Fight Aging! Newsletter, June 5th 2023

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit:

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more:


Self-Reported Data From Several Hundred Rapamycin Self-Experimenters

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

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

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

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

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

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

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

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

Does an Actin Cytoskeletal Stress Response Exist and Have Relevance to Aging?

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

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

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

More than a loading control: actin regulation in aging

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

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

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

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

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

Raised Basal Metabolic Rate Correlates with Reduced Life Expectancy in Humans

Resting (or basal) metabolic rate has been shown to broadly correlate with mammalian species life span, in that species with short life spans tend to have high metabolic rates, and species with long life spans tend to have low metabolic rates. It also tends to be the case that large mammals live longer than short mammals, with lower metabolic rates. Great longevity in primates when compared to other similarly sized mammals may have required a reduction in metabolic rate to have evolved. Species that do not follow this trend tend to be of interest to researchers investigating the comparative biology of aging. Some species of bats are small, long-lived, and exhibit very high metabolic rates. The long-lived naked mole-rat is metabolically unusual in any number of ways, including metabolic rate.

Do differences in resting metabolic rate between individuals in the same species predict life expectancy, however? There is evidence for this to be the case in humans. Resting metabolic rate does decline with age, and there have been efforts to use that decline as a biomarker of aging. Higher resting metabolic rate correlates with a shorter life expectancy and increased risk of age-related disease, however. We might argue that this has something to do with the level of activity undertaken by damaged cells in damaged tissues, and its influence on cancer risk. We might also argue that this has to do with the activity of the immune system, and the burden of infectious disease. Historically, human body temperature has declined over the period for which good records exist. Body temperature is a crude proxy for resting metabolic rate, and the burden of infectious disease has declined dramatically over this same period of time.

Effect of basal metabolic rate on lifespan: a sex-specific Mendelian randomization study

Metabolism has long been linked to the process of aging and longevity but the evidence from studies of their associations is not always in accordance. Total daily energy expenditure consists of basal metabolic rate (BMR), thermic effects of food, and energy expenditure from physical activity. BMR reflects the daily energy requirement for maintaining basic bodily functions. It is the major source of energy expenditure and is an important parameter for estimating daily energy requirements.

Observationally, the association of BMR with mortality is mixed, although some ageing theories suggest that higher BMR should reduce lifespan. It remains unclear whether a causal association exists. In this one-sample Mendelian randomization study, we aimed to estimate the casual effect of BMR on parental attained age, a proxy for lifespan, using two-sample Mendelian randomization methods. We obtained genetic variants strongly and independently predicting BMR from the UK Biobank and applied them to a genome-wide association study of parental attained age based on the UK Biobank.

A total of 178 and 180 genetic variants predicting BMR in men and women were available for father's and mother's attained age, respectively. Genetically predicted BMR was inversely associated with father's and mother's attained age (years of life lost per unit increase in effect size of genetically predicted BMR, 0.46 and 1.36), with a stronger association in women than men. In conclusion, higher BMR might reduce lifespan. The underlying pathways linking to major causes of death and relevant interventions warrant further investigation.

Betting Against Progress Turns Out Poorly, But Can Work in the Short Term in a Slow Field

Setting oneself up as a spokesperson for "we will not achieve this goal", as the fellow noted here is choosing to do, is a bet against technological progress. A glance at any few decade period in the past two hundred years suggests that such a bet will almost certainly fail in time, sometimes quite rapidly. In highly regulated fields that move as slowly as is the case for medicine, however, one can profitably continue to be a skeptic for quite some time. While progress is rapid and impressive in the lab and in animal studies, a skeptic can continue to shrug and point to the lack of human therapies.

This is the result of an excessive burden of regulatory cost: rapid progress in the lab, in a revolutionary era of increasing capacity, improving tools, and falling costs, runs up against a wall of regulatory delay and vast expense. It takes twenty years to move from early research to mode of therapy to clinical approval, and few programs make it all the way, abandoned in the face of a cost that no-one is willing to pay. All skeptics setting themselves up in general opposition to technological progress will look silly at some point, it just takes longer when the state has decided that progress in a given field will be slow and burdened.

When selective and intelligent, skepticism serves a useful purpose, as every grand endeavor, every new field will attract a problematic minority of the fraudulent, the mistaken, the grandiose, and the rent-seekers. There certainly exist a handful of modern day alchemists and would-be demagogues who care little about scientific truth amidst the majority of earnest, scientifically-minded folk in the longevity community. But to set oneself up as a full-on skeptic of the ability to meaningfully extend human life span? That is just as bad, and for similar reasons.

The Longevity Skeptic

At the Longevity Investors Conference last October in Switzerland, speakers described breakthrough therapies being developed to manipulate genes for longer lifespans. Swag bags bestowed pill bottles promising super longevity, stirring hopes for centuries of youth. Then Charles Brenner took the stage. The biochemist from City of Hope National Medical Center, in Los Angeles, addressed these ideas and treatments one by one, picking them apart, explaining that they're based on faulty research. We can't stop aging, he told the crowd. We can't use longevity genes to stay young because getting older is a fundamental property of life.

Over the past year, Brenner has been challenging life-extension theories on Twitter, YouTube, and the conference circuit, where he's been introduced as the "longevity skeptic." Brenner tells people the reasons for suspicion date back to Herodotus' made-up account of the Fountain of Youth in 425 B.C. Some things never change, he says, even as the field of aging research has picked up scientific momentum in recent years. Investments in longevity startups are predicted to jump from $40 billion to $600 billion in the next three years. Lured by funding from digital age tycoons such as Jeff Bezos and Peter Thiel, top scientists are aligning with companies to advance their work.

Brenner is critical of several big promises emanating from these companies and researchers, such as claims that cellular reprogramming could halt aging. At best, Brenner says, scientists can develop therapies that maintain the health of older people and help keep them out of the hospital-an increasingly important goal as the average age in the United States and elsewhere keeps climbing. Brenner is tackling this problem as the chief scientific advisor of a bioscience company called ChromaDex, which markets supplements for "healthy aging." But believing we can rewrite the operating manual for lifespan itself, Brenner told me, is like "believing in the tooth fairy."

Long Term Hypoxia Slows Aging in an Accelerated Aging Mouse Model

Researchers here show that a mouse model of accelerated aging lives considerably longer when in a low-oxygen atmosphere for most of its life span. This is quite interesting, even given that large effect sizes in accelerated aging models should be taken with a grain of salt. It is most likely that any effect on normal mice would be smaller, and also likely that any form of life extension achieved through manipulation of stress responses, such as the response to hypoxia, will produce much smaller effects in long-lived mammals than in short-lived mammals.

As is always the case, recall that when we say "accelerated aging" what we really mean is that the mouse lineage in question exhibits some deficiency that allows one specific form of cellular dysfunction to accumulate rapidly. These models can appear a little like accelerated aging, but they are not actually exhibiting accelerated aging, just the accumulation of one form of damage. Normal aging is a mix of numerous different types of cellular dysfunction and damage, and that difference matters. In this case, the model has a mutation that impairs DNA repair. The large effect size for hypoxia in this model in turn might imply that hypoxic stress is good at improving DNA repair efficiency, but more research would be needed to confirm that hypothesis.

Hypoxia extends lifespan and neurological function in a mouse model of aging

To the best of our knowledge, the current study is the first to report that hypoxia extends lifespan in a mouse model of aging. We have demonstrated that continuous hypoxia (11% oxygen) - or "oxygen restriction" - significantly extends lifespan of Ercc1 Δ/- mice and delays neurologic morbidity. In this model, hypoxia appears to be the second strongest intervention to date, second only to dietary restriction.

Our findings add to a nascent but burgeoning literature on the beneficial effect of hypoxia in a wide variety of neurologic disease models. Chronic continuous hypoxia has been reported as beneficial in at least three other mouse models of neurologic disease. In two mitochondrial disease models, hypoxia corrects defects that arise as a consequence of the genetic lesion. In the experimental autoimmune encephalitis model of multiple sclerosis, continuous 10% oxygen promotes vascular integrity and apoptosis of infiltrating leukocytes. The ability of hypoxia to alleviate brain degeneration in such diverse models points either to the pleiotropic effects of oxygen restriction, or alternatively, the existence of a downstream and convergent neuroprotective mechanism.

An important future goal is to define the mechanism by which chronic continuous hypoxia is extending lifespan in this model, and the extent to which this mechanism overlaps with that of pathways known to be involved in aging, such as mTOR and insulin signaling. Three plausible mechanisms are the following: (i) activation of the HIF pathway; (ii) diminution of oxidative stress; and (iii) interruption of the vicious cycle of neurodegeneration and neuroinflammation.

Epidemiologic evidence suggests that lifelong oxygen restriction might slow the aging process in humans. Though there are many potential confounders to this finding, recent cross-sectional studies in Bolivia have demonstrated significant enrichment for nonagenarians and centenarians at very high altitudes. There is also intriguing data that suggests there are potential benefits of moving to altitude in adulthood. In a longitudinal study of over 20,000 soldiers of the Indian Army assigned to serve at 2 to 3 mile elevations above sea level for 3 years between 1965 and 1972, their risk of developing the major sources of age-related morbidity in modern societies was a fraction of the risk of their comrades serving at sea level.

An HDAC/PI3K Inhibitor Shows Potential as a Senolytic Drug

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

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

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

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

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

Germinal Centers Become Dysfunctional with Age, Impairing the Immune Response

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

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

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

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

Mitochondrial Quality Control in Microglia in the Aging Brain

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

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

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

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

To Improve Vaccination in the Elderly, Target Mechanisms of Aging

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

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

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

APOE4 Variant May Increase Inflammation in Early Alzheimer's Disease

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

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

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

Examining a Low Socioeconomic Status Group that Lives Longer than Expected

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

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

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

LEAP2 / Ghrelin Ratio as a Marker of Cognitive Decline

Ghrelin signaling is a part of being hungry. The cell signaling involved in the state hunger appears to be an important part of the process by which fasting and calorie restriction improve cell metabolism, tissue function, and long-term health. Researchers here investigate LEAP2, an inhibitor of ghrelin signaling, finding that more of it correlates with worse cognitive function with age. Given what we know of the way in which hunger affects health, LEAP2 may also prove to be yet another target for future therapies that can mimic some of the effects of calorie restriction.

Elderly individuals frequently report cognitive decline, while various studies indicate hippocampal functional declines with advancing age. Hippocampal function is influenced by ghrelin through hippocampus-expressed growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR antagonist that attenuates ghrelin signaling. Here, we measured plasma ghrelin and LEAP2 levels in a cohort of cognitively normal individuals older than 60 and found that LEAP2 increased with age while ghrelin marginally declined. In this cohort, plasma LEAP2/ghrelin molar ratios were inversely associated with Mini-Mental State Examination scores.

Studies in mice showed an age-dependent inverse relationship between plasma LEAP2/ghrelin molar ratio and hippocampal lesions. In aged mice, restoration of the LEAP2/ghrelin balance to youth-associated levels with lentiviral shRNA Leap2 downregulation improved cognitive performance and mitigated various age-related hippocampal deficiencies such as CA1 region synaptic loss, declines in neurogenesis, and neuroinflammation.

Our data collectively suggest that LEAP2/ghrelin molar ratio elevation may adversely affect hippocampal function and, consequently, cognitive performance; thus, it may serve as a biomarker of age-related cognitive decline. Moreover, targeting LEAP2 and ghrelin in a manner that lowers the plasma LEAP2/ghrelin molar ratio could benefit cognitive performance in elderly individuals for rejuvenation of memory.

Cellular Senescence in Disc Degeneration

The better understanding developed in recent years of the harmful effects of lingering senescent cells in the tissues of older individuals has led to a burst of research into cellular senescence in many areas of medicine. One of the more active parts of the field of late, judging by number of publications, is degenerative disc disease. Therapies that can efficiently remove senescent cells may well turn out to greatly slow the widespread age-related dysfunction observed in intevertebral disc tissue.

Closely associated with aging and age-related disorders, cellular senescence is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy.

Senescent cells increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of cellular senescence on onset and progression of age-related IDD. The discussion includes the molecular pathways involved in cellular senescence such as p53-p21CIP1, p16INK4a, NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways. We propose several mechanisms of cellular senescence in IDD including mechanical stress, oxidative stress, genotoxic stress, nutritional deprivation, and inflammatory stress. There are still large knowledge gaps in disc cellular senescence research, an understanding of which will provide opportunities to develop therapeutic interventions to treat age-related IDD.

Herpes Zoster Vaccination Reduces Alzheimer's Risk

Evidence exists for herpesvirus infection to increase the risk of suffering Alzheimer's disease. The evidence is mixed, however, with some studies showing no effect. There is some suggestion that the interaction of multiple viruses is the real contributing effect, which is why looking at just one virus type may produce problematic data. Researchers here show that vaccination against herpes zoster reduces Alzheimer's risk, though one might as to whether this is because of reduced viral impact, or because vaccinations can produce a trained immunity effect, reducing chronic inflammation in older people.

There is growing interest in the question if infectious agents play a role in the development of dementia, with herpesviruses attracting particular attention. To provide causal as opposed to merely correlational evidence on this question, we take advantage of the fact that in Wales eligibility for the herpes zoster vaccine for shingles prevention was determined based on an individual's exact date of birth. Those born before September 2 1933 were ineligible and remained ineligible for life, while those born on or after September 2 1933 were eligible to receive the vaccine. The percentage of adults who received the vaccine increased from 0.01% among patients who were merely one week too old to be eligible, to 47.2% among those who were just one week younger. No other interventions used the exact same date-of-birth eligibility cutoff as was used for the herpes zoster vaccine program.

This unique natural experiment allows for robust causal, rather than correlational, effect estimation. We show that receiving the herpes zoster vaccine reduced the probability of a new dementia diagnosis over a follow-up period of seven years by 3.5 percentage points, corresponding to a 19.9% relative reduction in the occurrence of dementia. Besides preventing shingles and dementia, the herpes zoster vaccine had no effects on any other common causes of morbidity and mortality. In exploratory analyses, we find that the protective effects from the vaccine for dementia are far stronger among women than men. Our findings strongly suggest an important role of the varicella zoster virus in the etiology of dementia.

Early Life Athletic Data Predicts Late Life Mortality

Early aging, in the 20s through 40s in our species, is poorly studied. This is likely because aging causes few serious problems and minimal mortality in this age range. Nonetheless, a 35 year old is not the same as a 25 year old, and visibly so in many cases. The same processes of damage accumulation that cause the dramatic mortality of late life are at work, slowly, in early life, but which of them are more significant, and how do they interact to produce the observed, often subtle changes of early aging? Studies such as the one here remind us that this early aging does exist, and that it sets the foundation for the accelerated process of late life aging that is to come.

Athleticism and the mortality rates begin a lifelong trajectory of decline during early adulthood. Because of the substantial follow-up time required, however, observing any longitudinal link between early-life physical declines and late-life mortality and aging remains largely inaccessible. Here, we use longitudinal data on elite athletes to reveal how early-life athletic performance predicts late-life mortality and aging in healthy male populations.

Using data on over 10,000 baseball and basketball players, we calculate age at peak athleticism and rates of decline in athletic performance to predict late-life mortality patterns. Predictive capacity of these variables persists for decades after retirement, displays large effect sizes, and is independent of birth month, cohort, body mass index, and height. Furthermore, a nonparametric cohort-matching approach suggests that these mortality rate differences are associated with differential aging rates, not just extrinsic mortality. These results highlight the capacity of athletic data to predict late-life mortality, even across periods of substantial social and medical change.

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.