Fight Aging!

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Contents

• Calorie Restriction Reduces the Number of Senescent T Cells in Older Mice
• Stem Cell Therapy Improves Mitochondrial Quality Control
• Actually, We Really Do Need to Keep Talking About Radical Life Extension as the Primary Goal of Research and Industry
• Upregulation of NRF2 in Mice Slows Neural Stem Cell Decline in Middle Age, but Not In Later Life
• The Extraordinary Longevity of Salamanders
• More Alzheimer's Immunotherapies Improve Biomarkers But Not Patient Outcomes
• Arguing for Metformin's Effects on Life Expectancy to be Due to Suppression of Excessive Inflammation
• Are Senescent Cells an Important Cause of Non-Alcoholic Fatty Liver Disease Pathology?
• CD22 Inhibition Improves Microglia Function in Old Mice
• MEOX1 as an Important Regulator of Fibrosis, and Target for Therapy
• The GrimAge Epigenetic Clock Reflects Mortality Risk Differences Between Twins
• Heart Failure Correlates with Increased Cancer Risk
• What Causes the Reproductive Caste of Eusocial Species to Evolve Greater Longevity?
• A Broad and Reversible Threshold for Hair Greying
• Age-Related Hearing Impairment Correlates with Age-Related Physical Impairment

Calorie Restriction Reduces the Number of Senescent T Cells in Older Mice
https://www.fightaging.org/archives/2021/06/calorie-restriction-reduces-the-number-of-senescent-t-cells-in-older-mice/

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.

Stem Cell Therapy Improves Mitochondrial Quality Control
https://www.fightaging.org/archives/2021/06/stem-cell-therapy-improves-mitochondrial-quality-control/

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.

Actually, We Really Do Need to Keep Talking About Radical Life Extension as the Primary Goal of Research and Industry
https://www.fightaging.org/archives/2021/06/actually-we-really-do-need-to-keep-talking-about-radical-life-extension-as-the-primary-goal-of-research-and-industry/

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."

Upregulation of NRF2 in Mice Slows Neural Stem Cell Decline in Middle Age, but Not In Later Life
https://www.fightaging.org/archives/2021/07/upregulation-of-nrf2-in-mice-slows-neural-stem-cell-decline-in-middle-age-but-not-in-later-life/

Today's open access paper provides an interesting example of a mechanism that slows a facet of aging only in middle age, when tested in mice. Researchers found that upregulation of NRF2 expression in the brain via gene therapy had meaningful positive effects on neural stem cell function in middle age only. We might consider that any given aspect of cell behavior is governed by multiple overlapping regulatory networks, and thus it is quite possible to see a particular point of intervention work under some circumstances but not under others, depending on the state of the cell, its environment, and which regulatory systems are dominant as a consequence.

Neural stem cells provide a supply of new neurons to the brain, which is very important for tissue maintenance, recovery from injury, and the workings of memory, among other processes. These stem cell populations, like all others elsewhere in the body, decline in activity with age. Much of this is a reaction to the molecular damage of aging throughout the body and consequent changes in the signaling environment, rather than any critical inherent damage to the stem cells themselves. Thus a broad range of strategies in medical research aim to force stem cells into greater, more youthful levels of activity, overriding their controlling mechanisms in order to do so. It remains to be seen as to the degree that the risk of cancer, due to increased cell activity in an environment of increased cell damage, is a problem that will significantly limit the use of this approach in any given case.

Enhanced NRF2 expression mitigates the decline in neural stem cell function during aging

Adult neural stem progenitor cells (NSPCs) are characterized by the ability to self-renew and differentiate into neuronal and glial cell types in the mature nervous system. This cell-level plasticity is not fixed, but rather a dynamic and highly modulated process. NSPC activity can be influenced by a range of factors, such as physical exercise, environmental enrichment, stress, and nutrition, but also importantly aging. In fact, aging contracts NSPC niches in the brain and significantly alters their function. Given the pivotal role of stem cells in tissues with lifelong regenerative capacity such as the brain, understanding stem cell aging will be important if we are to understand aging at the organ level. More broadly, comprehending stem cell aging will also support the development of interventions that could improve both health and lifespan.

In this context, our previous studies, conducted in naturally aging rodents, identified a specific temporal pattern of change in NSPC dynamics during aging. In particular, the studies highlighted a critical time during middle age (13-15 months), when the regenerative function of NSPCs showed a striking decline. The studies also determined the reduced expression of nuclear factor (erythroid-derived 2) like 2 (or NRF2), as a key mechanism mediating this phenomenon. As such, this work provided first evidence of an important regulatory role for NRF2 in NSPC aging.

NRF2 is a redox-sensitive transcription factor known to be essential to the cell's homeostatic mechanism. NRF2 is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, inflammatory agents, and excessive nutrient/metabolite supply. In particular, NRF2 can up-regulate a range of classical ARE (antioxidant response element)-driven genes, encoding major antioxidants and other detoxification enzymes. In addition to its classical function in regulating the stress response, NRF2 has been linked to cell growth, proliferation, mitochondrial and trophic functions, protein quality control, and increased lifespan.

Given that NRF2 loss accentuates NSPC aging, in this study, we investigated whether increasing NRF2 levels could boost NSPC function with age. In particular, we studied whether inducing high intrinsic NRF2 expression can potentially mitigate the decline in NSPC regeneration during the critical middle-age period between 13 and 15 months, identified in our previous work. NRF2 was delivered to rat subventricular zone (SVZ) NSPCs through recombinant adeno-associated viral (AAV) vectors injected either before (at 11 months of age) or well after the critical aging period (at 20 months of age). We find that the administration of AAV-NRF2-eGFP vectors before the initiation of the critical period substantially improved SVZ NSPC regeneration and associated behavioral function, as compared to controls (AAV-eGFP delivery). On the other hand, application of AAV-NRF2-eGFP after the conclusion of the critical period failed to significantly promote NSPC activity and function. This data establishes a major governing role for NRF2 in NSPCs and support targeting the NRF2 pathway as a potential approach to advantageously modulate NSPC function with age.

The Extraordinary Longevity of Salamanders
https://www.fightaging.org/archives/2021/07/the-extraordinary-longevity-of-salamanders/

An impressive regenerative capacity often goes hand in hand with longevity. Salamanders are capable of regrowth of lost limbs and injured internal organs, and are unusually long-lived for their size. Like other smaller species that exhibit an exceptional life span, salamanders are the subject of research initiatives that aim to find the relevant biochemical differences that produce greater species longevity. Additionally, scientists are very interested in understanding the specific mechanistic differences between mammals, largely incapable of regeneration without scarring, and species such as salamanders that are capable of scarless regeneration.

More inroads have been made into the question of regeneration than the question of longevity, and it remains far too early to say whether or not there is anything in salamander biochemistry that can be adapted into therapies and safely applied to a mammal in order to lengthen life span. The genetics and cellular metabolism that underlies differences in species life span is a complex swamp of detail piled upon detail, poorly understood and poorly mapped. Progress is slow, as there are only so many researchers in this part of the field, and only so much funding.

Salamander Insights Into Ageing and Rejuvenation

A salient feature of salamander regeneration is its resilience. Urodele regenerative capacity does not decline with time, and most studies suggest it is not impaired by repetitive regeneration events. A landmark study tracked the process of lens regeneration over 16 years in Japanese newts, removing the lens from the same animals 18 times and allowing them to undergo regeneration. Remarkably, the resulting lenses were structurally identical to the original ones and expressed similar levels of lens-specific genes. Subsequent analysis revealed that the transcriptomes of young and old (19-times regenerated) lenses are nearly indistinguishable, showcasing the robustness of newt lens regeneration. Of note, by the end of the study the specimens were at least 30 years old, representing a geriatric population in this species. This provides an interesting contrast to the declines in regenerative capacities observed in most vertebrate contexts.

Additional studies indicate that repetitive amputations do not affect tail regenerative potential in the newt Triturus carnifex, as examined over a 10 year period with up to nine tail regeneration cycles, nor that of the axolotl limb, challenged by five regeneration rounds during 3 years. Taken together, the evidence to date suggests that the ability of urodeles to regenerate complex structures does not decline with time or serial regeneration cycles. In mammals, loss of regenerative potential with ageing has been largely attributed to the ageing of stem cell populations and/or their niche. Whether the prevalence of dedifferentiation as a regenerative mechanism in salamanders is linked to the indefinite nature of their regenerative potential remains an outstanding question.

Beyond their remarkable regenerative abilities, salamanders exhibit extraordinary longevity, constituting lifespan outliers with respect to organismal size. Among animal species, there is a notable correlation between body mass and lifespan, with larger animals living longer. Yet, salamanders break this rule by several orders of magnitude. For example, axolotls - average mass: 60-110g - live over 20 years, and cave olms - Proteus anguinus; average mass: 17g - can surpass 100 years. Indeed, they match and in some cases exceed the lifespan/body mass ratios found in other well-known outliers such as the naked mole rat and Brandt's bat. This is even more remarkable given that most salamander longevity data derive from specimens in the wild, where animals are exposed to environmental challenges, predation, pathogens, and food source fluctuations. Thus, salamanders are not only lifespan outliers, but also in many cases their longevity may be underestimated.

More Alzheimer's Immunotherapies Improve Biomarkers But Not Patient Outcomes
https://www.fightaging.org/archives/2021/06/more-alzheimers-immunotherapies-improve-biomarkers-but-not-patient-outcomes/

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.

Arguing for Metformin's Effects on Life Expectancy to be Due to Suppression of Excessive Inflammation
https://www.fightaging.org/archives/2021/06/arguing-for-metformins-effects-on-life-expectancy-to-be-due-to-suppression-of-excessive-inflammation/

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."

Are Senescent Cells an Important Cause of Non-Alcoholic Fatty Liver Disease Pathology?
https://www.fightaging.org/archives/2021/06/are-senescent-cells-an-important-cause-of-non-alcoholic-fatty-liver-disease-pathology/

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.

CD22 Inhibition Improves Microglia Function in Old Mice
https://www.fightaging.org/archives/2021/06/cd22-inhibition-improves-microglia-function-in-old-mice/

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.

MEOX1 as an Important Regulator of Fibrosis, and Target for Therapy
https://www.fightaging.org/archives/2021/06/meox1-as-an-important-regulator-of-fibrosis-and-target-for-therapy/

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."

The GrimAge Epigenetic Clock Reflects Mortality Risk Differences Between Twins
https://www.fightaging.org/archives/2021/06/the-grimage-epigenetic-clock-reflects-mortality-risk-differences-between-twins/

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.

Heart Failure Correlates with Increased Cancer Risk
https://www.fightaging.org/archives/2021/07/heart-failure-correlates-with-increased-cancer-risk/

Age-related disease results from the underlying cell and tissue damage that causes aging. Different people accumulate that damage at modestly different rates, the result of lifestyle choices and exposure to infectious disease. Thus the presence of a sufficient burden of damage to produce one age-related disease will be accompanied by a raised risk of other age-related conditions. The conditions themselves need not have any direct relationship with one another, but can be distinct outcomes of the same root causes. Here, however, researchers propose that heart failure may provoke increased cancer risk via inflammatory and other signaling pathways. This may or may not be the case. The inflammatory signaling certainly exists, but it is always a challenge to determine the relative significance of the many possible contributing mechanism in the onset and progression of age-related disease.

Our study demonstrates that heart failure patients have a significantly increased incidence of cancer in general and of each individual cancer type studied. The data - based on a collective of over 100,000 heart failure patients - confirm the results of previous evaluations in smaller study populations. The data do not prove a causal relationship but instead show a statistical relationship between heart failure and cancer. Nevertheless, these results allow us to speculate that there may be a causal relationship between heart failure and an increased cancer rate.

The particularly high incidence of oropharyngeal carcinoma in heart failure patients suggests that common extrinsic risk factors such as nicotine are a possible trigger of the co-morbidity. In this regard, one limiting factor of our study is that our database does not provide data on nicotine use or alcohol consumption. In addition to these external risk factors, cancer in general and cardiovascular diseases share common risk factors such as obesity and diabetes. As our data are adjusted for these risk factors, our highly significant results cannot be explained by these factors alone.

One possible explanation could be the occurrence of certain pathomechanisms such as chronic inflammation or increased free radical formation, which may interact with a certain genetic background to connect both heart failure and cancer. Another interesting hypothesis suggests that heart failure is an oncogenic condition. This means that the failing heart may promote tumourigenesis or tumour growth. New data from animal studies suggest that the secretion of certain proteins may be up-regulated in failing hearts, promoting the secretion of certain tumour growth factors.

Supporting evidence comes from a study demonstrating that serum levels of heart failure markers such as N-terminal pro-brain natriuretic peptide and troponin T were elevated in cancer patients even before the application of anticancer therapy, suggesting that subclinical myocardial injury exists in cancer patients. The specific interaction of cardiac stress-induced proteins with oncogenic signalling pathways is a relatively new branch of research with great potential. Some of these potential heart failure / oncogenic pathway interactions may be organ specific. In this context, studies such as ours that link large collectives of heart failure patients not only to cancer development in general but also to individual organ systems may be helpful.

What Causes the Reproductive Caste of Eusocial Species to Evolve Greater Longevity?
https://www.fightaging.org/archives/2021/07/what-causes-the-reproductive-caste-of-eusocial-species-to-evolve-greater-longevity/

A eusocial species is divided into specialized castes. The reproductive caste (queens) exhibits a much longer life span than members of the other non-reproductive castes (workers), yet the members of all castes are genetically similar. Researchers here discuss the ways in which this divergent life span might evolve so reliably whenever a species is eusocial. It is observed across widely divergent species, from insects to mammals. This sort of work complements investigations into the biochemistry of this exceptional longevity of the reproductive caste, mostly carried out in insect species.

Queens of eusocial species live extraordinarily long compared to their workers. So far, it has been argued that these lifespan divergences are readily explained by the classical evolutionary theory of ageing. As workers predominantly perform risky tasks, such as foraging and nest defense, and queens stay in the well-protected nests, selection against harmful genetic mutations expressed in old age should be weaker in workers than in queens due to caste differences in extrinsic mortality risk, and thus, lead to the evolution of longer queen and shorter worker lifespans. However, these arguments have not been supported by formal models.

Here, we present a model for the evolution of caste-specific ageing in social insects, based on the antagonistic pleiotropy theory of ageing. In individual-based simulations, we assume that mutations with antagonistic fitness effects can act within castes, that is, mutations in early life are accompanied by an antagonistic effect acting in later life, or between castes, where antagonistic effects emerge due to caste antagonism or indirect genetic effects between castes. In monogynous social insect species with sterile workers, large lifespan divergences between castes evolved under all different scenarios of antagonistic effects, but regardless of the degree of caste-specific extrinsic mortality. Mutations with antagonistic fitness effects within castes reduced lifespans of both castes, while mutations with between-caste antagonistic effects decreased worker lifespans more than queen lifespans, and consequently increased lifespan divergences.

Our results challenge the central explanatory role of extrinsic mortality for caste-specific ageing in eusocial organisms and suggest that antagonistic pleiotropy affects castes differently due to reproductive monopolization by queens, hence, reproductive division of labor.

A Broad and Reversible Threshold for Hair Greying
https://www.fightaging.org/archives/2021/07/a-broad-and-reversible-threshold-for-hair-greying/

This research into the fine details of hair greying is interesting but of limited practical application, I suspect. It is nonetheless a good illustration of the point that there are few sharp dividing lines in the biochemistry of aging. Even seemingly binary changes such as hair going grey represent a broad threshold that is crossed slowly, and under the hood there are likely numerous competing and conflicting mechanisms and regulatory systems that only incrementally come to a consensus on cell behavior. None of this really changes the best way forward for the treatment of any part of aging: identify the causative damage and repair that damage, in the expectation that many of the consequences that make up degenerative aging will reverse themselves as cell behavior returns to a youthful state.

Hair greying is a visible sign of aging that affects everyone. The loss of hair color is due to the loss of melanin, a pigment found in the skin, eyes and hair. Research in mice suggests stress may accelerate hair greying, but there is no definitive research on this in humans. This is because there are no research tools to precisely map stress and hair color over time. But, just like tree rings hold information about past decades, and rocks hold information about past centuries, hairs hold information about past months and years.

Hair growth is an active process that happens under the skin inside hair follicles. It demands lots of energy, supplied by structures inside cells called mitochondria. While hairs are growing, cells receive chemical and electrical signals from inside the body, including stress hormones. It is possible that these exposures change proteins and other molecules laid down in the growing hair shaft. As the hair grows out of the scalp, it hardens, preserving these molecules into a stable form. This preservation is visible as patterns of pigmentation. Examining single-hairs and matching the patterns to life events could allow researchers to look back in time through a person's biological history.

Researchers here report a new way to digitize and measure small changes in color along single human hairs. This method revealed that some white hairs naturally regain their color, something that had not been reported in a cohort of healthy individuals before. Aligning the hair pigmentation patterns with recent reports of stress in the hair donors' lives showed striking associations. When one donor reported an increase in stress, a hair lost its pigment. When the donor reported a reduction in stress, the same hair regained its pigment. Researchers mapped hundreds of proteins inside the hairs to show that white hairs contained more proteins linked to mitochondria and energy use. This suggests that metabolism and mitochondria may play a role in hair greying.

The new method for measuring small changes in hair coloring opens up the possibility of using hair pigmentation patterns like tree rings. This could track the influence of past life events on human biology. In the future, monitoring hair pigmentation patterns could provide a way to trace the effectiveness of treatments aimed at reducing stress or slowing the aging process. Understanding how 'old' white hairs regain their 'young' pigmented state could also reveal new information about the malleability of human aging more generally.

Age-Related Hearing Impairment Correlates with Age-Related Physical Impairment
https://www.fightaging.org/archives/2021/07/age-related-hearing-impairment-correlates-with-age-related-physical-impairment/

It should not be surprising to find correlations between manifestations of age-related degeneration, even those in which it is debatable as to whether age-related condition A can contribute meaningfully to the progression of age-related condition B, as is the case for hearing loss and physical frailty. All age-related conditions and aspects of aging arise from the same set of underlying forms of cell and tissue damage. Different people accumulate that damage at somewhat different rates, due largely to lifestyle choices and environmental factors. If someone exhibits greater consequences of aging in one part of the body, the odds are good that degeneration in the rest of the body is also more advanced.

Physical functioning is necessary for independent living and tends to decline with age. Hearing impairment, which affects approximately two-thirds of adults older than 70 years, is a risk factor for various adverse outcomes. Hearing impairment may also adversely affect physical functioning through reduced perception of auditory input that contributes to walking and balance. However, research characterizing the association between hearing impairment and objective physical function and walking endurance measures is limited.

Associations between self-reported hearing impairment and poorer physical function have been reported previously. However, self-reported hearing impairment is prone to measurement error and has been shown to underestimate associations with objective measures of function. Although studies with audiometrically assessed hearing, the criterion-standard clinical measure, have revealed associations with slower gait and poorer physical function, these studies did not assess associations with physical function components separately. Therefore, we investigated the association of hearing impairment with physical function and walking endurance in a cohort of community-dwelling older adults in the US.

In this cohort study, hearing impairment was associated with poorer physical function and walking endurance in cross-sectional analysis and faster declines in physical function in longitudinal analysis. These associations were graded in general, with stronger associations among individuals with worse hearing. The differences in gait speed and walking endurance between participants with severe hearing impairment vs those with normal hearing were clinically meaningful according to previous literature. Collectively, these findings suggest that individuals with hearing impairment may be at greater risk for physical function limitations.