fasting has become one of the most compelling topics of the Nutrition Era. In the last five years, interest has passed from the Mediterranean to the Ketogenic Era, including the concept of caloric restriction and 'only water' fasting. Recently, research in animal models and humans has highlighted the potential health-promoting physiological responses to fasting including ketogenesis, hormone modulation, reduced oxidative stress and inflammation, and increased stress resistance, lipolysis, and autophagy. Although the panorama of evidence on fasting and caloric restriction is wide, there is a lack of a correct and safe fasting protocol to guide nutritionists and physicians in its application.

The act of fasting gained an increased focus in the scientific panorama thanks to several pieces of research developed around 30 years ago. The first studies referred to minor organisms and not directly to humans, because fasting and caloric restriction were considered tough interventions, combined with health risks if not adequately structured. Initially, studies on yeasts and murine models brought remarkably interesting results, later to be replicated in humans.

Some people, to be committed to their health, try adopting new habits as nutritional styles change. Nowadays, people are motivated by information from various sources: media, social networks, doctors, gyms, health coaches, and, simply, word of mouth and rumor. The accumulated information is not in line with scientific discoveries and safety protocols. Mere abstinence from food cannot result in efficacy if it is not well contextualized within a structured nutritional intervention. Fasting improves blood biomarkers for metabolic health, stress resistance, and suppresses inflammation. For example, most Westerners emulate their idols, picking up a fasting model that is supposed to help with losing and sustaining weight, keeping mentally sharp, and promoting longevity. Most of the time they do not experience the suggested benefits because of an unbalanced diet.

In the light of the above, the goal of our paper is to examine the context in which fasting could be practiced, and the most important discoveries in fasting used in pathological conditions such as chronic degenerative diseases. Moreover, it aims to offer to clinical experts in nutrition a specific guide to be consulted and personalized for each patient.

Link: https://doi.org/10.3390/nu13051570

It is possible in principle to organize low-cost human trials capable of providing potentially interesting data; much of the cost of formal clinical trials is unrelated to the essentials. The Lifespan.io staff and volunteers have demonstrated this point by successfully raising the modest amount needed to run a 200 person study of the impact of rapamycin use on aging-related biomarkers of health. Rapamycin inhibits mTOR, both the mTORC1 and mTORC2 protein complexes, which have different effects on metabolism. mTOR signaling is involved in the beneficial response to calorie restriction and upregulation of the cellular maintenance process of autophagy, and its inhibition extends healthy longevity in short-lived species such as mice.

The immunosuppressive effects of rapamycin, and a consensus that mTORC2 inhibition is probably undesirable, have led the research community to focus on building specific inhibitors of mTORC1, which are at various stages of clinical development. The the benefits to be obtained from the use of mTOR inhibitors are likely modest, less than those resulting from the actual practice of calorie restriction, but it is certainly the case that more human data is better than less human data. Further, the Lifespan.io study provides a good blueprint for later organizers who may wish to conduct low cost trials for more meaningful interventions, such as the established senolytic combination of dasatinib and quercetin.

PEARL Is Funded, Rapamycin Longevity Clinical Trials Begin

Today is a doubly important day: it marks the final day of the PEARL campaign and it is a celebration of another victory for the life extension community. PEARL smashed its initial fundraising goal and sailed through its two stretch goals, raising just under $183k thanks to the generous support of the community. The Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study, or PEARL, will launch the first large-scale placebo-controlled clinical trial to determine the effects of rapamycin on human aging. The principal investigator is Dr. James P. Watson based at UCLA.

Pearl: Participatory Evaluation of Aging with Rapamycin for Longevity

The PEARL trial will follow up to 200 participants over 12 months testing four different rapamycin dosing regimens. It will be double-blind, randomized, placebo-controlled and registered with clinicaltrials.gov. The principal investigator is Dr. James P Watson at UCLA, who was also a principle investigator for the famous TRIIM trial. To ensure safety the participants' blood will be regularly monitored and side effects noted.

A battery of tests and measurements will be taken, both after 6 and 12 months. These will include autonomic health tests, blood tests, body composition tests, fecal microbiome testing, immune and inflammation health tests, methylation age clock testing, and skeletal muscle tests. With your help we will find out if and how well rapamycin works to combat human aging. And, armed with a positive result, we will finally be able to help slow down onset of age related damage for you and those who you love and care about.

Senescent cell accumulation appears to be a major player in the pathology of most of the joint-related issues that occur in older individuals. Senescent cells secrete signals that provoke a state of chronic inflammation, alter nearby cell behavior, and disrupt tissue structure and maintenance. Clearance of these cells reverses numerous age-related conditions and measures of aging in mice. Hence the advent of senolytic therapies that selectively destroy senescent cells is a much anticipated development in medicine. Indeed, the first such therapies are pre-existing drugs, such as the dasatinib and quercetin combination, are already in human trials, producing promising initial data, and in principle available to any individual who can convince a physician to write an off-label prescription.

Aging is one of the major risk factors for degenerative joint disorders, including those involving the temporomandibular joint (TMJ). TMJ degeneration occurs primarily in the population over 65, significantly increasing the risk of joint discomfort, restricted joint mobility, and reduced quality of life. Unfortunately, there is currently no effective mechanism-based treatment available in the clinic to alleviate TMJ degeneration with aging.

We now demonstrate that intermittent administration of the senolytic combination of dasatinib and quercetin, which can selectively clear senescent cells, preserved mandibular condylar cartilage thickness, improved subchondral bone volume and turnover, and reduced Osteoarthritis Research Society International (OARSI) histopathological score in both 23- to 24-month-old male and female mice. Senolytics had little effect on 4 months old young mice, indicating age-specific benefits.

Our study provides proof-of-concept evidence that age-related TMJ degeneration can be alleviated by pharmaceutical intervention targeting cellular senescence. Since the senolytics used in this study have been proven relatively safe in recent human studies, our findings may help justify future clinical trials addressing TMJ degeneration in old age.

Link: https://doi.org/10.1111/acel.13394

Researchers here suggest that exercise interventions affect the turnover rate of senescent cells in older people, mostly likely by both reducing the pace at which cells become senescent, and improving the pace of clearance by the immune system. The size of the effect is modest, as one might expect, given that exercise cannot hold a candle to the benefits produced by senolytic drugs when it comes to reversing measures of aging in mice. This and other recent evidence increasingly suggests that individual senescent cells do not linger for very long in the body in later life. The observed accumulation with age is instead the outcome of a progressively growing imbalance between mechanisms of creation and mechanisms of destruction.

Cellular senescence has emerged as a significant and potentially tractable mechanism of aging and multiple aging-related conditions. Biomarkers of senescent cell burden, including molecular signals in circulating immune cells and the abundance of circulating senescence-related proteins, have been associated with chronological age and clinical parameters of biological age in humans. The extent to which senescence biomarkers are affected by interventions that enhance health and function has not yet been examined.

Here, we report that a 12-week structured exercise program drives significant improvements in several performance-based and self-reported measures of physical function in older adults. Impressively, the expression of key markers of the senescence program, including p16, p21, cGAS, and TNFα, were significantly lowered in CD3+ T cells in response to the intervention, as were the circulating concentrations of multiple senescence-related proteins. Moreover, partial least squares discriminant analysis showed levels of senescence-related proteins at baseline were predictive of changes in physical function in response to the exercise intervention.

Our study provides first-in-human evidence that biomarkers of senescent cell burden are significantly lowered by a structured exercise program and predictive of the adaptive response to exercise.

Link: https://doi.org/10.1111/acel.13415

Why does psychological stress cause an apparent acceleration of measures of aging? Effects on immune function have been considered, given that stress produces measurable changes in immune-affecting signaling and inflammation, as well as on the average telomere length in immune cells taken from blood samples. That metric indicates increased replication stress placed on immune cells. Telomeres, caps of repeated DNA at the ends of chromosomes, shorten with each cell division. When too short, somatic cells - such as immune cells - become senescent or self-destruct. Immune cell replication is governed by the response to invasive threats, driven by signals that are also triggered to some degree by psychological stress and the molecular damage of aging.

The accumulation of senescent cells is a meaningful cause of aging. Even in late life, their numbers appear to be quite dynamic, but the rate of creation is raised and the rate of clearance by the immune system is reduced. Senescent cells secrete a mix of signals that provokes chronic inflammation and numerous forms of changed cell behavior that cause tissue dysfunction. Clearing senescent cells in mice results in a sizable degree of rejuvenation, achieved quite rapidly. Senescent cells actively maintain a distorted, dysfunction state of metabolism, and removing them is an important goal.

Here researchers provide concrete data for the effects of stress on the aging of the brain to involve an increased generation of senescent cells. In recent years, researchers have demonstrated that senescent supporting and immune cells in the brain are an important cause of neurodegeneration, with benefits achieved in mouse models via clearance of senescent cells. One can begin to form a hypothesis in which any situation in which immune cells are pressured into greater replication, such as persistent infection, presence of molecular waste such as amyloid-β, or psychological stress, will increase the number of problem senescent cells in the brain, thus contributing to neurodegeneration.

Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress

When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. Recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging.

We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16INK4a was increased in the hippocampus, and senescence-associated β-galactosidase (SA-β-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-β-gal or p16INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits.

Our data suggests that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline. Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits.

First generation mesenchymal stem cell therapies have been shown over the years to fairly reliably suppress chronic inflammation for some time, whether disease-associated or aging-associated. The transplanted cells die quickly, but the effects of their brief burst of signaling can last for months. Other intended benefits, such as increased regeneration or function, are in comparison unreliable at best. In part the challenge is that there is no standard in this part of the field, every clinic uses different methodologies and cell sources. These differences appear to matter greatly, and the fine details of why they matter greatly remain poorly cataloged and poorly understood.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can be isolated from the bone marrow, adipose tissue, dental tissues, skin, salivary gland, limb buds, menstrual blood, and perinatal tissues. Although MSCs do not differentiate into immune cells, MSCs provide a supporting microenvironmental niche for hematopoietic stem cells (HSCs) to differentiate into myeloid and lymphoid cells, which are essentially the immune cells. One of the speculated theories of declining immunity as the host ages is the MSC senescence. Subsequently, the functions and structures of MSCs, which are significant in maintaining the immune system, diminishes.

Numerous studies have proven that MSCs have low immunogenicity, excellent immunomodulatory function, and homing capability to regenerate damaged tissues through multipotent differentiation and paracrine secretion. Despite that, current studies are not primarily focused on aging or the restoration of the immune system. There have been extensive studies conducted on pathological conditions than actual aging itself. Aging and MSC were studied separately, but the similarities of the immune markers involved may come into convergence. The proliferative capacity and immunomodulatory function of MSCs could aid in the restoration of the immune cells and reduce the pro-inflammatory markers since these parameters are observed in aging as well. MSCs might not be a permanent solution to restore a healthy cell population, however. MSCs may have been seen as effective in past studies due to their paracrine effects but not cell replacement. This may explain the relatively fast drop in the inflammatory state when MSC therapy commences.

Some evidence shows that the ameliorating effects of MSCs on the immune system are not due to direct engraftment and cell replacement, but rather paracrine manner and direct cell-to-cell contact. MSCs secrete soluble paracrine factors and express IL-10, which is an anti-inflammatory and immunoregulatory cytokine. Furthermore, they produce IL-6 and IL-8, which are known to be associated with MSC tissue repair potential. Subsequently, MSCs control the inflammatory state as evidence of the reduced expression of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and CRP. Moreover, MSC-secreted TGF-β has a role in macrophage polarization towards the M2 phenotype. These M2 macrophages stimulate the expression of IL-10, which alleviates inflammation. The mechanism of action of MSCs on the immune system is not constitutively inhibitory, but is acquired after exposure to the inflammatory environment with IFN-γ. IFN-γ is one of the cytokines released by T cytotoxic cells during inflammation. Therefore, in Th17 centered inflammatory response, MSC treatment would require the addition of regulatory T cells to successfully regulate the inflammation.

Immunosenescence is an inevitable phenomenon that involves the remodeling of the immune system with age. This complex interaction between the age-accumulated insults, aged HSCs bias to myeloid cells, and both the innate and adaptive immune system results in a chronic, subclinical systemic inflammation termed as 'inflammaging'. The individuals over 65 years old have increased risk of infection, cancer, higher morbidity, and mortality of disease, and reduced vaccine efficacy. Currently, there are no effective countermeasures available to ameliorate immunosenescence. MSC therapy is a promising modality to rejuvenate the aged immune system. As of now, studies have shown that MSCs can safely reduce the inflammatory markers, restore the T cell repertoire, and improve the histopathology of inflammatory disease.

Link: https://doi.org/10.3390/ijms22115749

Researchers here suggest that the combined effects of mitochondrial dysfunction and lysosomal dysfunction in long-lived cells in old brains lead to a leakage of mitochondrial DNA into the body of the cell, where it provokes maladaptive inflammatory reactions that continue to the onset and progression of neurodegenerative conditions such as Parkinson's disease. The data is interesting, but needs confirmation in more relevant models than those used to date. The challenge with research into the mechanisms of neurodegeneration is that the animal models are highly artificial. They have relevance to the mechanism under study, but are by no means a reflection of the human condition. At the present time there really is no practical way to show true relevance other than by putting a therapy into people.

A novel finding utilizing cellular and zebrafish models has demonstrated how the leakage of mitochondrial dsDNA into the cytosol environment of the cell can contribute to the impairment of brain tissue of patients with Parkinson's disease (PD). "Our results showed for the first time that cytosolic dsDNA of mitochondrial origin leaking and escaping from lysosomal degradation can induce cytotoxicity both in cultured cells, as well as in zebrafish models of Parkinson's disease. This study showed that the leakage of this mitochondrial nucleic material may occur as a result of mitochondrial dysfunction, which may involve genetic mutations in genes encoding mitochondrial proteins or incomplete degradation of mitochondrial dsDNA in the lysosome - which is a 'degradation factory' of the cell. Upon the leakage into the cytoplasm, this undegraded dsDNA is detected by a 'foreign' DNA sensor of the cytoplasm (IFI16) which then triggers the upregulation of mRNAs encoding for inflammatory proteins."

Using a PD zebrafish model (gba mutant), the researchers demonstrated that a combination of PD-like phenotypes including accumulation of cytosol dsDNA deposits, reduced number of dopaminergic neurons after 3 months. Lastly, they further generated a DNase II mutant zebrafish model which exhibited decreased numbers of dopaminergic neurons and demonstrated accumulated cytosolic DNA. Interestingly, when the gba mutant zebrafish was complemented with human DNAse II gene, the overexpression of human DNAse II decreased cytosolic dsDNA deposits, rescued neuro-degradation by rescuing the number of dopaminergic and noradrenergic neurons after 3 months. This demonstrated that neurodegenerative phenotype of gba mutant zebrafish induced by dsDNA deposits in the cytosol can be restored by DNAse II.

In a step further, to determine the effect of cytosolic dsDNA of mitochondrial origin in human brain with PD, researchers inspected postmortem human brain tissues from patients who were diagnosed with idiopathic PD. They observed abundance of cytosolic dsDNA of mitochondrial origin in medulla oblongata of postmortem brain tissues, the levels of IFI16 were also markedly increased in these brain tissues.

Link: https://www.eurekalert.org/pub_releases/2021-06/nu-nsg061021.php

Is it possible to safely introduce developmental signaling characteristic of the developing embryo and fetus into an aged adult in order to spur greater regeneration of tissues? The past decades of work on embryonic stem cell therapies and induced pluripotent stem cell therapies, and the slow investigation of how most of these therapies produce their benefits via cell signaling, suggest that this goal is in principle possible. Similarly, research into species capable of proficient regeneration, such as salamanders and zebrafish, suggests broad similarities between the biochemistry of organ development and the biochemistry of organ regrowth.

The issue for we mammals has all along been the question of cancer. Would developmental signaling result in an unacceptable cancer risk, either by directly breaking regulatory systems important in tissue maintenance, or by forcing greater cell activity in an environment of age-related damage?

Researchers continue to investigate the mechanisms of stem cell therapies, the contents of pro-regenerative extracellular vesicles and their effects on bystander cells, and partial cell reprogramming in vivo. As this work progresses, numerous potential approaches are arising to the delivery of specific developmental signals. The paper here takes a look at one very narrow slice of this part of the regenerative medicine field, what is know of developmental peptide signals, and particularly thymosin beta-4, that might be exploited to boost adult regeneration in later life.

Utilizing Developmentally Essential Secreted Peptides Such as Thymosin Beta-4 to Remind the Adult Organs of Their Embryonic State - New Directions in Anti-Aging Regenerative Therapies

Reversing age-related alterations of the body is a long-desired goal of humankind. Despite the extravagant premise, the dream of returning to our youth may not be so far-fetched. Nature actually provides an enormous list of molecules, some of which are silenced after birth but could serve as a potential treatment to reverse age, at least at the level of a single yet complicated organ such as the heart. The question remains: can postnatal increase of developmentally relevant proteins and peptides reverse organ ageing or damage in a beneficial way? We believe the answer to this question is yes. In our earlier research, we introduced a naturally secreted small molecule, Thymosin beta-4 (TB4), which is capable of such miracles not only regarding the heart but in the brain and kidneys.

TB4 was first purified from the thymus and binds and alters the cytoskeletal actin filaments by sequestering actin monomers and in doing so, influences actin filament assembly and regulates migration of various cell types such as endothelial cells, myocardial cells, or epicardial progenitors. It equally inhibits cellular death by activating and binding numerous players in the focal adhesion complex, which, eventually, results in the activation of Akt, a proven substrate of ILK with wide-ranging signalling functions that affect growth, survival, and motility. Naturally, all the other mechanisms by which TB4 initiates the increase of cardiac function are still under investigation by a host of scientists worldwide. Undoubtedly, its capability in activating the adult epicardium and its ability to resemble its embryonic function without risking injury suggests grounds for hope that the molecule does achieve the same in other organs.

Reminding adult cells of their highly proliferative state is not without risk, as the applied treatment may easily result in unwanted malignancies. Although TB4 was reported to be a prognostic marker for highly metastatic cancer states and its tumor promo-ting properties were equally demonstrated, its true nature regarding tumorigenesis is controversial. In our hands, the molecule significantly inhibited the progression of pancreatic cancer following systemic administration in mice in vivo. An additional factor supporting this result is that TB4 was equally introduced as a candidate tumor suppressor in male breast cancer and was demonstrated to have a tumor suppressive function in myeloma development by other research teams. In addition, the high safety profile observed in Phase I and Phase II clinical trials this far strongly anticipate that TB4 will be safe and efficacious at the applied local or systemic dose for broad clinical applications in the future.

We still do not know all the details regarding this special molecule; however, we genuinely believe there are more like it concealed in the human body, awaiting discovery. With their help, we may be capable of fulfilling our dream of reversing age.

Researchers here discuss the ongoing development of biomarkers of aging and age-related disease based on glycosylation of proteins, the attachment of a glycan to a protein. Various forms of post-translational modification occur to proteins throughout the body, changing their function, and are, to varying degrees on a case-by-case basis, necessary, tolerated, problematic, and targeted for removal by cell maintenance processes. These processes shift in response to the metabolic changes of aging, and at least some of them may useful as metrics of age-related degeneration and risk of age-related disease. At least one company, GlycanAge, works in this space, and there will likely be other similar efforts in the future.

Protein glycosylation is the biochemical process for which a carbohydrate molecule is covalently attached to a protein functional group. In biology, glycosylation mainly refers to the enzymatic process that binds glycans to proteins, affecting intracellular processes like folding and transport, and playing an important role in many cellular signaling and communication events.

Three major n-glycan structures present in human blood glycoproteins (serum, plasma, and immunoglobulins fraction) have shown clear changes with ageing. Agalactosyl n-linked oligosaccharides (NG0A2F and NG0A2FB) increase with age whereas core-fucosylated biantennary n-glycans (NA2F) decrease with age. A similar trend was observed in a study which aimed to evaluate the effects of the age and gender on the human serum n-glycans profiles: NGA2F and NGA2FB increased gradually with ageing whereas NA2F decreased. Additionally, before the age of 50 years these three glycans changed only slightly with age, but the difference between age groups 41-50 and 51-60 years was statistically significant, indicating that the age-related physiological changes occurred in the fifties.

An ageing biomarker named GlycoAgeTest has been developed, which could possibly forecast disease progression during ageing. This marker is the log of the ratio of two glycans (NGA2F and NA2F), which remains steady up to the age of 40 years and thereafter gradually increases to reach its highest level in nonagenarians. Furthermore, patients with dementia or Cockayne syndrome have shown to have a higher GlycoAgeTest level than age-matched healthy individuals. It was concluded that the value of GlycoAgeTest is better than chronological age for estimating the physiological age of a human individual, and that it could be used as an ageing biomarker for healthy humans.

Glycome analysis is emerging as a source of potential biomarkers in different pathological states. Its analysis is not easy, as the diverse structures of glycans are complex and heterogenic. Moreover, there is a wide range of possible monosaccharide combinations and linkages, that result in structurally complex glycans, which can be attached to proteins, conforming glycosylation post-translational modifications. In clinical studies, the comparison of glycans levels altered in specific diseases often leads to inconsistent results, which cannot be explained completely by the different statistical methods. This may be due to the diversity of the glycome in different populations and even in different environments. Furthermore, the use of a wide range of glycomic methodologies leads to low comparability between studies which hinders the production of clear results.

Link: https://doi.org/10.3390/ijms22115788

Some years back, the Methuselah Foundation partnered with NASA to launch the Vascular Tissue Challenge, to attempt to spur greater efforts on the part of research groups and companies working on the production of vascularized tissue. The presence of a sufficiently small-scale, dense vascular network is the limiting factor in the size of engineered tissue that can be produced via techniques such as bioprinting. Absent a capillary network, nutrients can only perfuse a few millimeters into solid tissue. Building a life-like vasculature of hundreds of tiny capillaries passing through every square millimeter of tissue in cross-section has proven to be a challenge, but one that numerous teams are now making meaningful progress towards solving.

Methuselah Foundation, which co-sponsored the Vascular Tissue Challenge with NASA, today announced the award-winning researchers achieved scientific breakthroughs that promise to dramatically change the future of human health. The first and second place Challenge winners announced by NASA today are the first scientific teams to engineer and sustain thick functioning human tissue in a lab. The Challenge, first conceived by Methuselah Foundation in 2013, was conducted to increase the pace of bioengineering innovations to benefit humans on Earth and future space explorers.

Eleven teams competed in the Challenge to produce an in-vitro, vascularized organ tissue that is more than 1 centimeter thick. Winning tissue had to provide adequate blood flow and survive at least 30 days. The first-place winner was Team Winston from the Wake Forest Institute for Regenerative Medicine, affiliated with Wake Forest School of Medicine. The team, led by Dr. James Yoo, was awarded $300,000. It will also receive $200,000 from CASIS (Center for the Advancement of Science in Space), to fund the cost of conducting a tissue generation experiment in zero gravity.

The second-place winner was Team WFIRM, also from the Wake Forest Institute for Regenerative Medicine. That team, led by Dr. Anthony Atala, was awarded $100,000. Both groups created lab-grown human liver tissues that were robust enough to survive and function like healthy liver tissue found inside our bodies. Winning entries were built using 3D printing technologies. Ongoing progress will ultimately enable physicians to 3D print human organs with a patient's unique DNA.

Link: https://www.prnewswire.com/news-releases/nasamethuselah-challenge-winners-make-history-by-engineering-sustaining-live-human-tissue-in-a-laboratory-301309212.html

The short version of the story regarding the failure of resTORbio's phase 3 trial of an mTORC1 inhibitor targeting immune function and influenza infection in old people is that the FDA forced a last minute change of the phase 3 endpoint from the phase 2 endpoint of a reduction in clinically confirmed infections to a more nebulous outcome of whether or not people reported feeling better. Which is far from the worst offense that FDA staff have committed in the course of hindering the adoption of new medical technologies, but it is illustrative of the obstacle that regulators pose. We can all speculate as to what was going on under the hood here, and which influences led to this outcome.

To my eyes, the field of mTOR based therapies remains something of a sideshow when it comes to human aging and longevity. The same is true of many of the metabolic manipulation approaches based on upregulation of stress response mechanisms. These mechanisms are known to produce sizable effects in short-lived species, but not in long-lived species such as our own. Thus here, mTORC1 inhibition does not produce a startling and large effect on infection rate and immune function, and nor should we expect it to, but it is cheap and it does produce some effect. mTORC1 inhibition replicates a thin slice of the beneficial calorie restriction response, and we know what calorie restriction can achieve in humans; this sort of approach isn't the path to very large gains.

We did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65-85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had an emergency room or hospitalisation for a respiratory tract infection (RTI) within the past 12 months. In the phase 3 trial, patients were aged at least 65 years, did not have COPD, and were not current smokers.

In the phase 2b trial, patients were randomly assigned to using a validated automated randomisation system to oral RTB101 5 mg, RTB101 10 mg once daily, or placebo in part 1 and RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus once daily, or matching placebo in part 2. In the phase 3 trial, patients were randomly assigned to RTB101 10mg once daily or matching placebo. The phase 2b primary outcome was the incidence of laboratory-confirmed RTIs during 16 weeks of winter cold and influenza season and the phase 3 primary outcome was the incidence of clinically symptomatic respiratory illness defined as symptoms consistent with an RTI, irrespective of whether an infection was laboratory-confirmed.

The purpose of our trials was to investigate whether targeting ageing biology with mTOR inhibitors could improve immune function and decrease the incidence of RTIs in older adults at doses that were well tolerated. The mTOR inhibitor RTB101 10 mg once daily for 16 weeks was well tolerated in adults aged at least 65 years, increased expression of IFN-stimulated antiviral genes in peripheral blood, and decreased the incidence of laboratory-confirmed RTIs (the phase 2b primary endpoint), but not the incidence of clinically symptomatic respiratory illness defined as respiratory symptoms consistent with an RTI irrespective of whether an infection was laboratory confirmed (the phase 3 primary endpoint).

Several possible explanations exist for the divergent results of the phase 2b and phase 3 trials, including the change in primary endpoint and changes in the way respiratory symptoms were collected between the two trials. In the phase 2b trial, respiratory illness symptoms were collected during twice weekly telephone calls with patients and the primary endpoint required predefined symptomatic criteria to be met as well as laboratory confirmation of an infection. In the phase 3 trial, respiratory illness symptoms were collected in eDiaries that patients filled out each evening and the primary endpoint was based on symptoms alone without requiring laboratory confirmation of an infection. Multiple investigators in the phase 3 trial anecdotally noted that patients reported in their nightly eDiary respiratory illness symptoms such as cough or headache that were part of the prespecified diagnostic criteria for a clinically symptomatic respiratory illness even when the patient and the investigator did not think that the patient had an RTI.

Despite the negative phase 3 results, important lessons were learned from this clinical development programme that is the largest to date targeting ageing biology in humans. First, the results show that it is possible to target mechanisms underlying ageing biology safely with therapies such as mTOR inhibitors in older adults. Second, the results suggest that therapies that target ageing biology in older adults might ameliorate at least some aspects of ageing organ system dysfunction (such as deficient IFN-induced antiviral responses). Further refinement of clinical endpoints and more precise identification of responder patient populations will be important in future trials of therapies that intervene in ageing biology to improve immune function in older adults.

Link: https://doi.org/10.1016/S2666-7568(21)00062-3

Somatic cells become senescent after reaching the Hayflick limit on replication. In the case of immune cells, that occurs more often in scenarios of infection or tissue damage that provoke an immune response and hence faster pace of replication. The central nervous system immune cells known as microglia are known to exhibit senescence in later life and neurodegenerative conditions, and the targeted elimination of these cells via senolytic therapies has been shown to reverse symptoms in animal models of these conditions.

Senescent cells secrete a mix of signals that produces chronic inflammation and disrupts tissue function; their presence is an important contributing cause of many age-related declines. Researchers here propose that replicative senescence of microglia is the connects forms of molecular damage and infection linked to Alzheimer's disease and the presence of senescent microglia that accelerate the condition. In other words that the immune response and increased pace of replication of microglia is an important factor in neurodegeneration.

The re-activation of microglial proliferative programs is the earliest response to pre-pathological events in chronic neurodegenerative diseases, with microglial proliferation increased in Alzheimer's disease (AD). Microglia have a very rapid proliferative response to the incipient accumulation of amyloid-β, during the onset of tau pathology, and in several other related models of neurodegeneration. We and others have demonstrated that the proliferation of microglia is a central contributor to disease progression. The inhibition of microglial proliferation, using CSF1R inhibitors, ameliorates amyloid and tau pathology, and has emerged as a promising target for clinical investigation.

Integrating our knowledge of microglial population dynamics renders an interesting hypothesis. When combined, the cycling events accumulated in microglia from development to disease would put these cells on a trajectory toward cellular senescence. Replicative senescence, the loss of mitotic potential accompanied by significant telomere shortening, occurs once a cell has undergone ∼50 replications, the so-called Hayflick limit. Thus, we hypothesized that the developmental setup of the population, combined with microglial turnover, would pre-condition these cells to undergo replicative senescence when challenged with additional proliferative events (i.e., as a consequence of brain pathology).

Some reports suggest that microglia show telomere shortening and decreased telomerase activity in both aging and end-stage AD. However, to date, no formal evidence has been provided supporting the idea that these progressive changes in the dynamics of microglia are driving the shift of the microglial response from beneficial to detrimental and therefore contributing to the initiation of AD.

Here, we provide evidence that microglia undergo replicative senescence in a model of AD-like pathology and in human AD. We demonstrate that microglia display a senescence-associated profile and that this is dependent on proliferation. Our data support that the early generation of senescent microglia contributes to the subsequent onset and progression of amyloidosis, as well as the associated neuritic damage that is observed in the early stages of AD.

Link: https://doi.org/10.1016/j.celrep.2021.109228

As the COVID-19 pandemic ran its course, and it became clear that mortality in the old and the obese was the result of a cytokine storm, there was some speculation that the use of senolytics to clear senescent cells from old tissues would be an appropriate treatment to reduce mortality. Here, researchers provide supporting evidence for this view, showing that senolytic treatment in old mice reduces coronavirus mortality, as well as mortality due to other viral infections.

The risk of suffering a fatal inflammatory event as the result of infection is higher in individuals with an existing high level of systemic inflammation - due to, for example, the accumulation of senescent cells in the body that occurs in later life. Senescent cells secrete pro-inflammatory signals that are an important contributing cause of the chronic inflammation of old age, as well as the raised inflammation that accompanies obesity.

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-senescent cells through a paracrine mechanism.

Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting senescent cells using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the senescent cell burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

Link: https://doi.org/10.1126/science.abe4832

It is not particularly controversial to say that aging causes Alzheimer's disease, at least in the most common version of the condition in which there is no gene variant known to accelerate pathology. How exactly aging causes Alzheimer's disease is very much debated, however. This is not unusual; most age-related conditions have the same issue and the same debate.

The end stage pathology of age-related conditions is fairly well mapped, and we have a good idea as to what the root causes of aging are, the forms of damage and disarray that accumulate as a result of the operation of a normal metabolism. In between what is known of the cause and what is known of the end result, the map is poor at best, however. Drawing clear lines of cause and effect between those two areas of study remains very challenging. The operation of metabolism is ferociously complex, and deciphering cause and effect in a network of interacting processes is not as easy as one might think.

It is likely the case that even when the first body of rejuvenation therapies based on periodic repair of root cause damage exists and is widely used, there will still be debate and investigation over how exactly the processes of aging combine to cause the more complicated age-related conditions.

When aging switches on Alzheimer's

Aging increases the risk for developing Alzheimer's disease (AD). Pathological hallmarks of AD include abnormal deposits of extracellular beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles, which are proposed to impair synaptic function to foster progressive cognitive impairment. Although aging and AD undeniably share a number of common features, such as oxidative stress, mitochondrial impairment, bioenergetic, and metabolic shifts, AD is not the inevitable co-morbidity of aging. This escape from AD arouses hope that anti-aging interventions could decelerate aging switches for AD dementia.

Our environment, lifestyle, stress, physical activity, and habits all modulate epigenetic control of gene expression for continuous environmental tracking. Age-related redox stress, often measured as oxidative stress in aging and AD, launches a global switch in the epigenetic landscape, widely affecting methylation, histone modification, and noncoding RNA regulation, to further drive downstream metabolic and energetic shifts.

According to a modified amyloid cascade hypothesis, amyloid-mediated oxidative stress triggers a cascade of downstream effects including mitochondrial dysfunction, excitotoxicity, synaptic loss, and neuroinflammation. However, the failure of anti-amyloid and anti-inflammatory therapy in clinical trials allows us to entertain other causal possibilities including an age-related oxidative redox shift as an upstream switch that changes amyloid processing, deposition, or clearance. Intriguingly, some resilient older individuals present with similar loads of Aβ and tangles compared to AD cases without experiencing dementia.

Further studies in resilient brains point out distinct upregulation of anti-inflammatory cytokines in entorhinal cortex, increased expression of neurotrophic factors and reduced expression of chemokines linked to microglial recruitment, which all suggest activated neuroglial inflammation in non-resilient AD. Since inflammation is switched on by an oxidative redox state, normal microglia that selectively remove excitotoxic synapses could be over-activated toward inflammatory neurodegeneration in AD. Suitable redox markers could enable measured redox therapies to decelerate inflammation and the neurodegenerative cascade.

There has been some research into the use of ultrasound for short-term disruption of the blood-brain barrier, to allow medication through without excessive delivery of unwanted materials into the central nervous system. In the course of this line of work, researchers observed that ultrasound treatments resulted in improved cognitive function in mice. Here, it is suggested that this has nothing to do with the blood-brain barrier effects, but instead it is in some way upregulating neurogenesis, the production of new neurons and their integration into neural circuits in memory-related areas of the brain. The present view on neurogenesis is that more of it would be a good thing, even in youth, and the decline of neurogenesis with age is an unfortunate outcome that should be prevented. Might suitable ultrasound treatments have a large enough effect to matter in humans? Perhaps; it is certainly an interesting proposal.

The idea that sound waves knocking at the skull could boost memory continues to sound far-fetched to many Alzheimer's researchers, but researchers report that scanning ultrasound improved synaptic signaling, increased neurogenesis, and sharpened spatial memory in old wild-type mice. Importantly, this worked without breaching the blood-brain barrier, a commonly used ultrasound trick to provoke a brain response. Whether this technique is appropriate for people remains to be seen, though early stage clinical trials in older adults indicate it may be safe.

Previous work had suggested ultrasound somehow opens TRPA1 calcium channels in astrocytes, which then release glutamate to activate NMDA receptors on nearby neurons. Researchers looked for signs of astrocyte-mediated activation in mouse hippocampal tissue via Western blots, and found that tissue from mice exposed to ultrasound contained more TRPA1 than tissue from control.

Evidence of NMDA activation came when the scientists separated hippocampal tissue into total and postsynaptic fractions. In the postsynaptic fraction, ultrasound had bumped up the amount of NR2B, a subunit of NMDA receptors that is needed for long-term potentiation (LTP), a form of synaptic plasticity. LTP is crucial for learning and memory and by 20 months of age, it has faded. However, the scanning ultrasound had restored LTP in aged mice, as judged by evoked potentials in hippocampal slices. Based on dentate gyrus expression of doublecortin, a marker of new neurons, the authors concluded that ultrasound upped neurogenesis 13-fold. The scientists did not track how long the memory changes lasted. "Because there are changes at the NDMA receptor level, my gut feeling is that ultrasound leads to long-lasting changes."

Link: https://www.alzforum.org/news/research-news/no-breach-needed-ultrasound-improves-memory-mice

Kidney function is very important to long-term health, influencing the operation of other organs. This is well illustrated by research into klotho, a longevity associated gene that appears to primarily function in the kidney, yet improves numerous measures of cognitive and cardiovascular aging when highly expressed. Here, researchers show that epigenetic age acceleration, in which epigenetic age is higher than chronological age, is associated with worse kidney function. Epigenetic age is in effect an assessment of cellular reactions to the aged tissue environment of damage, dysfunction, and altered signaling, and it is interesting to see it reflect kidney function in this way.

The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.

We identified 23 significant associations in our large trans-ethnic meta-analysis with a consistent direction of effect across studies. Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as the 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate).

Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging, and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

Link: https://doi.org/10.1186/s13148-021-01082-w

Aging is poorly defined as anything other than an outcome, as is pointed out in today's open access paper. Aging is the rise in mortality risk due to intrinsic causes over time, a definition that is hard to argue with, but that provides next to no insight. There are more complicated and detailed definitions, but near all are all quite similar in being a catalog of symptoms rather than a catalog of processes. The SENS view of aging, on the other hand, is in fact a list of causative processes, but is by no means widely agreed upon, nor expected to remain unchanged by later data.

Definitions of aging that are in effect a taxonomy, in the sense that we put these humans into the "old" bucket because they exhibit measurable symptoms A through Z, are really not helpful at all when it comes to the development of therapies to treat aging. One needs to know what to target. What processes must be interrupted? What damage must be repaired? This is the entire point of the SENS view of aging: that we need this description of aging as a set of processes, rather than as a set of symptoms, in order to even start building effective rejuvenation therapies.

Sadly, validating a consensus definition of aging is only going to be achieved via the production of working rejuvenation therapies. If one repairs a form of damage and that actually works to produce rejuvenation, then that is supportive of definitions of aging that include that specific form of damage. It seems likely to me that there will be active debate over the causes of aging all the way through the process of producing a first generation package of good-enough rejuvenation therapies that adds decades to healthy life spans. That active debate will take place alongside a great deal of wasted research and development effort, as people attempt to validate incorrect approaches.

The SENS view of aging is very important, not just because its conclusions as to areas of study and forms of therapy seem likely to be the best way forward to practical human rejuvenation, but also because, philosophically, everyone else should stop building taxonomies of aging and start thinking about causes and processes of aging. It will be a messy process all the way from here to the goal of physical immortality and medical control of aging, but it seems that there could be a lot less wasted effort along the way than is presently the case. Incidentally, the paper noted here starts off well, and is an interesting read, but then falls into the pit of suggesting that aging is an intrinsic property of life, and thus not amenable to effective treatment.

An essay on the nominal vs. real definitions of aging

Several recent publications, including the one entitled "What if there is no such thing as aging?", have brought out an astonishing trend: the mere existence of biological aging is being questioned. The title reiterates the famous proposition "There is no such thing as aging and cancer is not related to it", and the paper suggests that the same is relevant to the other age-associated conditions: "...we are not studying a single biological phenomenon, but an assortment of loosely related processes that we find convenient to lump together"; ultimately, "... the concept of aging does not reflect any underlying biological reality".

Being intentionally provocative, the paper does however reflect the trend, which is developing, paradoxically, in parallel with the increasing prevalence of aged people in the world and with the recently emerged discipline called "geroscience". According to the geroscience agenda, the best way to combat the most prevalent age-associated conditions, such as atherosclerosis, cancer, type II diabetes, and neurodegeneration, is to target their common risk factor rather than each of the conditions specifically. The common risk factor is aging.

Apart of that the very practice of piling up of newly invented scientific disciplines and respective terms is questionable, a problem with the geroscience agenda relates to the feasibility of evaluating the benefits of its implementation. The benefits of targeting of a disease may be evaluated, based on its commonly accepted definition (diagnostic criteria), as a decrease in the incidence of cases recognized according to this definition. Can we decrease the incidence of aging otherwise than by making people dead before they get old? Any answer to this question depends on the criteria used to distinguish (i) aging from all the rest that may occur to living bodies and (ii) living bodies from all other kinds of bodies, in other words, on the definition of (biological) aging. The lack of consensus on the definition of aging is long recognized and has recently been highlighted by asking several basic questions about aging to recognized authorities in aging research. Answers to each of the questions differed up to antipodal extremes.

Based on several scores of definitions found in the most highly cited (that is the most representative and influential) papers on aging, the following features commonly used to define aging have been distinguished: (1) structural damage, (2) functional decline, (3) depletion of a reserve required to compensate for the decline, (4) typical phenotypic changes or their cause, and (5) increasing probability of death. Noteworthy, these characteristics are not really five definitions of aging, but rather five defining features of aging. This the above inventory to the kind of definitions that in philosophy of science is known as "nominal" and is opposed to "real"

By its nominal definition, water is a colorless and odorless liquid having defined specific gravity, viscosity etc. By its real definition, water is a compound comprised of two hydrogen atoms and one oxygen atom connected in a certain order. Noteworthy, the real definition is senseless for people ignorant of atoms. Likewise, the nominal definition of aging as a set of observable features should be supplemented, if not replaced, with its real definition. The latter is suggested here to imply that aging is the product of chemical interactions between the rapidly turning-over free metabolites and the slowly turning-over metabolites incorporated in macromolecules involved in metabolic control.

The phenomenon defined in this way emerged concomitantly with metabolic pathways controlled by enzymes coded for by information-storing macromolecules and is inevitable wherever such conditions coincide. Aging research, thus, is concerned with the elucidation of the pathways and mechanisms that link aging defined as above to its hallmarks and manifestations, including those comprised by its nominal definitions. Esoteric as it may seem, defining aging is important for deciding whether aging is what should be declared as the target of interventions aimed at increasing human life and health spans.

Here is a theory as to why, in this era of rejuvenation research and a growing longevity industry, most people continue to say that they would not wish to take advantage of medical technologies that allowed for a radical life extension of decades or centuries. We as a species discount the value of future gains quite aggressively. Being alive and in good health three decades from now is just not worth that much to the processes in our minds that assess values and balance them against actions and goals. Conforming to common behaviors in the primate hierarchy here and now, such as by not saying things that are too far out of the ordinary for one's demographic and peer group, will tend to win out. Most people will value present declarations of conformity more than they value any future gain in health and longevity.

Biomedical technology holds the promise of extending human life spans; however, little research has explored attitudes toward life extension. Investigated attitudes toward life extension about young adults, younger-old adults, and older-old adults. This survey asked young adults (n = 593), younger-old adults (n = 272), and older-old adults (n = 46) whether they would take a hypothetical life extension treatment as well as the youngest and oldest age at which they would wish to live forever.

Age cohorts did not vary in their willingness to use life extension; however, in all three age cohorts, a plurality indicated that they would not use it. Men indicated a higher level of willingness to use the life extension treatment than women. Younger-old and older-old adults indicated that they would prefer to live permanently at an older age than younger adults. If a life extension treatment were to become available that effectively stopped aging, young adults may be likely to use such a treatment to avoid reaching the ages at which older cohorts say they would prefer to live forever.

Link: https://doi.org/10.1016/j.jaging.2021.100931

While it may or may not turn out to hold true for every stem cell population in the body, there is a fair amount of evidence for muscle stem cells to remain competent and in principle capable of maintaining tissue well into later life. The loss of function that we observe in muscle tissue in old age is much more a matter of inactivity rather than incapacity. This inactivity may be an evolved response to a damaged environment, lowering cancer risk at the expense of a slow decline into frailty, or it may be the consequence of age-related molecular damage rising to pathological levels in the stem cell niche tissue, or both. That stem cells remain capable in old tissue suggests a shorter path to useful regenerative therapies - building treatments that work by rousing existing cells to action, rather than having to deliver new cells.

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration.

In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.

Link: https://doi.org/10.1111/acel.13411

A few years back, researchers noted that a common growth hormone receptor gene variant was associated with greater life expectancy in humans. There was some theorizing as to possible mechanisms at the time, following the usual paths for anything that touches on growth hormone or its receptor. In short-lived mammals such as mice, loss of function in growth hormone or its receptor produces small body size and increased healthy longevity. The present record for mouse longevity is held by a growth hormone receptor knockout lineage. In humans, members of the small Laron syndrome population exhibit an analogous disruption of growth hormone metabolism, and while there are signs that they might be more resistant to some forms of age-related disease, they do not live notably longer than the rest of us. It is usually the case that metabolic alterations of this nature, in this part of metabolism, have large effects in short-lived species and much smaller effects in long-lived species.

Given the example of Laron syndome to suggest that the usual explanations regarding growth hormone metabolism may not be useful here, how might variants in the growth hormone receptor gene actually produce an effect on human longevity? Researchers have been working to answer that question, and in today's open access paper it is proposed that some variants reduce the negative impacts of raised blood pressure, or hypertension. Blood pressure is very influential on health and mortality in later life. Raised blood pressure causes damage to delicate tissues in organs throughout the body, and particularly in the brain. It also accelerates the progression of atherosclerosis, and makes it more likely that atherosclerotic vessels burst or become blocked. It also contributes to heart failure. Hypertension causes so many forms of downstream damage that control of raised blood pressure via current standards of medication, approaches that in no way address the underlying causes of the condition, can nonetheless reduce mortality risk by a sizable amount.

Association of growth hormone receptor gene variant with longevity in men is due to amelioration of increased mortality risk from hypertension

Growth hormone (GH) and its receptor (GHR) are not only important for regulating growth, they have many other important biological functions including response to nutrients, regulation of metabolism, and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. Growth hormone signaling is an important regulator of aging. GH deficiency leads to slower growth, delayed maturation, reduced body size, and can result in attenuation of the rate of aging, increased health-span, and increased longevity. Key to this are evolutionarily conserved pathways of insulin/insulin-like growth factors and mechanistic target of rapamycin, where there are trade-offs between anabolic processes/growth and lifespan.

We have reported a significant negative association between height and longevity in our large cohort of American men of Japanese ancestry. More recently, in a case-control study of 13 single nucleotide polymorphisms (SNPs) of GHR in this cohort, SNP rs4130113 was associated with greater lifespan of nonagenarian men aged ≥ 95 years. In the present longitudinal study, we tested the hypothesis that genetic variation in GHR affects lifespan at least in part by protection against the detrimental effects of one or more aging-related diseases, namely diabetes, hypertension, coronary heart disease, and/or cancer.

The present study has found that the longevity-associated AA genotype (frequency 35.3%), but also the GG genotype (frequency 17.1%), of GHR SNP rs4130113 is associated with protection against risk of mortality in hypertensive elderly American men of Japanese ancestry. As a result, those individuals lived longer, whereas individuals with the AG genotype (frequency 47.6%) died sooner. Moreover, the survival curve for hypertensive AA/GG subjects did not differ significantly from the survival curve for normotensive subjects with the AA/GG genotype. This indicated that possession of the GHR longevity-associated genotype can mitigate the adverse effects on lifespan of having hypertension.

The mechanisms of aging produce a range of detrimental effects on bones, most evidently the progressive loss of density and resilience that becomes osteoporosis in its later and severe stages. It is known that strength training blunts the loss of muscle mass and strength that occurs with age, and reduces mortality risk in later life. Here, researchers show that it can also slow the aging of bone tissue. The effect size is small, but note that the researchers are comparing well trained athletes with adequately trained athletes, rather than with the general population.

Cross-sectional and interventional studies suggest that high-intensity strength and impact-type training provide a powerful osteogenic stimulus even in old age. However, longitudinal evidence on the ability of high-intensity training to attenuate age-related bone deterioration is currently lacking. This follow-up study assessed the role of continued strength and sprint training on bone aging in 40- to 85-year-old male sprinters (n = 69) with a long-term training background.

Peripheral quantitative computed tomography (pQCT)-derived bone structural, strength, and densitometric parameters of the distal tibia and tibia midshaft were assessed at baseline and 10 years later. The groups of well-trained (actively competing, sprint training including strength training ≥2 times/week; n = 36) and less-trained (less than 2 times/week, no strength training, switched to endurance training; n = 33) athletes were formed according to self-reports at follow-up. Longitudinal changes in bone traits in the two groups were examined.

Over the 10-year period, group-by-time interactions were found for distal tibia total bone mineral content (BMC), trabecular volumetric bone mineral density (vBMD), and compressive strength index, and for mid-tibia cortical cross-sectional area, medullary area, total BMC, and BMC at the anterior and posterior sites. These interactions reflected maintained (distal tibia) or improved (mid-tibia) bone properties in the well-trained and decreased bone properties in the less-trained athletes over the 10-year period. Depending on the bone variable, the difference in change in favor of the well-trained group ranged from 2% to 5%.

In conclusion, our longitudinal findings indicate that continued strength and sprint training is associated with maintained or even improved tibial properties in middle-aged and older male sprint athletes, suggesting that regular, intensive exercise counteracts bone aging.

Link: https://doi.org/10.1002/jbm4.10513

One can't maintain dismissive skepticism forever in the face of scientific and medical development communities that are ever more engaged in the development of therapies to address the mechanisms of aging. To pick one example, senolytic treatments that clear senescent cells from aged tissues are producing consistently amazing data in mice: rejuvenation, extension of healthy life, reversal of measures of many specific age-related diseases. We'll soon know how well the more viable senolytics perform in human trials, as the preliminary data from the use of dasatinib and quercetin shows that it does selectively destroy senescent cells in humans as it does in mice. Given the serious prospect of living longer in good health, I would expect the previously doom and gloom crowd of naysayers to capitulate and admit that, yes, actually it would be pleasant to have more health, more life, and less pain, suffering, and death.

People are living longer, staying healthier longer and accomplishing things late in life that once seemed possible only at younger ages. And it's not just superstars. The fraction of over-85s in the U.S. classified as disabled dropped by a third between 1982 and 2005, while the share who were institutionalized fell nearly in half. As a whole, Americans seem to be aging more slowly than before. Researchers compared how men 60 to 79 years old aged in 1988 to 1994 and in 2007 to 2010. They found that in those later years, the men they studied had a biological age four years less than the men in the earlier years, in part because of improvements in lifestyle and medications. This suggests that not only are people living longer, they're also staying healthier longer.

On one level, greater health and longevity is an old story. In 1900, life expectancy in the U.S. was about 47 years and now it's about 78. But we may also be on the cusp of something new. Over the course of the 20th century, we primarily aided longevity by tackling disease. In the first half of the century vaccines and other innovations prevented people from dying young of communicable diseases. In the second half, improvements in lifestyle and other medical breakthroughs prevented many people from dying in middle age of things like heart attacks and cancer.

But while these improvements have made it more likely that people will live to be 65, after that, aging itself takes an inexorable toll. Even if you beat lung cancer or survive a heart attack, your body's deterioration will finish you off before too long. The average 80-year-old suffers from around five diseases. That's why even if we could totally cure cancer, it would add less than three years to average life expectancy. A total cure for heart disease would give us at best two extra years. To keep the longevity train rolling it may not be enough to cure diseases. We may also need to address the underlying condition of aging itself, which is, after all, the primary risk factor for late-life decline.

S. Jay Olshansky has said "While there are no documented interventions that have been proven safe and effective in slowing aging in humans today, we are on the verge of a breakthrough." For example, as we age, we build up more and more "senescent" cells, which secrete inflammatory molecules that can effectively accelerate aging. In 2011, researchers removed these cells from mice and extended their life spans. Clinical trials on people began in 2018. It's likely that all Americans could be living longer, healthier lives. I imagine an 80-year-old bounding from bed, biking in the morning and playing softball in the afternoon. We're all on borrowed time. More time is more life, and more of it will be sweet.

Link: https://www.nytimes.com/2021/06/03/opinion/age-life-expectancy.html

Aging is damage, and the body fails in the same way that any complex, damaged machine fails. If one slows the pace of damage accumulation, as technological progress over the past century has achieved to a modest degree, albeit by accident rather than intent, both overall life span and the time spent in a period of damage and dysfunction at the end of life should extend. This is what we see happening, as is noted by the authors of today's open access paper. In order to extend healthy life and put off that period of damage and dysfunction, periodic repair of the underlying damage of aging is required. You make a machine last longer in a useful way by maintaining it.

This approach of repair, targeting the cell and tissue damage that causes aging, was not attempted by the scientific and medical communities until quite recently. The first repair based rejuvenation therapies worthy of the name are the various senolytic treatments that selectively remove senescent cells from aged tissues. Lingering senescent cells actively disrupt tissue maintenance and function, and eliminating them has been shown to reverse aspects of aging in mice. Senolytics emerged in the past decade, and are only now entering human clinical trials as a means of turning back selected conditions in which they are known to be a major component of pathology. There is still a lot more of aging to address if we want to change the past trend of increasing life span coupled to a longer period of damage and decline.

Trends in health expectancies: a systematic review of international evidence

Populations are ageing worldwide. Globally, the proportion of those aged 65 and over has increased by 9% in the last two decades, and is expected to grow by a further 16% by 2050. This demographic shift will require societies to adapt. If longer lives are spent in poor health, governments face the challenge of providing accessible, high quality and sustainable long-term care. The growth in life expectancy is a positive, but with this comes a responsibility to ensure people have the support they need as they age, and to facilitate ageing in place.

In 2019, the World Health Organisation (WHO) renewed its commitment to support countries to achieve longer and healthier lives with the Decade of Healthy Ageing 2020-2030 strategy. A critical part of achieving longevity is understanding whether longer lives are typified by more years spent in good health (compression of disability) or poor health (expansion of disability). This has important implications for the provision of health and care services to respond to the needs of people as they age. It is, therefore, crucial to keep abreast of trends, specifically how the growth in life expectancy is matched by a growth in years spent in good health.

Metrics to assess this most commonly include healthy life expectancy and disability-free life expectancy. Both provide an estimate of life expectancy spent in good health, but differ slightly with respect to their measurement. Healthy life expectancy tends to rely on single item questions of self-reported health, and is thus subject to fluctuations as expectations of health change over time. Disability-free life expectancy is often calculated from multiple items about activity limitations and/or dependencies, and therefore does not bear the same limitations as that of healthy life expectancy.

Previous reviews have summarised trends in total, healthy, and disability-free life expectancy, the most recently in 2016. Typically, such evidence shows that while people are living longer, gains in life expectancy are not consistently matched by a growth in the number of years lived in good health and free of disability. Nevertheless, this is an evolving evidence base requiring ongoing scrutiny.

This systematic review was undertaken to update our current understanding of trends in health expectancies in OECD high-income countries. The principal finding is that changes in health expectancies have not kept pace with the growth in life expectancy in a number of high-income countries. One clear exception was Sweden, where gains in women's disability-free life expectancy were greater than gains in life expectancy over a period of almost 20 years. In conclusion, a number of high-income countries, changes in health expectancies over time have not kept pace with the growth in life expectancy. That is, people are living longer but disability and poor health are occupying an increasing proportion of later life. Our findings suggest that countries still need to make significant progress to achieve the WHO's Decade of Healthy Ageing goal of healthier, longer lives for all.

The immune system is a very complex network of many different cell types, signals, and layered responses. It is much more subdivided and varied than the broad distinction between innate and adaptive immune components might lead one to believe. As a whole the immune system runs awry in later life, becoming both overly active and incompetent at the same time. Chronic inflammation and an inability to adequately defend against pathogens is the result. Many researchers are engaged in picking apart the details of this failure state, and the work here is a representative example of this sort of work, with a narrow focus on one smaller portion of the immune system and its responsibilities.

Chronic sub-clinical inflammation of aging, resulting from lifetime exposures to pathogens in concert with impaired immune responses, poses an obstinate challenge to the health span of the growing elderly population. Several factors contribute to the increased morbidity/mortality of older adults, including loss of naïve lymphocytes, exhaustion of adaptive immunity, and a skew toward proinflammatory responses. Additionally, loss of intestinal homeostasis and perturbations in epithelial barrier protective immune functions have recently emerged as key factors underlying chronic inflammation and age-related comorbidities.

Defense of epithelial barriers against invading pathogens and maintenance of mucosal homeostasis mainly relies on the Th17-type immunity, also known as type-17 and Th3 immunity, which is characterized by IL-17/IL-22 cytokine production. IL-17 predominantly triggers the influx of neutrophils and tissue repair, while IL-22 stimulates proliferation of epithelial cells, and regulates epithelial permeability, production of mucus, antimicrobial proteins, and complement to help maintain barrier integrity.

Our laboratory has shown that systemic inflammation in older macaques was associated with reduced Th17-type cytokine functions of CD161+ immune cells. This correlated with circulating biomarkers of leaky gut and microbial translocation, suggesting a link between intestinal barrier dysfunction and inflammaging. There is significant evidence showing that Th17-type immunity and epithelial barrier functions have an important role in the immune response and inflammation of aging; however, the precise cellular and molecular mechanisms underlying altered Th17-type responses in aging humans remain to be elucidated.

The health and diversity of our microbiome and how it influences Th17-type responses should also be of value for mucosal immunity in the context of aging. A clear understanding of epithelial barrier protective Th17-type responses will aid the development of targeted therapies, specifically tailored for the elderly.

Link: https://doi.org/10.18632/aging.203119

Researchers here propose an approach to measure the progression of sarcopenia, the loss of muscle mass and strength with aging, via ultrasound assessment of muscle structure. The present most widely practiced approaches involve assessment of muscle mass, grip strength, walking speed, ability to stand up from a chair, and the like. As understanding of the underlying mechanisms of the condition grow, a more rigorous form of assessment becomes desirable, one that can hopefully be extended into detecting the earliest stages of sarcopenia, with an eye towards prevention.

While the definition of sarcopenia is an evolving concept that started with a classification based on muscle mass alone, this has progressively moved to a more operational definition that includes the loss not only of muscle mass but also of muscle strength, with a risk of adverse outcomes such as physical disability, poor quality of life, and even death. However, as recognized by the latest definition of sarcopenia, low muscle mass or quality is a determinant factor for confirming sarcopenia in the presence of low muscle strength, otherwise known as dynapenia. Hence, the measurement of muscle mass remains a key requirement for the clinical diagnosis of sarcopenia. Typically, this has been achieved using dual X-ray absorptiometry (DXA), MRI, or bioelectrical impedance. The use of these methods has been widespread and has been instrumental for the diagnosis of sarcopenia in clinical settings.

In 2003, we reported for the first time that the loss of muscle mass associated with sarcopenia not only entails a decrease in muscle cross-sectional area and volume but also alterations in the spatial arrangement of muscle fibres within the muscle. Knowledge of the spatial arrangement of muscle fibres within a muscle is particularly important because muscle architecture is one of the most important determinants of muscle force and velocity. Using ultrasonography, we were able to show, for several locomotor muscles, that the key parameters of muscle architecture are significantly altered in sarcopenic muscle.

If changes in muscle architecture were to scale harmonically with the decrease in muscle volume due to sarcopenia, one would expect the ratio of fascicle length (Lf) to muscle thickness (Tm) to remain constant. However, muscle length (and thus fascicle length) is constrained by its connections into the proximal and distal tendons that insert into bony structures. Although fascicle length has been found to decrease with ageing, this effect should be limited by the proximal and distal tendon insertions into bone, unless tendons were to elongate, which is most unlikely. Hence, the reduction in muscle mass with ageing should be due more to a decrease in muscle thickness than in fascicle length, that is, it should involve a greater loss of sarcomeres in parallel than in series. Recent observations made in our laboratory in different populations of older individuals (active, sedentary, and mobility impaired) seem to confirm this assumption: with increasing degree of sarcopenia, the decrease in muscle thickness (Tm) exceeds that of fascicle length (Lf).

These findings prompted us to formulate the hypothesis that the Lf/Tm ratio, which we shall refer to as 'ultrasound sarcopenia index' (USI), may be used as a marker of the loss of muscle mass associated with sarcopenia. An important advantage of using a marker based on an anatomical ratio rather than on absolute values is its independence from gender and body dimensions. Further, there are several important advantages to be considered regarding the use of ultrasound for assessing muscle architecture, both for clinical and practical purposes. Ultrasound can be delivered at a fraction of the cost of MRI, and has a very good reliability and reproducibility when performed by properly trained personnel.

Link: https://doi.org/10.1002/jcsm.12720

The burden of infectious disease falls most heavily upon the old. The attention given to COVID-19 has highlighted that point, though much of the media seems determined to avoid talking about the fact that near all mortality due to the condition occurs in the old and the cormorbid. It is nothing new, of course. Influenza kills tens of thousands of old people every year in the US alone, without much attention given to it. That the elderly suffer and die is old news. It is, however, old news that we should revisit in this era of revolutionary progress in medical biotechnology. The causes of aging and age-related mortality are amenable to treatment. The first rejuvenation therapies exist already, in the form of first generation senolytic treatments that destroy senescent cells.

COVID-19 mortality is strongly linked to inflammation. People with raised levels of chronic inflammation, such as the obese and the old, are much more vulnerable to suffering a runaway inflammatory event, a cytokine storm, and consequent severe illness and death. Today's open access paper is a novel consideration of this state of affairs that pulls in to this discussion what is known of the age-related dysfunction in coagulation. If a higher baseline inflammatory status leads to greater risk of severe inflammation due to infection, then, analogously, a greater baseline degree of dysfunction in mechanisms of coagulation leads to a greater risk of pathological disruption of coagulatory processes due to infection.

Do inflammaging and coagul-aging play a role as conditions contributing to the co-occurrence of the severe hyper-inflammatory state and deadly coagulopathy during COVID-19 in older people?

Older people with COVID-19 infection often suffer a severe form of interstitial pneumonia accompanied to an excessive human immune response with a hyper-inflammatory condition characterized by the increase of many plasma cytokines, including IL-6, interleukin 8 (IL-8), interferon (IFN), and tumor necrosis factor levels increase, particularly of IL-6 (the so-called "cytokine storm"). What drives such intense hyper-inflammation in COVID-19 is not yet known; however, the upregulation of IL-6 seems the pivotal pro-inflammatory function is contributing to COVID-19 severity.

Herein, we suggest that the preexisting upregulation of cytokine expression of inflammaging may trigger, and also support, the excessive hyper-inflammatory state in older people. Indeed, the superimposed SARS-CoV-2 infection in older adults may acutely exaggerate the already present pro-inflammatory background of inflammaging, predisposing older people to greater COVID-19 disease severity and mortality. The co-occurrence of the COVID-19 infection, constituting a second-hit to the preexisting pro-inflammatory condition of inflammaging, leading to a dysregulation of inflammation, which becomes harmful, reaching a severe pathological threshold.

We must also consider the impact of a pro-inflammatory state on coagulation because of the crosstalk between inflammation and coagulation. It is well established that the systemic inflammatory state of elderly people and coagulation disorder are closely linked, a phenomenon which here we refer to as "coagul-aging". Physiological aging is associated with increased plasma levels of many proteins of blood coagulation together with fibrinolysis impairment; this may be of great concern in view of the known association between vascular and thromboembolic diseases and aging, a condition which, here we suggest, may also contribute to the co-occurrence of the high incidence of coagulopathy in older COVID-19 patients.

In the future, we hope to carry out more studies on inflammaging and coagul-aging, which will enable us to understand the mechanism in-depth and find measures to intervene in the corresponding processes. More studies will not only help elderly patients with severe infections like COVID-19, but can also have the potential to intervene in the aging-associated pro-inflammatory state and the senescence process itself.

Research into the comparative biology of regeneration suggests that mammals are in principle capable of proficient, full regeneration of complex tissues, but some critical difference in cell signaling and behavior leads instead to the formation of scar tissue in adults. In recent years, scientists have focused on the role of macrophages in coordinating the process of regeneration. In proficient regenerators like salamanders and zebrafish, the presence of macrophages is essential to the regenerative process. Absent macrophages, scar tissue forms in the same way as it does in mammals. Researchers now aim to understand exactly what is different in the behavior of macrophages in mammals and highly regenerative species.

The axolotl, a Mexican salamander that is now all but extinct in the wild, is a favorite model in regenerative medicine research because of its one-of-a-kind status as nature's champion of regeneration. While most salamanders have some regenerative capacity, the axolotl can regenerate almost any body part. Since mammalian embryos and juveniles have the ability to regenerate - for instance, human infants can regenerate heart tissue and children can regenerate fingertips - it's likely that adult mammals retain the genetic code for regeneration, raising the prospect that pharmaceutical therapies could be developed to encourage humans to regenerate tissues and organs lost to disease or injury instead of forming a scar.

Researchers compared immune cells called macrophages in the axolotl to those in the mouse with the goal of identifying the quality in axolotl macrophages that promotes regeneration. The research builds on earlier studies in which it was found that macrophages are critical to regeneration: when they are depleted, the axolotl forms a scar instead of regenerating, just like mammals. The recent research found that although macrophage signaling in the axolotl and in the mouse were similar when the organisms were exposed to pathogens, when it came to exposure to injury it was a different story: the macrophage signaling in the axolotl promoted the growth of new tissue while that in the mouse promoted scarring.

Specifically, the signaling response of a class of proteins called toll-like receptors (TLRs), which allow macrophages to recognize a threat such an infection or a tissue injury and induce a pro-inflammatory response, were unexpectedly divergent in response to injury in the axolotl and the mouse. The finding offers an intriguing window into the mechanisms governing regeneration in the axolotl. The discovery of an alternative signaling pathway that is compatible with regeneration could ultimately lead to regenerative medicine therapies for humans.

Link: https://mdibl.org/press-release/mdi-biological-scientist-identifies-signaling-underlying-regeneration/

The gene Cdkn1a (or P21) generates two different RNA transcripts that both lead to the production of the same protein. Researchers here provide evidence to suggest that the less well explored second transcript is a good marker of aging and cellular senescence, at least in mice. The biochemistry of senescence seems to be well conserved across species, so with luck the same data will be replicated in humans in the near future. Better and less invasive approaches to robustly assess senescent cell burden, improvements on the the current standard of tissue samples and immunohistochemistry, are very much needed. A well-validated blood test, for example, would be a step forward in terms of speeding up the development of senolytic therapies to clear senescent cells.

Cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16Ink4a and p21Cip1/Waf1. In mice, the p21Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized. We show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues.

Importantly, mouse cells induced to senescence in culture by genotoxic stress (ionizing radiation or doxorubicin) upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics. Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice. Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.

Link: https://doi.org/10.18632/aging.203110

The underside of the approval of aducanumab, an immunotherapy that clears amyloid-β from the brain, is very much a textbook case of regulatory capture. While the treatment does clear amyloid-β, it doesn't help patients all that much. Benefits observed in trials were marginal to the point of non-existence. The arm-wrestling under the hood has nothing to do with the welfare of patients and everything to do with maintenance of bureaucracy and control for the sake of bureaucracy and control on one side versus rent seeking on the other. An ugly business.

The silver lining is that now it will be easier to work on combination therapies that remove amyloid-β and address other issues. Amyloid-β is either a side-effect of the development of Alzheimer's disease, or one of several important mechanisms, most or all of which must be meaningfully addressed in order to help patients. It is hard to make progress in the latter scenario if regulators insist on only testing one thing at a time, and also have an efficacy bar for approval.

The regulatory system is dramatically broken. Absent regulators, it would cost a tenth as much as it does now, or less, to prove out new therapies in human volunteers. For most medicines, there really isn't a sizable practical difference between the over the top rigor of GMP manufacture and ordinary, sensible quality control on a batch by batch basis. The enormous cost imposed by the the FDA process really isn't essential to producing safe medicines, or to testing efficacy. Yet here we are, in a world in which progress is glacial because the powers that be have decided that pursuing the unattainable goal of zero risk is worth any cost in lives and funding, and the population at large never sees the medical progress that would have taken place absent the regulators.

FDA's Decision to Approve New Treatment for Alzheimer's Disease

Today FDA approved Aduhelm (aducanumab) to treat patients with Alzheimer's disease using the Accelerated Approval pathway, under which the FDA approves a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug's clinical benefit.

We are well-aware of the attention surrounding this approval. We understand that Aduhelm has garnered the attention of the press, the Alzheimer's patient community, our elected officials, and other interested stakeholders. The late-stage development program for Aduhelm consisted of two phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.

We know that the Peripheral and Central Nervous System Drugs Advisory Committee, which convened in November 2020 to review the clinical trial data and discuss the evidence supporting the Aduhelm application, did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval. As mentioned above, treatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit. After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for Accelerated Approval.

The need for treatments is urgent: right now, more than 6 million Americans are living with Alzheimer's disease and this number is expected to grow as the population ages. Alzheimer's is the sixth leading cause of death in the United States. Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients.

Aggregation of amyloid-β is a feature of the slow buildup towards Alzheimer's disease that takes place in later life, though it remains unclear as to whether this protein aggregation is a cause or a side-effect in the progression of the condition. Separately, loss of capillary density is a feature of aging in tissues throughout the body. In energy-hungry tissues such as the brain, this is a real problem, contributing to an insufficient supply of nutrients and consequent loss of function. The exact causes of this reduced capillary density are poorly understood. Here, researchers suggest that amyloid-β aggregation is one such cause, disrupting the balance of mechanisms needed to maintain capillary vessels in tissue.

Researchers have discovered a new mechanism of Alzheimer's disease that disorganises the blood vessels around amyloid plaques, one of the characteristic features of the disease. The mechanism put forward in this study is mediated by the dysfunction of a physiological process, angiogenesis. This mechanism is important during development to form the vessels of the brain and in adulthood to revert possible damage to pre-existing vessels. The study shows that Alzheimer's disease induces angiogenesis dysfunction that causes the loss of vessels instead of the formation of new ones, undoubtedly aggravating the pathology. By identifying the molecular pathways involved, new therapeutic strategies to alleviate the effects of this disease can be rationally designed.

A characteristic feature of Alzheimer's patients is the accumulation of highly toxic substances in their brains, known as senile plaques. The brain has the capacity to clean these toxic substances via transport through the blood. Thus the fact that the plaques cause the loss of the vessels constitutes a vicious circle: having fewer vessels reduces the ability to clean the brain thus allowing more toxic substances to accumulate, which in turn continue to destroy the vessels and worsen the situation. The brain consumes much of the body's oxygen and nutrients. Thus a local reduction in the supply of these substances through the blood represents an additional strain above and beyond the existing strain from the accumulation of toxic substances.

Link: https://www.eurekalert.org/pub_releases/2021-05/uos-amt053121.php

Rebuilding lost tooth enamel is an important goal in a world in which robust control over the bacteria responsible for producing cavities has not yet been achieved. In a welcome advance in this part of the field, researchers will soon conduct trials of a low cost approach to achieve reconstruction of enamel, slowly over time.

Researchers are preparing to launch clinical trials of a lozenge that contains an engineered peptide, or chain of amino acids, along with phosphorus and calcium ions, which are building blocks of tooth enamel. The peptide is derived from amelogenin, the key protein in the formation of tooth enamel, the tooth's crown. It is also key to the formation of cementum, which makes up the surface of the tooth root.

Each lozenge deposits several micrometers of new enamel on the teeth via the peptide, which is engineered to bind to the damaged enamel to repair it while not affecting the mouth's soft tissue. The new layer also integrates with dentin, the living tissue underneath the tooth's surface. Two lozenges a day can rebuild enamel, while one a day can maintain a healthy layer.

The lozenge produces new enamel that is whiter than what tooth-whitening strips or gels produce. It has another distinct advantage: Conventional whitening treatments rely on hydrogen peroxide, a bleaching agent that can weaken tooth enamel after prolonged use. Since tooth enamel can't regrow spontaneously, the underlying dentin can be exposed, with results ranging from hypersensitivity to cavities or even gum disease. The lozenge, on the other hand, strengthens, rebuilds, and protects teeth.

In addition, the researchers are investigating a gel or solution with the engineered peptide to treat hypersensitive teeth. This problem results from weakness in the enamel that makes the underlying dentin and nerves more vulnerable to heat or cold. Most common products currently on the market can put a layer of organic material on the tooth and numb nerve endings with potassium nitrate, but the relief is only temporary. The peptide, however, addresses the problem permanently at its source by strengthening the enamel.

Link: https://dental.washington.edu/trials-begin-on-lozenge-that-rebuilds-tooth-enamel/

Evidence suggests that the gut microbiome is influential on long-term health and late life mortality, to perhaps a similar degree as exercise. The various populations of microbial life found in the gut change with age; microbes producing beneficial metabolites are lost, while microbes that provoke chronic inflammation or other issues increase in number. Experiments in short-lived species have shown that transplanting a youthful microbiome into an older individual results in improved health and extended life span. In principle, similar effects could be achieved by some sort of intensive oral probiotic treatment, but that has not yet been demonstrated in animal studies. Researchers have also shown that guiding the immune system to more aggressively attack problem gut microbes can improve the microbiome and its influence on health.

In today's open access paper, researchers propose that regional differences in diet mean that there is unlikely to be one optimal gut microbiome to promote longevity. This seems a reasonable prediction, given the degree to which human diet does vary around the world, and the way in which diet interacts with the gut microbiome. It still seems likely that there are universally beneficial changes that one can make to any aged microbiome, in humans or other species, such as enabling the immune system to better remove problem microbes. Early approaches to therapies are likely to involve such universal, narrow improvements; personalized medicine is more challenging problem.

Regional Diets Targeting Gut Microbial Dynamics to Support Prolonged Healthspan

Centenarians, who have escaped or survived lethal diseases earlier in life, may be considered a spontaneous model of healthy ageing. The gut microbial composition of centenarians has consistently been reported to differ in phylogenetic composition from that of younger people. Interestingly, within centenarian populations, species have been reported to display regional characteristics, further supporting that environmental and/or lifestyle factors including the diet, shape microbial composition.

For example, in an Italian cohort, the centenarian microbiome was found to be dominated by the same two microbial families as in the other age groups (<75 years old) of the population, namely Veillonellaceae and Ruminococcaceae (Firmicutes phylum), but was specifically enriched in the genera Akkermansia, Bifidobacterium, and Christensenella. In contrast, the Chinese Hainan Centenarian Cohort was dominated by Bacteroides (Bacteroidetes phylum) and Escherichia (Proteobacteria phylum). Long-term elderly care residents in the Irish ELDERMET Cohort also had a gut microbiome dominated by Bacteroidetes. Importantly, although the aggregate faecal microbiome in ELDERMET was dominated by Bacteroidetes, the residents showed extraordinary inter-individual variation with 3-92% Bacteroidetes and 7-94% Firmicutes, hinting at a long-term effect of their dietary habits.

The results of the Italian study are also in contrast to those of another Chinese Centenarian Cohort from the Guangxi region, who harboured significantly higher abundance of the genera Escherichia and Roseburia, and reduced abundance of Akkermansia, Lactobacillus, Faecalibacterium, Parabacteroides, Butyricimonas, Coprococcus, Megamonas, Mitsuokella, and Sutterella. A Korean centenarian study found trends similar to both Italian and Guangxi Chinese centenarians, with higher abundance of Akkermansia and Christensenella, and Escherichia, respectively. They also displayed increased abundance of Clostridium and Collinsella, and reduced abundance of Faecalibacterium and Prevotella compared to the general population.

At present, we do not have a good understanding to explain these geographical variations in the centenarian gut microbial composition or to unequivocally answer if there are certain microbial species globally associated with longevity. In the reviewed studies, some microbial genera associated with healthy elderly populations include Roseburia, Escherichia, Akkermansia, Christensenella, Bifidobacterium, and Clostridium, but they are all highly variable across populations. Based on these cross-sectional observations, it seems unlikely that a universal pro-longevity gut microbiome exists. Rather, the optimal microbiome for healthspan appears to be conditional on the microbial functionality acting on regional- and ethnicity-specific trends driven by cultural food context.

Researchers here hypothesize that the normal level of oxygen supply to the hippocampus, the area of the brain most involved in memory, is just barely adequate. As soon as any age-related decline in blood supply occurs, memory symptoms are the result, and hence memory symptoms occur early in the aging of the brain. There are numerous mechanisms by which the supply of blood to the brain can decline with age, such as a lack of physical fitness and the ability of the heart to pump blood uphill to the brain, or the loss of capillary density that occurs in tissues with age. One interesting point that is not brought up in the research materials here: it is known that physical exercise improves cerebral blood flow and memory function in the short term. This might be taken as supportive of the hypothesis that normal blood flow to the hippocampus is only just sufficient for correct function.

Researchers have studied brain activity and blood flow in the hippocampus of mice. The team used simulations to predict that the amount of oxygen supplied to hippocampal neurons furthest from blood vessels is only just enough for the cells to keep working normally. "These findings are an important step in the search for preventative measures and treatments for Alzheimer's, because they suggest that increasing blood flow in the hippocampus might be really effective at preventing damage from happening. If it's right that increasing blood flow in the hippocampus is important in protecting the brain from diseases like Alzheimer's, then it will throw further weight behind the importance of regular exercise and a low-cholesterol diet to long-term brain health."

"We think that the hippocampus exists at a watershed. It's just about OK normally, but when anything else happens to decrease brain blood flow, oxygen levels in the hippocampus reduce to levels that stop neurons working. We think that's probably why Alzheimer's disease first causes memory problems - because the early decrease in blood flow stops the hippocampus from working properly. The same factors that put you at risk of having a heart attack make you more likely to develop dementia. That's because our brains need enough blood flow to provide energy - in the form of oxygen and glucose - so brain cells can work properly, and because blood flow can clear away waste products such as the beta amyloid proteins that build up in Alzheimer's disease. Now we want to discover whether the lower blood flow and oxygen levels in the hippocampus are what causes beta amyloid to start to build up in Alzheimer's disease. Understanding what causes early damage will be really important to help us learn how to treat or prevent disease."

Link: https://www.sussex.ac.uk/news/research?id=55494

A small but increasing fraction of the supporting glial cells of the brain become senescent in later life, and there is good evidence from animal studies for this to be an important contributing cause of neurodegeneration. Senescent cells secrete a mix of signals that provoke chronic inflammation, as well as detrimental changes to tissue structure and cell function. Inflammation in the brain is an important component of neurodegenerative disease, and researchers have proposed that the most common forms of dementia are driven in large part by cellular senescence and consequent inflammation in the brain.

Accumulating evidence suggests that the sympathetic nervous system (SNS) overactivity plays a crucial role in age-related increase in the risk for cardiovascular diseases such as hypertension, myocardial infarction, stroke, and heart diseases. Previous studies indicate that neuroinflammation in key brainstem regions that regulate sympathetic outflow plays a pathogenic role in aging-mediated sympathoexcitation. However, the molecular mechanisms underlying this phenomenon are not clear. While senescent cells and their secretory phenotype (SASP) have been implicated in the pathogenesis of several age-related diseases, their role in age-related neuroinflammation in the brainstem and SNS overactivity has not been investigated.

To test this, we isolated brainstems from young (2-4 months) and aged (24 months) male C57BL/6J mice and assessed senescence using a combination of RNA-in situ hybridization, PCR analysis, multiplex assay, and SA-β gal staining. Our results show significant increases in p16Ink4a expression, increased activity of SA-β gal and increases in SASP levels in the aged brainstem, suggesting age-induced senescence in the brainstem. Further, analysis of senescence markers in glial cells enriched fraction from fresh brainstem samples demonstrated that glial cells are more susceptible to senesce with age in the brainstem. In conclusion, our study suggests that aging induces glial senescence in the brainstem which likely causes inflammation and SNS overactivity.

Link: https://doi.org/10.18632/aging.203111

The state of the aged adaptive immune system can be assessed in a practical way in animal studies, such as via exposure to influenza or other well-calibrated infectious disease. This assessment is also carried out on the human population as a whole in every influenza season, but for individual humans one wants a metric that is a little less do or die. The adaptive immune system is made up of many different subtypes of B cell and T cell, each serving a different purpose. While the overall population of T cells remains fairly consistent with age, the size of different T cell subtype populations changes in characteristic ways. Based on this, metrics of immune function can be created.

T cells are characterized by the surface markers they expose, and the number of cells with a given marker or combination of markers can be counted in a flow cytometry machine, given a blood sample to work with. There are a very large number of these markers, and countless combinations, but some are established to be much more important than others. CD4 is a marker of T helper cells, which serve a variety of coordinating roles in the immune response, for example, while CD8 is a marker of cytotoxic T cells, responsible for killing errant cells and pathogens. This is an overly simplistic description of a very complex array of cell states and behaviors, but it is useful, as demonstrated by the fact that the CD4/CD8 ratio of T cells in a blood sample does, on balance, reflect the state of the immune system as a whole. A low CD4/CD8 ratio correlates with a greater degree of frailty and comorbidity in older people.

Immunological features beyond CD4/CD8 ratio values in older individuals

The CD4/CD8 T-cell ratio is emerging as a relevant marker of evolution for different pathologies and therapies, including cardiovascular diseases. Immune alterations related to cellular immunosenescence, together with persistent inflammation, are known to be involved in the process of deleterious aging, which underlies the failure to maintain global health status during aging. The CD4/CD8 ratio might be related to cellular immunosenescence, and potential factors affecting the CD4/CD8 ratio in older people have been extensively studied.

Cytomegalovirus infection has been widely reported as the main cause of CD8 T-cell oligoclonal expansion. Additionally, free radicals, which accumulate during aging, may have an impact because subjects with an inverted CD4/CD8 ratio exhibit reduced levels of antioxidant defenses and higher oxidative stress. Hence, factors associated with cumulative cellular senescence and oxidative stress appear to trigger a reduction in the CD4/CD8 ratio; however, the immunological features beyond CD4/CD8 T-cell ratio values require further exploration.

It is reasonable that CD4/CD8 T-cell ratio values, particularly in older people, might reflect different degrees of immune capabilities both for responding to antigens and for preserving health status in this population. Although thymic output is the main regulator of T-cell homeostasis, whether it relates to the CD4/CD8 T-cell ratio in older individuals has not yet been explored. Notably, the thymus undergoes progressive atrophy throughout life, reducing its activity by approximately 3% per year until middle age, when it slows down to less than 1% per year.

Nevertheless, the thymus remains active in adults, contributing to the renewal of the pool of naïve T-cells, even though thymic function is highly variable in older people. In fact, intrathymic CD4+CD8+ double-positive T cells obtained from thymic biopsies correlate not only with age (negative) but also with the frequency of naïve T cells (positive). Interestingly, a relationship between thymic function and the CD4/CD8 T-cell ratio exists in HIV infection, which is a different scenario but shares several immunosenescence traits with aging. On the other hand, it is also reasonable that CD4/CD8 T-cell ratio values might correlate with different inflammatory profiles. To better understand the biological meaning of the CD4/CD8 ratio in the elderly, we explored the phenotypic profiles of both CD4 and CD8 T-cells, as well as the thymic output and several inflammation-related parameters, in a population of older subjects classified according to CD4/CD8 ratio value.

The lower CD4/CD8 ratio group showed a lower thymic output and frequency of naïve T-cells, concomitant with increased mature T-cells. In these subjects, the CD4 T-cell subset was enriched in CD95+ but depleted of CD98+ cells. The regulatory T-cell (Treg) compartment was enriched in CTLA-4+ cells. The CD8 T-cell pool exhibited increased frequencies of CD95+ cells but decreased frequencies of integrin-β7+ cells. Interestingly, in the intermediate CD4/CD8 ratio group, the CD4 pool showed greater differences than the CD8 pool, mostly for cellular senescence.

Regarding inflammation, only high sensitivity CRP was elevated in the lower CD4/CD8 ratio group; however, negative correlations between the CD4/CD8 ratio and β2-microglobulin and soluble CD163 were detected. These subjects displayed trends of more comorbidities and less independence in daily activities. Altogether, our data reveal that different thymic output and immune profiles for T-cells across CD4/CD8 ratio values that can define immune capabilities, affecting health status in older individuals. Thus, the CD4/CD8 ratio may be used as an integrative marker of biological age.

It is well known that regular exercise can slow the progression of many age-related declines, and reduce mortality risk in late life. Different forms of exercise, such aerobic exercise versus strength training, appear to produce different, overlapping benefits. This is concretely demonstrated in animal models, while the human epidemiological data, which can only show correlations, is supportive of the thesis that exercise produces changes in metabolism that modestly slow the onset of age-related declines.

Exercise is a lifestyle intervention with known antiaging effects capable of counteracting several of the hallmarks of aging including senescence and age-associated inflammation. We propose that 5' adenosine monophosphate-activated protein kinase (AMPK) can orchestrate many of the antiaging effects of exercise through its regulation of diverse cellular pathways in the setting of energetic stress.

Activating AMPK is sufficient to extend lifespan in many organisms. It is naturally activated in response to muscle contraction and nutrient depletion, both of which are components of exercise. Whereas most of the studies supporting AMPK as an antiaging strategy are based in animal models, the use of metformin (an AMPK activator) in clinical trials (TAME) as an antiaging drug is based on its capacity to delay heart disease, cancer, cognitive decline, and death in people with diabetes. These results suggest that the antiaging effects of AMPK are also relevant in humans, but the molecular mechanisms underlying these effects remain to be determined.

A landmark 21-year longitudinal study that followed runners and compared them with a sedentary group, found that those who exercise had a significantly lower risk of dying (15%) during that time frame than the sedentary group (34%) while also having reduced disabilities. It is unclear whether the beneficial effects of exercise in this study were due to a delay in secondary aging or to countering of the effects of sedentarism. Regardless of this limitation, numerous studies have shown that maintaining a minimum quantity and quality of exercise improves cardiorespiratory fitness and muscle function, flexibility, and balance.

Current guidelines recommend a minimum of 150 min/week of moderate intensity aerobic activity for maximum longevity benefits, with higher duration and intensity increasing cardiovascular and metabolic effects. It has been estimated that performing three to five times the recommended physical activity (450-750 min/week) reaches the maximal healthspan benefit that can be achieved with endurance exercise. Strength training should be added to minimize loss of muscle mass that is characteristic of aging and disease.

In summary, exercise is an effective strategy to prevent aging and enhance longevity and health span both on a clinical and a cellular level due to its capacity to modulate all nine hallmarks of aging. Additionally muscle, one of the main systemic effectors of exercise, is recognized as an endocrine organ that produces and releases myokines, implying a complex cross talk between muscles and other tissues. The AMPK pathway, a well-known mediator of exercise effects in muscle could be activated in different tissues and drive many of the health-promoting and lifespan-extending capabilities of exercise. We propose that it is a central effector node able to impact the hallmarks of aging and integrate the effects of exercise on many tissues.

Link: https://doi.org/10.18632/aging.203051

There was a great deal of interest in sirtuin 1 in relation to aging and life span some years ago, very much overhyped as it turned out. Nothing of any practical use emerged from that research. Sirtuin 6 has a more robust effect on mouse life span, perhaps via improvement of mitochondrial function. Like all such exercises in metabolic manipulation that attempt to slow the progression of aging, targeting processes known to be involved in cellular responses to stress, it is likely that the beneficial effects diminish as species life span increases. A sirtuin with better results in mice remains unlikely to move the needle all that much on human life span.

Of the seven mammalian sirtuins, SIRT1-7, SIRT1, and SIRT6 protein levels increase upon dietary restriction and fasting in various mouse tissues and human cell lines. Interestingly, whole-body SIRT1 overexpression in mice leads to improvement in parameters reflecting healthspan, but not lifespan. Whereas whole-brain-specific SIRT1 overexpression did not affect lifespan and brain plasticity, hypothalamic SIRT1 overexpression delays aging. However, whole-body SIRT6 overexpression in mice background leads to a significant extension of male lifespan and healthspan, associated with inhibition of IGF-1 signaling.

Here, we show that overexpression of SIRT6, but not SIRT1, extends lifespan in C57BL/6JOlaHsd mice in both sexes. SIRT1 does not synergize with SIRT6 to further increase median or maximal survival. Overexpression of SIRT6 reduced the age-related metabolic decline in energy metabolism pathways and inhibited frailty by preserving hepatic NAD+ levels, gluconeogenesis capacity, and maintenance of normoglycemia, key markers of healthy aging. These results emphasize the potential of targeting SIRT6 for maintaining energy metabolism and reducing age-related frailty.

Link: https://doi.org/10.1038/s41467-021-23545-7

The research community is devoting an increasing amount of attention to the use of cellular reprogramming in vivo as a basis for therapies, rather than as a way to produce pluripotent cells outside the body. It has been only fifteen years or so since the first practical reprogramming approach was developed, using Yamanaka factors to transform somatic cells into induced pluripotent stem cells. Only in the past few years have researchers tried in earnest to introduce reprogramming factors into living animals in order to produce benefits to health and tissue function. It is somewhat surprising, perhaps, that this can be done without the immediate consequences of cancer and loss of tissue function, but the dose makes the poison.

Reprogramming of cells not only changes their state, but also resets epigenetic marks characteristic of cells in aged tissues and restores lost mitochondrial function. Research suggests that this beneficial restoration of function can be to some degree decoupled from the change in cell state, and that the process of undergoing programming is a complicated time course, with important differences by cell type, that can be manipulated in numerous ways. Cells can be partially reprogrammed for a short time, gaining restored function, without losing their state and behavior. This is a necessary goal if reprogramming is to be deployed as a therapy to restore function in aging tissues.

In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche

Reprogramming of somatic cells to a pluripotent state by overexpressing the Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc [OSKM]) is a long and complex process. Cellular reprogramming is widely utilized for disease modeling in vitro. However, reprogramming in vivo induces tumor development. Our lab showed that partial reprogramming by short-term expression of reprogramming factors ameliorated aging hallmarks without tumor formation, opening a possible application of this approach in vivo. Recently, other reports have demonstrated rejuvenation of dentate gyrus cells, retinal ganglion cells, chondrocytes, and muscle stem cells using reprogramming factors, reinforcing its potential application in clinical settings. Besides amelioration of cellular aging hallmarks, reprogramming factors promote tissue regeneration in aged mice. However, it is unknown whether OSKM-improved regeneration is solely a result of its rejuvenating effect.

Muscle regeneration is primarily mediated by muscle stem cells, also known as satellite cells (SCs), which reside in a characteristic niche located between the basal lamina and plasma membrane of myofibers. The regenerative capacity of SCs is influenced by both intrinsic modulators and the extrinsic microenvironment. We have shown that partial reprogramming promotes skeletal muscle regeneration in 12-month-old mice, but these studies were performed by expressing OSKM systemically (i.e., in all cell types). It is therefore unclear whether intrinsic or niche-specific factors contributed to the observed improvement in muscle regeneration.

In this work, we generate myofiber- and SC-specific OSKM induction mouse models to investigate the effect of OSKM induction on extrinsic and intrinsic modulators of SCs, respectively. In addition, we chose young mice to investigate whether the improvement of regeneration can be achieved by OSKM induction regardless of its rejuvenating effect. Our data shows that myofiber-specific OSKM induction accelerates muscle regeneration through downregulating the myofiber-secreted niche factor, Wnt4, to induce the activation and proliferation of SCs. In contrast, SC-specific OSKM induction does not improve muscle regeneration in young mice. We conclude that partial reprogramming via OSKM can remodel the SC niche to induce SC activation and proliferation and accelerate muscle regeneration.

You may recall the data on cardiovascular health published in recent years for the Tsimane population in Bolivia, characterized by a physically active lifestyle and a diet that lacks most of the problem components found in wealthier parts of the world. The rates of cardiovascular disease are far lower in the Tsimane than in US populations. While there are certainly inevitable processes of aging that can only be addressed by the development of new medical biotechnologies, it is also the case that a sizable fraction of cardiovascular and muscle degeneration in the wealthier populations of the world appears to be self-inflicted. Too little physical activity and a diet containing too many calories comes with costs. As the research materials here illustrate, that cost also falls on the brain.

Although people in industrialized nations have access to modern medical care, they are more sedentary and eat a diet high in saturated fats. In contrast, the Tsimane have little or no access to health care but are extremely physically active and consume a high-fiber diet that includes vegetables, fish and lean meat. "The Tsimane have provided us with an amazing natural experiment on the potentially detrimental effects of modern lifestyles on our health."

The researchers enrolled 746 Tsimane adults, ages 40 to 94, in their study. To acquire brain scans, they provided transportation for the participants from their remote villages to Trinidad, Bolivia, the closest town with CT scanning equipment. That journey could last as long as two full days with travel by river and road. The team used the scans to calculate brain volumes and then examined their association with age for Tsimane. Next, they compared these results to those in three industrialized populations in the U.S. and Europe.

The scientists found that the difference in brain volumes between middle age and old age is 70% smaller in Tsimane than in Western populations. This suggests that the Tsimane's brains likely experience far less brain atrophy than Westerners as they age; atrophy is correlated with risk of cognitive impairment, functional decline, and dementia. The researchers note that the Tsimane have high levels of inflammation, which is typically associated with brain atrophy in Westerners. But their study suggests that high inflammation does not have a pronounced effect upon Tsimane brains.

According to the study authors, the Tsimane's low cardiovascular risks may outweigh their infection-driven inflammatory risk, raising new questions about the causes of dementia. One possible reason is that, in Westerners, inflammation is associated with obesity and metabolic causes. In the Tsimane, however, it is driven by respiratory, gastrointestinal, and parasitic infections. Infectious diseases are the most prominent cause of death among the Tsimane.

Link: https://news.usc.edu/187075/tsimane-amazon-indigenous-people-healthy-brain-aging-usc-study/

Oisin Biotechnologies is one of the older startup biotech companies in the still young and growing longevity industry. The company develops a programmable suicide gene therapy platform, initially targeted at the selective destruction of senescent cells and cancerous cells. Of interest in a recent press release regarding funding is the note that their senolytic program will be used to treat chronic kidney disease. Other groups are running human trials of the dasatinib and quercetin combination as a treatment for chronic kidney disease. Positive data there will help Oisin Biotechnologies, in the sense that it will further validate the use of senolytics as a class of therapy for this condition, but at the same time set a bar for success that will need to be beaten.

Oisín Biotechnologies, a privately held, preclinical biotechnology company focused on mitigating the effects of age-related diseases, today announced it has completed an oversubscribed round raising $5 million in new seed funding. Led by early-stage investing firm Althea Group, LLC, the round brings Oisín's total funding to $9.5 million. Oisín will use the proceeds to advance its preclinical pipeline, including its most advanced investigational therapy aimed at chronic kidney disease (CKD).

"The support for Oisín's novel approach to slowing or halting age-related diseases has been strong. Chronic kidney disease (CKD), our initial therapeutic focus, has seen little in the way of therapeutic advances over the past several decades. We believe Oisín is well positioned to address this unmet medical need and will continue to explore other applications in tandem."

Oisín's highly precise, DNA-based interventions are designed to clear senescent cells, which can trigger aging pathologies and shorten lifespan, from the body. Its proprietary technology is a third-wave innovation that uses a novel proteo-lipid vehicle drug delivery platform to induce a senescent cell to trigger apoptosis without harming surrounding healthy cells. In preclinical studies, Oisín's investigational therapeutics have significantly reduced senescent cell burden in naturally aged mice and extended lifespan by more than 20%, even when the treatment was started in old age.

Oisín expects the first readouts from its preclinical study in CKD later this year. The initial data will inform its next series of studies and eventually, its first proposed clinical trial design. While using this latest funding to accelerate its CKD work, the company is continuing to progress other planned studies in its preclinical program, advance additional pipeline indications and move towards a regulatory filing to begin its first clinical trial.

Link: https://www.businesswire.com/news/home/20210527005467/en/Ois%C3%ADn-Biotechnologies-Raises-Seed-Funding-to-Advance-Therapies-for-Age-Related-Diseases

The immune system is deeply integrated into tissue function throughout the body. This goes far beyond merely identifying and chasing down invaders such as fungi, bacteria, and viruses. Immune cells of various types also help to coordinate tissue maintenance, regeneration from injury, and the destruction of damaged, cancerous, and senescent cells. In the brain, immune cells are involved in the maintenance and alteration of synaptic connections between neurons. Immune cells mediate inflammatory signaling, and that signaling is in turn highly influential on the behavior of other cells, altering tissue function, particularly when inflammation becomes chronic.

One possibly overly simplistic view of the evolution of the immune system is that its present state is a balance between (a) providing a good-enough defense against pathogens and errant cells, and (b) minimizing harmful side-effects resulting from the inflammatory response. Too aggressive a response and individuals will lapse into chronic inflammation and early death. Too little of a response, and the pathogens win, again causing early death. Somewhere there is a happy medium that allows enough individuals to reproduce to ensure evolutionary success. But there are likely many other trade-offs under constant selection pressure, as discussed in today's open access paper.

Functional conservation in genes and pathways linking ageing and immunity

At first glance, longevity and immunity appear to be different traits that have not much in common except the fact that the immune system promotes survival upon pathogenic infection. Substantial evidence however points to a molecularly intertwined relationship between the immune system and ageing. Although this link is well-known throughout the animal kingdom, its genetic basis is complex and still poorly understood.

In this review, we combined curation and analysis of orthologs between D. melanogaster, C. elegans, mice, and humans to reveal that genes currently known to be pleiotropically involved in immunity, lifespan, and ageing reside in a few core pathways mediating the immuno-ageing interplay. We identified 7 evolutionarily conserved signalling cascades, the insulin/TOR network, three MAPK (ERK, p38, JNK), JAK/STAT, TGF-β, and Nf-κB pathways that act pleiotropically on ageing and immunity. However, we highlight that these pathways not only cross-talk, but also clearly act pleiotropically to regulate pathogen resistance, lifespan, and ageing among many other physiological processes such as metabolism and stress resistance.

Our review demonstrates that loss of immune homeostasis is a central determinant of ageing across diverse phyla. Yet, whether immunosenescence and the age-associated decline in other traits is a cause or result of ageing remains a fundamental problem difficult to resolve. Knowing the exact time and place of changes related to immunity and ageing would be a huge step in answering this question. Moreover, how environmental effects, including life-long pathogenic challenges, variation in the microbiome, or nutrition affect age-related changes in immunity is poorly understood. To date most studies are restricted in resolution, particularly in terms of analysed tissues, time points, phenotypes, and experimental conditions. Cutting-edge technologies such as single-cell sequencing can be useful in that respect and could be utilized to characterize molecular changes during ageing and infection in specific cell types. In combination with genome-wide CRISPR knockout screens, new immuno-ageing genes can be discovered and the cross-talk between immunity and ageing further deciphered.

Currently, the level of detail needed to solve the causality enigma of ageing is likely not achievable in humans but may be addressed in shorter lived model organisms that are easier to manipulate. Once we understood ageing at this unprecedented level, it will be possible to optimize lifestyle factors and emerging drug therapies treating senescence to facilitate healthy ageing and extend lifespan.

Senescent cells accumulate with age and cause a great deal of harm in the aged body. Their numbers are not thought to be very high in most tissues, perhaps a few percent of all cells by late life, but senescent cells secrete a potent mix of signals that has a widespread disruptive effect. This signaling spurs chronic inflammation and causes malfunctioning of the normal processes of tissue regeneration and maintenance, amongst other issues. In organs like the kidney, this results in a lack of resilience to injury, increased fibrosis, and eventually chronic kidney disease. Researchers have shown that senolytic treatment to destroy senescent cells is beneficial in animal models of chronic kidney disease, and a human trial is ongoing, with encouraging early results. Here, researchers show that senolytic treatment can also restore some degree of lost regenerative capacity in aged kidneys.

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy.

We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor β1, induced fibrosis, and inhibited tubular proliferative capacity after injury.

Treatment of aged and irradiated mice with the senolytic drug ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.

Link: https://doi.org/10.1126/scitranslmed.abb0203

The Gero staff have in recent years performed scientifically interesting modeling of data, from aging animals and humans, in support of their drug development program. One might look back on their categorization of age-related degeneration into two components, which they call "aging" and "frailty", but which are really just labels for what appear to be two distinct aspects of biomarker progression with chronological age that emerge from their data. Humans and mice have quite different balances of "aging" versus "frailty", which could in principle inform unbiased screening programs for drugs that might slow the progression of aging. In this open access paper, the Gero team look at human biomarkers of aging over time to build a model of loss of resilience; again scientifically interesting.

Most important factors that are strongly associated with age are also known as the hallmarks of aging and may be, at least in principle, modified pharmacologically. In addition to that, the dynamic properties such as physiological resilience measured as the recovery rate from the organism state perturbations were also associated with mortality and thus may serve as an early warning sign of impending health outcomes.

We conducted a systematic investigation of aging, organism state fluctuations, and gradual loss of resilience in a dataset involving multiple Complete Blood Counts (CBC) measured over short periods of time (a few months) from the same person along the individual aging trajectory. Instead of focusing on individual factors, to simplify the matters, we followed and described the organism state by means of a single variable, henceforth referred to as the dynamic organism state indicator (DOSI) in the form of the all-cause mortality model predictor. First, we observed that early in life the DOSI dynamics quantitatively follows the universal ontogenetic growth trajectory. Once the growth phase is completed, the indicator demonstrated all the expected biological age properties, such as association with age, multiple morbidity, unhealthy lifestyles, mortality and future incidence of chronic diseases.

Late in life, the dynamics of the organism state captured by DOSI along the individual aging trajectories is consistent with that of a stochastic process (random walk) on top of the slow aging drift. The increase in the DOSI variability is approximately linear with age and can be explained by the rise of the organism state recovery time. The latter is thus an independent biomarker of aging and a characteristic of resilience. Our analysis shows that the auto-correlation time of DOSI fluctuations grows (and hence the recovery rate decreases) with age from about 2 weeks to over 8 weeks for cohorts aging from 40 to 90 years. The divergence of the recovery time at advanced ages appeared to be an organism-level phenomenon.

We put forward arguments suggesting that such behavior is typical for complex systems near a bifurcation (disintegration) point and thus the progressive loss of resilience with age may be a dynamic origin of the Gompertz law of mortality. Finally, we noted, by extrapolation, that the recovery time would diverge and hence the resilience would be ultimately lost at the critical point at the age in the range of 120-150 years, thus indicating the absolute limit of human lifespan, absent novel interventions.

Link: https://doi.org/10.1038/s41467-021-23014-1

Progeria (more correctly Hutchinson-Gilford progeria syndrome) is a condition in which a protein vital to cell structure, lamin A, is mutated. Cells with abnormal structure due to loss of function in lamin A are dysfunctional in many ways, including being very prone to senescence. Patients rarely live past their teens, and exhibit a range of conditions such as cardiovascular disease that appear similar to the age-related diseases suffered in later life by non-mutated people. Calling progeria accelerated aging is incorrect and a source of confusion, however, as illustrated by a recent commentary on the topic.

What Do Treatments For Accelerated Aging Tell Us About Normal Aging?

Children with progeria have a mutation in the relevant gene; instead of producing lamin A, they produce a defective mutant protein called progerin. The cell tries to build the nuclear lamina out of defective progerin instead of normal lamin A, and as a result the cell nucleus is screwed up and can't maintain a normal shape. So then aging happens? My sources don't seem to have a great explanation of this. The UniProt database says that this "acts to deregulate mitosis and DNA damage signaling, leading to premature cell death and senescence". This paper goes a little further, saying that the screwiness in the nuclear lamina prevents DNA repair proteins from doing their job.

So a unified theory of progeria goes: the lamin mutation causes accumulation of defective protein in the nucleus, preventing DNA repair. This makes people accumulate DNA damage faster, and since DNA damage is a major cause of aging, it makes these people age more quickly. Lornafarnib interferes with the production of the defective progerin protein. All of this suggests lornafarnib shouldn't help prevent normal aging. After all, normal aging is caused by lots of processes including gradual expected accumulation of DNA damage - not just the downstream effects of one weird mutant protein.

...except that in doing this research I kept finding people saying that maybe some of aging is caused by this one weird mutant protein. I don't really get what's going on here. I know that often, as age-related damage degrades DNA, a lot of weird malformed proteins pop up and accumulate. Maybe progerin is one of these proteins and causes some of the problems commonly associated with aging?

Age-related diseases occur due to damage and loss of function. As a result of damage, cells are misbehaving, broken, lost and not replaced, following incorrect programs, and so forth. In normal aging, this is the result of a particular balance of various forms of damage and their consequences: cellular senescence, buildup of resilient metabolic waste, mitochondrial damage and dysfunction, stem cell decline, and so forth. In progeria, a completely different form of damage dominates, with the result that cells are misbehaving, broken, lost and not replaced, and so forth. It is not that different, conceptually, from a slow poisoning that interferes with vital cellular functions, some forms of which can also superficially replicate the effects of aging.

The point here being that any form of damage that leads to widespread cellular dysfunction, that is not so severe as to kill the patient quickly, will likely have among its outcomes something that looks like a range of age-related conditions. That doesn't make it aging, nor does it say anything at all about how to go about addressing aging itself. The best way to approach aging is to periodically repair the cell and tissue damage that causes it. The strategies for that repair depend absolutely on the type of damage being repaired. Treatments for poisoning or progeria will, on balance, have little to no relevance to the strategies needed to effectively treat aging.

In the case of progeria this is slightly complicated by the discovery that there is a little broken lamin A to be found in normal old humans. Present thinking is that this is likely connected to cellular senescence. The numbers of senescent cells rise with age, and are clearly important to aging, but likely not because of lamin A. Alternatively, the creation of broken lamin A is happening at a very low level throughout the body as a result of other forms of damage and dysfunction in cells, and it is thus a downstream effect and not all that relevant. The challenge in much of biochemistry is that absent a way to selectively eliminate one mechanism without affecting all of the others, it is very hard to say which of these mechanisms are actually more or less important to the observed outcome.

Another challenge is that researchers do tend to exaggerate the relevance of the work they are doing in order to assist in the grant writing process, but that is a whole different topic. So of course anyone writing a paper on lamin A in normal aging is going to say, absent proof otherwise, that it looks like this may be relevant to aging, and more research into this mechanism is justified.

Is malformed lamin A at all relevant to normal aging? Setting aside the reasonable guess of "no", one can imagine a study of senolytic drugs to clear senescent cells in normally aged animals or humans, with before and after tests of the level of malformed lamin A in various tissues in the body. That would be informative. An effective gene therapy to deliver functional lamin A would also be informative, but the present state of gene therapy vectors is that it is very challenging to deliver a vector even close to globally in the body at usefully high levels. Near all of it ends up in the liver and lungs, usually. That would likely be beneficial for progeria patients, while not beneficial enough to save their lives, but seems unlikely to tell us much in a normally aged animal or human.

It is always interesting to see studies that compare the outcomes of calorie restriction and intermittent fasting. In this case, researchers provide evidence to suggest that, at the same mild overall calorie reduction versus ad libitum feeding, intermittent fasting produces larger effects on memory function. If those effects are driven in large part by the biochemistry of hunger, then we might think that intermittent fasting produces more time spent hungry, and thus a larger effect size. The choice of amount of calorie reduction may well influence the outcome of any such comparison for other reasons, however.

Daily calorie restriction (CR) and intermittent fasting (IF) enhance longevity and cognition. Despite the positive effects of CR and IF in neurodegenerative and affective conditions, the specific behavioral contributions and mechanisms that differentiate both interventions remain largely unknown. Answering these questions is pivotal to adapting these regimens to human populations, given the challenges of adhering to a long-term CR regimen when compared to the improved adherence to variations of the IF paradigm.

Here, we directly compared the effects of IF to a matched 10% daily CR regimen upon learning and memory in mice. A 10% energy restriction protocol was chosen for the CR group following the observation that IF mice overall consume 10% less calories on a weekly basis. IF improved long-term retention memory to a greater extent than CR and was associated with increased adult hippocampal neurogenesis and upregulation of the longevity gene Klotho. Though klotho protein is produced primarily in the kidney, it is also highly expressed in some brain areas, including the dentate gyrus of the hippocampus and in particular by its mature neurons.

The function of klotho in the brain is still largely unknown but it has been proposed that it plays an important role in cognition because increased serum levels of klotho were associated with increased cognitive ability in humans and rodents. Here, we confirm previous evidence suggesting that Kl is an important regulator of adult hippocampal neurogenesis and propose it as a novel molecular player through which IF may enhance cognitive performance.

Link: https://doi.org/10.1038/s41380-021-01102-4

Researchers have delivered a non-human photosensitive protein to the retina of a patient long blind from the loss of photoreceptor cells caused by retinitis pigmentosa. The outcome as described is not as good as the results produced by implantation of grids of electrodes into the retina, but that strategy has been under development for a somewhat longer number of years. This approach is in the very early stages: it is unclear as to how well one can engineer the retina to use alternative means of translating light into signals to the optic nerve, and how well the brain will adapt to such new sources of information over time. Still, the prospects for the blind are becoming more promising year after year, as the number of approaches to regeneration or replacement grows.

Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding the channelrhodopsin ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells.

The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalographic recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy.

Link: https://doi.org/10.1038/s41591-021-01351-4