Fight Aging!

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.

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.

Link: https://www.eurekalert.org/news-releases/990288

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."

Link: https://www.helsinki.fi/en/news/brain/new-information-development-alzheimers-disease-study-reveals-possible-cause-inflammation

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.

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.

Link: https://doi.org/10.1186/s12979-023-00348-6

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 regulates 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 counteract abnormal neuronal death. More in-depth studies remain to be completed in this area.

Link: https://doi.org/10.3389/fnagi.2022.1100133

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.

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.

Link: https://www.babraham.ac.uk/news/2023/05/lost-immune-cells

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.

Link: https://doi.org/10.18632/aging.204616

The aging of the brain is driven by many factors. Animal studies have demonstrated that the composition of the gut microbiome is one such factor. With age, the balance of microbial populations shifts to favor harmful, inflammatory microbes at the expense of helpful microbial species that produce metabolites necessary for tissue function. Chronic inflammation is a feature of many age-related conditions, neurodegenerative conditions particularly, and the aging gut microbiome contributes to that inflammatory state. Further, the microbiome generates metabolites such as butyrate that support neurogenesis, the creation of new neurons necessary for learning and memory function. Butyrate production falls with advancing age as the microbiome changes.

Fecal microbiota transplant from a young animal to an old animal has been demonstrated to produce a lasting rejuvenation of the gut microbiome, restoring a more youthful balance of populations. In some studies this has resulted in extended life span, in others improved physical and cognitive function. It is a comparatively simple procedure that is already used in a limited way in human medicine, as a treatment for C. difficile infection. It can be carried out width considerably less expense and medical support than the use of the FDA approved procedure, of course. Services like Human Microbes sell screened stool samples from young donors. Further, the measurement of gut microbiome composition and function, a way to clearly and accurately assess outcomes following fecal microbiota transplant, is available via low cost commercial services.

The use of fecal microbiota transplants from young individuals is promising, cost-effective, easy to conduct, and easy to assess as a self-experimenter in the present environment. The procedure should undergo broad clinical testing as a treatment to improve late-life health, but both academia and industry tend to be very slow to undertake clinical trials for a low-cost existing treatment that cannot be effectively patented and monopolized. Given that, setting up one or more low cost clinical trials of fecal microbiota transplant in a few hundred individuals would be a good project for a philanthropic initiative, a way to accelerate the adoption of a way to improve health in a lasting way for hundreds of millions of older people.

The gut microbiota is an emerging target for improving brain health during ageing

While the impact of ageing on the mammalian and human gut microbiome is well established, the impact of the gut microbiota on brain ageing has only recently been investigated, and relies dominantly on preclinical evidence and association analysis derived from small clinical trials. Studies utilising fecal microbiota transplantation (FMT) have demonstrated that the gut microbiota from aged individuals has the capacity to hinder cognitive performance and neurobiological phenotypes when transferred to younger individuals. For instance, transplanting microbes from aged and diseased models to young mice has been shown to impair learning, memory, and neuroplasticity in recipient young mice. Furthermore, young mice who received gut microbiota from aged donors suffered increased rates of mortality following ischemic stroke, along with increased levels of pro-inflammatory plasma cytokines and impaired motor strength. Conversely, aged mice who were colonised with the microbiota from young donor mice had increased survival and improved recovery post-stroke, demonstrating the functional differences between microbiota derived from young or aged individuals in influencing brain recovery following trauma.

Fascinatingly, the gut microbiota from young mice appears to harness properties that enable it to rejuvenate aspects of brain ageing when transferred into aged mice. Two studies recently confirmed similar findings, wherein FMT from young mice to aged mice improved ageing-related deficits in memory and learning ability. Microbiota from young mice restored age-related changes in peripheral and hippocampal immune responses and reversed age-related alterations in hippocampal transcriptional profiles and metabolites suggesting potential mechanisms by which the gut microbiota from young mice improve cognitive performance by modulating immune and metabolic pathways. In this regard, the microbially-derived metabolite δ-valerobetaine, which is increased in aged mice and humans, was shown to directly impair learning and memory abilities, and was reduced in aged mice following FMT from young donor mice. Relatedly, other gut microbiota-derived metabolites which are linked to age-related shifts in the gut microbiota and are increased in aged humans indicate that specific microbially-derived metabolites can impair cognitive abilities during ageing.

As the causal relationships between the gut microbiota and host brain ageing become increasingly clear, it is critical to continue to investigate whether microbiota-targeted therapeutics hold the potential to ameliorate the effects of ageing onto the brain. Several approaches to altering the gut microbiota, including medical interventions such as FMT and antibiotics, as well as lifestyle choices such as diet including probiotics, prebiotics, Mediterranean diet, and intermittent fasting, and exercise, may hold the key to the fountain of brain youth.

Calorie restriction is the practice of eating fewer calories while still obtaining an optimal intake of micronutrients. In recent years work in flies has expanded the understanding of how perception of food and regulation of hunger interacts with the health benefits and slowed aging that result from calorie restriction. Allowing flies to scent food removes the benefits of a lowered calorie intake, for example.

Here, researchers generate a lineage of flies that can be induced to be constantly hungry, and they find that this produces similar benefits to calorie restriction even while the flies eat more than their unmodified peers. Relatedly, work on various different forms of calorie restriction in mammals suggests that time spent hungry is the common denominator leading to slowed aging and improved health; the signaling related to hunger is an important determinant of altered cell behavior, perhaps, not just the present availability of nutrients to any given cell.

Researchers induced hunger in flies in several ways. The first was to alter the amount of branched-chain amino acids, or BCAAs, in a test snack food and later allow the flies to freely feed on a buffet of yeast or sugar food. Flies fed the low-BCAA snack consumed more yeast than sugar in the buffet than did the flies fed the high-BCAA snack. This kind of preference for yeast over sugar is one indicator of need-based hunger. The researchers note that this behavior wasn't due to the calorie content of the low-BCAA snack; in fact, these flies consumed more food and more total calories. When flies ate a low-BCAA diet for life, they also lived significantly longer than flies fed high-BCAA diets.

To look at hunger apart from dietary composition, researchers used a unique technique, activating neurons associated with the hunger drive in flies using exposure to red light, using a technique called optogenetics. These flies consumed twice as much food than did flies who were not exposed to the light stimulus. The red-light activated flies also lived significantly longer than flies used as a control. What's more, the team was able to map the molecular mechanics of hunger to changes in the epigenome of the neurons involved - and to identify that neurons responded to the presence or absence of a specific BCAA, isoleucine, in the diet. These changes can affect how much of specific genes are expressed in the brains of flies and, consequently, their feeding behavior and aging.

Link: https://www.michiganmedicine.org/health-lab/feeling-hunger-itself-may-slow-aging-flies

Exercise is demonstrated to improve memory function, both immediately in the short-term, and over the long term of regular exercise and improved physical fitness. Exercise is also known to improve measures of neurogenesis, the creation of new neurons and integration into existing neural networks in the brain. This process is essential to learning and memory. Researchers here investigate the effects of exercise on neurogenesis in mice by labeling neurons in order to determine the contribution of adult neurogenesis to neural networks in the areas of the brain important to memory.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear if adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity.

To address this issue we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in 2-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing 'old' new neurons. We identified and quantified the direct afferent inputs to the adult-born neurons within the hippocampus and (sub)cortical areas.

Here we show that long-term running substantially modifies the network of the neurons generated in young adult mice upon middle-age. Exercise increases input from hippocampal interneurons onto 'old' adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of 'old' new neurons, born during early adulthood, within a network that is important for memory function during aging.

Link: https://doi.org/10.1523/ENEURO.0084-23.2023

While no-one likes to be reminded of it, there are clear, albeit minor signs of aging that arise in as young a stage of life as the late 20s and early 30s. These early manifestations of aging are very poorly understood; perhaps understandably, near all research into mechanisms of aging is focused on late life pathology and its causes. Thus we are left with a very unsatisfactory understanding of what exactly is going in early adult life that makes a mid-30s adult physiologically different from an immediately post-development teenager.

In today's open access commentary, researchers report on evidence implicating senescent cells in these differences, at least in skin, and this is quite interesting. Present understanding holds that the accumulation of senescent cells in later life is most likely driven by immune dysfunction that impairs the timely clearance of newly created senescent cells. A similar immune-driven slowdown in clearance in the 20s and 30s, as described here, is unexpected.

Immune dysfunction over the course of life is thought to proceed along much the same lines as cancer risk, because of the role of the immune system in suppressing precancerous lesions. Risk of cancer doesn't start to meaningfully increase until the 50s and on. Still, it is also clear that the gut microbiome begins to change in the 30s as well, and there also the immune system is implicated, as immune cells are responsible for gardening the gut microbiome, destroying problematic microbes. We might speculate that these recent discoveries are setting the stage for the realization that early immune aging both exists and is a driver of the comparatively small changes in physiology that take place in the 20s and 30s.

Changes of senescent cell accumulation and removal in skin tissue with ageing

Senescent cells are known to secrete various inflammatory cytokines (known as the senescence-associated secretory phenotype factors: SASP factors) and adversely affect surrounding tissues. Senolytic drugs that selectively induce the death of senescent cells are under development. We reported that skin inherently possesses mechanisms to remove senescent cells. In the epidermis, this is achieved by the binding of JAG1, a Notch ligand expressed on adjacent non-senescent keratinocytes, to Notch1 receptors expressed by senescent keratinocytes, which promotes the exclusion of senescent cells from the basal layer by inducing differentiation. Meanwhile, in the dermis, senescent cells are phagocytosed by macrophages through recognition by the phosphatidyl serine (PS) receptor STAB1. However, since ageing is associated with the accumulation of senescent cells in skin tissue, it is hypothesized that this accumulation is preceded by a decline in the ability to remove them.

Here, we tested this hypothesis by analysing in detail the changes in the number of senescent cells and the ability of them to be removed from the skin with ageing. Marginal skin tissues at the time of surgery were collected from patients who had provided informed consent. Paraffin-embedded sections prepared from the unexposed skin tissue were subjected to immunostaining with the major senescent cell marker p16INK4A to analyse the number of senescent cells. To characterize the ability for senescent cells to be removed from the skin, the expression of JAG1 in the epidermal keratinocytes and STAB1 in macrophages was analysed. The results confirmed that senescent cell accumulation was increased with age in both epidermis and dermis. We also found that the ability to remove senescent cells decreased with age.

In addition, it was observed that while the accumulation of senescent cells was detected after 30s, the removal capacity began to decrease at 20s. Although there was a delay of the age at which senescent cell accumulation starts after the onset of declining of senescent cell removal ability, there appears to be a correlation across all ages between the removal ability and the accumulation of senescent cells. The reason of the decline in the senescent cell removal function in the 20s, before senescent cells accumulate, is still a mystery. We believe that environmental factors such UV radiation, reactive oxygen species, and exposure to SASP factors released by transiently senescent cells in young age may have an impact on the function of senescent cell removal. Future plans for this research include a closer look at these factors and the techniques for enhancing the efficiency of senescent cell removal.

Maintaining physical fitness remains one of the most proven approaches to modestly slow the progression of aging. The large study noted here provides an example of the long-term benefits of exercise. The scientists observe a reduction in Parkinson's disease incidence in more active individuals. This is a pattern observed in near all age-related conditions, a good argument for putting in the time and effort needed to remain physically fit and active as one moves into later life.

The study included 95,354 female participants, mostly teachers, with an average age of 49 who did not have Parkinson's disease at the start of the study. Researchers followed participants for three decades during which 1,074 participants developed Parkinson's disease. Over the course of the study, participants completed up to six questionnaires about types and amounts of physical activity. Researchers assigned each activity a score based on the metabolic equivalent of a task (METs), a way to quantify energy expenditure. For each activity, METs were multiplied by their frequency and duration to obtain a physical activity score of METs-hours per week. For example, a more intense form of exercise like cycling was six METs, while less intense forms of exercise such as walking and cleaning were three METs. The average physical activity level for participants was 45 METs-hours per week at the start of the study.

Participants were divided into four equal groups of just over 24,000 people each. At the start of the study, those in the highest group had an average physical activity score of 71 METs-hours per week. Those in the lowest group had an average score of 27 METs-hours per week. Among the participants in the highest exercise group, there were 246 cases of Parkinson's disease or 0.55 cases per 1,000 person-years compared to 286 cases or 0.73 per 1,000 person-years among participants in the lowest exercise group.

After adjusting for factors such as place of residence, age of first period and menopausal status, and smoking, researchers found those in the highest exercise group had a 25% lower rate of developing Parkinson's disease than those in the lowest exercise group when physical activity was assessed up to 10 years before diagnosis. The association remained when physical activity was assessed up to 15 or 20 years before diagnosis. Results were similar after adjusting for diet or medical conditions such as high blood pressure, diabetes, and cardiovascular disease. Researchers also found that 10 years before diagnosis, physical activity declined at a faster rate in those with Parkinson's disease than in those without, likely due to early symptoms of Parkinson's disease.

Link: https://www.aan.com/PressRoom/Home/PressRelease/5086

Researchers here observe that triglyceride depletion in very aged muscles produces benefits, looking much like a form of calorie restriction that improves cell metabolism. This work was carried out in killifish, a highly regenerative species, so it remains to be seen as to whether a similar process operates in mammals, or whether it is in any way interesting or novel as a basis for therapy. Finding modest benefits in very late life is a poor alternative to focusing instead on methods of rejuvenation.

Sarcopenia, the age-related decline in muscle function, places a considerable burden on health-care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish - an extremely short-lived vertebrate - revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an "early-life" state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span.

In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life-like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long-lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.

Link: https://doi.org/10.1111/acel.13862

A person who sleeps six hours rather than eight hours every day, give or take, is effectively gaining a bonus 12.5% additional time spent alive and active. From that perspective, there isn't all that much difference between being able to sleep two hours less every night throughout life, without consequences, and being able to live for the better part of an additional decade in good health. There are mutations that produce this effect in humans, other mammals, and lower animals such as flies, and at least one of them does so without any apparent negative side-effects.

Today's open access paper offers an exploration of one of these mutations, a small alteration in DEC2, which not only reduces the need for sleep, thereby granting additional subjective life span, but is also found to extend actual life span in flies. The size of the effect is larger than many of the calorie restriction mimetic compounds explored in recent years. Interestingly, the authors here argue that reduced need for sleep is more a reflection of increased robustness and health resulting from this mutation than any independent, top-down alteration of the regulation of sleep.

A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila

One of the most well-studied examples of natural short sleepers in the human population are individuals with rare genetic mutations in the dec2 gene. Dec2 is a transcriptional repressor that, in mammals, is recruited to the prepro-orexin promoter and represses the expression of orexin, a neuropeptide that promotes wakefulness. A single point mutation in dec2 (dec2P384R) inhibits the ability of Dec2 to bind the prepro-orexin promoter, resulting in increased orexin expression. Consequently, wakefulness increases, and individuals sleep on average 6hrs/day instead of 8hrs/day.

Intriguingly, these natural short sleepers do not appear to exhibit any phenotypes typically associated with chronic sleep deprivation, and expression of the dec2P384R mutation in mice suppresses neurodegeneration. Thus, it has been suggested that individuals harboring the dec2P384R mutation may employ compensatory mechanisms that allow them to thrive with chronic sleep loss. However, whether the dec2P384R mutation directly confers global health benefits has not yet been tested experimentally in any system.

In this study, we used a Drosophila model to understand the role of the dec2P384R mutation on animal health and elucidate the mechanisms driving these physiological changes. We found that the expression of the mammalian dec2P384R transgene in fly sleep neurons was sufficient to mimic the short sleep phenotype observed in mammals. Remarkably, dec2P384Rmutants lived significantly longer with improved health despite sleeping less. In particular, dec2P384R mutants were more stress resistant and displayed improved mitochondrial fitness in flight muscles. Differential gene expression analyses further revealed several altered transcriptional pathways related to stress response, including detoxification and xenobiotic stress pathways, that we demonstrate collectively contribute to the increased lifespan and improved health of dec2P384R mutants.

Finally, we provide evidence that the short sleep phenotype observed in dec2P384R mutants may be a result of their improved health rather than altered core sleep programs. Taken together, our results highlight the dec2P384R mutation as a novel pro-longevity factor and suggest a link between pro-health pathways and reduced sleep pressure.

The primary challenge in understanding how calorie restriction slows aging and extends life is that it changes near everything in the operation of cellular metabolism. Finding the important differences is a matter of searching for the needle in the haystack. The most compelling evidence to date points to increased autophagy as the important determinant, greater effort made by cells to repair damage, maintain function, and recycle components. It remains likely that other mechanisms are also important, however. Here, researchers focus on regulation of the innate immune system in response to a reduced calorie intake; they are working with nematodes, but many of the noteworthy aspects of calorie restriction are much the same across all species.

Dietary restriction (DR) is a practically effective and reproducible nutritional intervention that extends lifespan in many organisms. Many studies have shown that DR improves immune function, and immune signaling components are required for DR-induced lifespan extension. These results support the idea that the immune system acts as an important mechanism for DR-induced longevity. Recently, analysis of genes that regulate aging or immune response in animal models, including C. elegans, Drosophila, mice, and even humans, has revealed that aging and immunity are controlled by the same signaling pathways, such as TOR/S6K signaling pathway, pleiotropically. DR-induced longevity is also associated with the modulation of the TOR/S6K signaling pathway. Thus, these results suggest that the immune function may be closely associated with aging regulation through DR.

In this study, we found that the F-box gene fbxc-58 is a downstream effector of the S6K signaling pathway, and that it regulates both pathogen resistance and aging in C. elegans. Furthermore, fbxc-58 is necessary for the effects of DR on lifespan extension. F-box protein acts as a modular E3 ubiquitin ligase adaptor protein, and the ubiquitin-dependent mechanisms have been shown to determine lifespan in response to DR or modulate the innate immune response. Therefore, we suggest that gaining insights into the detailed mechanistic aspects of fbxc-58 signaling pathway could elucidate the conserved signaling mechanism that links innate immunity and DR-induced healthy aging in animals.

Further, DR prevents or reduces the burden of age-related diseases or disabilities. Especially, in an aging and sedentary society, sarcopenia, an age-associated muscle disease, is beginning to be recognized as an acute disease condition. Although an effective sarcopenia treatment regime has not yet been identified, nutritional intervention is considered an effective method of preventing sarcopenia. In this study, we found that DR prevents muscle aging via fbxc-58 in C. elegans. fbxc-58 is essential for DR-mediated alleviation of the age-associated decline in muscle activity and protection of mitochondrial network in body wall muscle. Thus, we propose that investigating the molecular mechanism of action of F-box proteins, including fbxc-58, in DR will shed light on means to prevent sarcopenia and offer a potentially practical means of encouraging healthy aging via DR.

Link: https://doi.org/10.18632/aging.204477

Analysis of a large epidemiological database here shows that sufficient exercise correlates with a halving of the risk of mortality due to influenza. Like many other studies, it also shows that too much exercise may be harmful, actually increasing the risk of mortality. While correlation does not imply causation, there is plenty of evidence for physical fitness and physical activity to reduce impacts of aging related to immune function. Alternative explanations revolve around the tendency of more robust individuals to conduct more exercise, while also tending to be more resilient independently of the effects of exercise.

A nationally representative sample of US adults (aged ≥18 years) who participated in the National Health Interview Survey from 1998 to 2018 were followed for mortality through 2019. Participants were classified as meeting both physical activity guidelines if they reported ≥150 minutes/week of moderate-intensity equivalent aerobic physical activity and ≥2 episodes/week of muscle-strengthening activity. Participants were also classified into five volume-based categories of self-reported aerobic and muscle-strengthening activity.

Among 577,909 participants followed for a median of 9.23 years, 1,516 influenza and pneumonia deaths were recorded. Compared with participants meeting neither guideline, those meeting both guidelines had 48% lower adjusted risk of influenza and pneumonia mortality. Relative to no aerobic activity, 10-149, 150-300, 301-600 and greater than 600 minutes/week were associated with lower risk (by 21%, 41%, 50% and 41%). Relative to fewer than 2 episodes/week of muscle-strengthening activity, 2 episodes/week was associated with 47% lower risk.

At the opposite end, we found that ≥7 muscle-strengthening activity episodes/week was associated with an increased risk. A J-shaped dose-response between muscle-strengthening activity and all-cause mortality has been observed elsewhere. While beyond the scope of this study, plausible explanations range from inaccurate responses (such as reporting occupational physical activity, which may not confer the same protective effect as leisure-time physical activity) to haemodynamic ramifications of frequent, high-intensity activity.

Link: https://doi.org/10.1136/bjsports-2022-106644

It is arguably the case that we should look at small molecule mTOR inhibitors, such as rapamycin and its descendant rapalog compounds, as the most effective of the calorie restriction mimetic approaches developed to date. The practice of calorie restriction, eating as much as 40% fewer calories while still obtaining optimal levels of micronutrients, produces sweeping changes to metabolism. Some of these, such as increased autophagy and other forms of cellular housekeeping, appear to be beneficial to long-term health. Keeping cells more free of damage leads to a slowing of aging.

In mice, that slowing of aging can lead to as much as a 40% extension of life span via calorie restriction. Rapamycin, on the other hand, managed a 5% to 10% extension of life span in the very rigorous Interventions Testing Program studies. This illustrates one of the issues with calorie restriction mimetic treatments, which is that they only capture a fraction of the beneficial metabolic change produced by calorie restriction, and are therefore considerably less effective.

The other issue is that the practice of calorie restriction certainly doesn't produce a 40% extension of life span in humans; that would be quite evident, and have been well known since antiquity. Long-lived mammals exhibit very similar short-term metabolic changes and improved measures of health in comparison to short-lived mammals when undergoing calorie restriction, but long-term effects on life span are much more muted.

It seems plausible that many of the metabolic changes caused by calorie restriction in short-lived species became permanent in the course of evolving longer life spans. Thus humans, one of the more long-lived mammals, likely gain only a few years from the practice of calorie restriction. This might lead one to the reasonable conclusion that calorie restriction mimetics are not the way forward to greatly improve late life health in humans. Nonetheless, there is considerable appetite and funding for this line of research and development.

Targeting the biology of aging with mTOR inhibitors

mTOR is an evolutionarily conserved serine-threonine protein kinase found in diverse species including mice and humans. The mTOR kinase forms the catalytic core of two distinct protein complexes, mTORC1 and mTORC2, each of which are composed of shared as well as unique protein subunits and phosphorylate different substrates. mTORC1 is regulated by a wide range of nutrients and hormonal cues, most notably by the availability of amino acids, but also glucose, oxygen, and cholesterol. mTORC1 activity drives a wide variety of anabolic processes, as well autophagy, through phosphorylation of substrates.

Beginning 20 years ago, researchers discovered a role for mTORC1 signaling in the aging process. Studies in yeast, worms, and flies found that genetic inhibition of mTORC1 or signaling pathways downstream of mTORC1 extends lifespan. These results quite logically spurred substantial interest in the possibility that a potent chemical inhibitor of mTORC1, rapamycin, could extend lifespan. This was indeed the case, and there are now numerous studies showing that rapamycin can extend the lifespan not only of model organisms including yeast, worms, and flies but also of both wild-type mice and in many disease models. In this review, we will discuss the results of these studies, as well as the possible mechanism by which reduced mTORC1 signaling via both dietary and pharmacological means may improve healthspan.

There is rapidly growing interest in using mTOR inhibitors to promote healthy aging and to treat, delay or reverse numerous age-related diseases. While there is incredibly strong preclinical evidence in mice that rapamycin can extend lifespan and healthspan, excitement about rapamycin has outpaced rigorous evidence that rapalogs are both safe and efficacious for diseases of aging in humans. There are many unanswered questions from the trials that have been conducted thus far, but a few general lessons can be taken from the clinical trials of mTOR inhibitors that have been performed thus far. In both humans and mice, treatment with low or intermittent doses of rapamycin or everolimus or treatment of mice with the mTORC1-selective inhibitor DL001, is much better tolerated than the high doses of mTOR inhibitors currently approved for organ transplant and oncology indications, with fewer metabolic side effects and less immunosuppression. In addition, low doses of mTOR inhibitors have been shown to have some beneficial effects on the function of aging human organ systems, in particular, the immune system.

There remains much work ahead to bring mTOR inhibitors into the clinic for age-related conditions and many open questions remain. While the safety profile of low-dose rapamycin and rapalogs in humans appears promising, the long-term safety and efficacy of low-dose regimens remain to be determined. A much better understanding is needed of the specific dose and duration of mTOR inhibitors that both maximize efficacy and minimize risk. In humans, higher doses (for example, 3 mg per day) of mTOR inhibitors such as everolimus inhibit T cell function and are therefore are used to suppress immune-mediated organ transplant rejection in patients. By contrast, a sixfold lower dose of everolimus for 6 weeks was associated with improved immune function as assessed by vaccination response. Thus, both dose and duration may contribute to whether mTOR inhibition has positive or negative effects on healthy aging, but, generally speaking, the lower the dose of a drug, the fewer expected side effects.

Over the next 5 years, we expect results from a rapidly expanding list of human clinical trials as well as work in canines and non-human primates to shed light on the viability of mTOR inhibition as a therapy for aging-related conditions. New mTORC1-specific molecules may help to widen the therapeutic window for rapalogs, limiting undesirable side effects resulting in whole or in part from inhibition of mTORC2. Collectively, we expect that researchers will soon be able to determine whether clinicians can safely and effectively bring mTOR inhibitors to the geriatric bedside.

Bone mineral density decreases with age, a growing imbalance between the activity of osteoblasts (depositing bone) and osteoclasts (breaking down bone). This leads eventually to meaningful risk of fracture and osteoporosis. Suffering bone injury due to bone weakness in later life is a spiral downwards into debilitating incapacity, and comes with a significantly raised risk of mortality. Here, researchers run the numbers to present the increased mortality risk following fracture as an adjustment to skeletal age, in the hope of increasing the use of existing therapies for osteoporosis.

Osteoporosis is a 'silent disease' which often has no immediate symptoms but gradually weakens bones and makes them more likely to break. A bone fracture caused by osteoporosis in people over the age of 50 is linked to long-term health decline and in some cases, even early death. However, poor communication of the mortality risk to patients has led to a low uptake of treatment, resulting in a crisis of osteoporosis management. The impact of a fracture on life expectancy is typically conveyed to patients and the public in terms of probability (how likely something is to occur) or the relative risk of death compared to other groups. However, statements such as "Your risk of death over the next 10 years is 5% if you have suffered from a bone fracture" can be difficult to comprehend and can lead to patients underestimating the gravity of the risk.

With the aim of devising a new way of conveying risks to patients, researchers analyzed the relationship between fracture and lifespan in over 1.6 million individuals who were 50 years of age or older. The findings showed that one fracture was associated with losing up to 7 years of life, depending on gender, age and fracture site. Based on this finding, researchers proposed the idea of 'skeletal age' as a new metric for quantifying the impact of a fracture on life expectancy. Skeletal age is the sum of the chronological age of a patient and the estimated number of years of life lost following a fracture. For example, a 60-year-old man with a hip fracture is predicted to lose an estimated 6 years of life, resulting in a skeletal age of around 66. Therefore, this individual has the same life expectancy as a 66-year-old person that has not experienced a fracture.

Skeletal age can also be used to quantify the benefit of osteoporosis treatments. Some approved treatments substantially reduce the likelihood of post-fracture death and translating this into skeletal age could help communicate this to patients. For instance, telling patients that "This treatment will reduce your skeletal age by 2 years" is easier to understand than "This treatment will reduce your risk of death by 25%".

Link: https://doi.org/10.7554/eLife.83888

Researchers have in recent years expressed a growing interest in the role of sirtuin 6 (SIRT6) in the mechanisms of calorie restriction and improved function that occurs in response to mild stress. Many forms of stress, such as lowered levels of nutrients, produce benefits via upregulation of cellular maintenance processes such as autophagy.

That said, it is unclear as to whether calorie restriction mimetic therapies will prove to be all that interesting as a class of therapy in humans, as calorie restriction only produces significant gains in life span in short-lived species. While scientists are far from a full accounting of how exactly the sweeping metabolic changes induced by calorie restriction lead to slowed aging, it is reasonable to think that long-lived species are long-lived precisely because many of the important changes induced by calorie restriction in short-lived species such as mice are already activated all of the time in long-lived species such as our own. Thus calorie restriction increases mouse life span by 40%, but it certainly doesn't do that in humans.

US-Israeli startup SIRTLab is focused on the development of therapeutics that boost levels of a key protein called sirtuin 6 (SIRT6), which is heavily implicated in longevity. It appears that high levels of SIRT6 also boosts physical performance and improves memory and cognitive function, even in young mice. By generating mice with overexpression of SIRT6, researchers have demonstrated average lifespan extension of 30%, and positive impacts on frailty. But, while the longevity and healthspan benefits of SIRT6 are well-known, no one has yet developed a therapeutic way to increase SIRT6 levels.

Of course, therapeutic approaches that have worked in animal models don't always translate into results in humans, but SIRTLab believes that SIRT6 expression has a good chance of delivering on its promising results in mice. SIRTLab has created a SIRT6-focused therapeutic platform, with multiple approaches to increasing SIRT6 levels in cells. "We have developed four different ways to therapeutically target SIRT6 production: messenger RNA (mRNA), small molecules, adeno-associated viruses (AAVs), and antagonists for microRNAs that control SIRT6 levels. There are different benefits to each approach, and it's even possible that a treatment could use a combination of two or more. We've seen in our experiments that our mRNA therapeutic boosts cellular levels of SIRT6 by 20 times, which is very exciting." The company hopes to commence its first human trials in 2024, after it completes toxicity studies this year.

Link: https://longevity.technology/news/does-sirt6-hold-the-key-to-human-longevity/

The immune system becomes more inflammatory and less competent with advancing age, undergoing sweeping changes in immune cell characteristics and relative population sizes. The cells, structures, and processes that produce immune cells similarly undergo significant changes. Taken together, this is called immunosenescence, though many researchers choose to break out the inflammatory component of dysfunction into its own category, calling it inflammaging. One of the most important goals for the research community is to find ways to improve immune function in older people.

Evidently, the decline of the immune system is an important aspect of aging. It produces many directly, obviously harmful consequences. The inability to defend against infectious disease leads to a tremendous death toll in older individuals, largely resulting from common infectious agents such as influenza, diseases that younger people can shrug off. Similarly, the ability to clear precancerous and senescent cells is also much reduced, driving the increased risk of cancer on the one hand, and the growing number of lingering senescent cells on the other. There are many more subtle issues, more poorly researched, however, in which aged immune cells play a harmful role, contributing to age-related disease and dysfunction in specific organs.

Immunosenescence: molecular mechanisms and diseases

Immunosenescence is a complex process that involves organ reorganization and numerous regulatory processes at the cellular level. As a result, immune system function decreases, leading to an inadequate response to infections or vaccines in elderly individuals. Although the full extent of the biological changes is unknown, several characteristic changes are typically observed such as thymic involution, hematopoietic stem cell (HSC) dysfunctions, disrupted naïve/memory ratio in T cells and B cells, inflammaging, accumulation of senescent cells, impaired new antigen response, mitochondrial dysfunction, genomic instability, and stress responses. Identifying hallmarks and characteristics associated with immunosenescence is crucial for exploring its impact and significance, particularly in age-related diseases.

Thymic involution plays a vital role in the imbalance of immune cell proportions, particularly for T cells. Thymic tissue can be divided into epithelial tissue and nonepithelial perivascular space without thymopoiesis. As the thymus atrophies, the epithelial spaces gradually disappear, and the perivascular space gradually fills the elderly thymus, leading to a decrease in naïve T cells, an increase in peripheral late-differentiated memory T cells, and diminished migration of naïve T cells to the periphery. According to the latest studies, thymic rejuvenation does not restore diversity, and we agree that thymic degeneration does not perfectly explain the decline in T-cell receptor (TCR) diversity in humans.

One of the hallmarks of immunosenescence is "inflammaging," which refers to a systemic state of chronic low-grade inflammation characterized by upregulated blood inflammatory markers and is considered the central pillar of aging. The accumulation of damaged macromolecules is responsible for inflammaging, and endogenous host-derived cell debris is the source of chronic tissue damage. Cellular senescence is central to the inflammaging process. Senescent cells exhibit a distinctive senescence-associated secretory phenotype (SASP), leading to the inflammaging phenotype. Cellular senescence has been hotly debated as a driver of immunosenescence.

As the immune system ages, metabolism undergoes changes that involve increased glycolysis, mitochondrial dysfunction, and reactive oxygen species (ROS). These features of immunosenescence are strongly related to high morbidity and mortality from age-associated diseases such as cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, metabolic diseases, and cancers in older patients. As the incidence of these disorders exponentially increases later in life, common cellular and molecular mechanisms likely contribute to their development. In this context, it is crucial to examine the molecular mechanisms, altered immune cell pool, and regulatory signaling impact on immunosenescence and age-related diseases.

Researchers here show that THBD signaling inhibition is an approach to selectively destroy senescent cells. There is an approved drug that can do this, vorapaxar, though at first glance its safety profile looks worse than that of dasatinib, the only senolytic so far proven to clear senescent cells in humans. One might wonder how much of vorapaxar's successes in clinical trials are due to clearance of senescent cells versus other mechanisms.

As is the case in many lines of research into cellular senescence, the focus here is on fibrosis, a progressive failure of tissue maintenance in which scar-like deposits form to disrupt tissue structure and function. Senescent cells are implicated in this process, and clearance of senescent cells has been shown to reverse fibrosis in a number of different organs and animal models.

Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis.

Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability.

Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.

Link: https://doi.org/10.1038/s41422-023-00820-4

The vasculature becomes increasingly dysfunctional with age in a number of different ways, from loss of capillary density to tissue stiffening and issues with smooth muscle function that lead to raised blood pressure, as well as the development of endothelial inflammation and atherosclerotic lesions that lead to heart attack or stroke. It isn't surprising to find that even simple measures of vascular aging, such as raised blood pressure, correlate fairly well with other aspects of aging, such as declines in physical function.

Approximately 10% of older adults have muscle weakness and diminished physical function that leads to adverse health outcomes and physical disability. A new study showed that vascular measures are associated with grip strength in cross-sectional analyses and change in gait speed (a measure of physical function) in longitudinal analyses. This is one of the first community-based studies to comprehensively examine relations of aortic stiffness and vascular function with age-related decline in physical function. Higher aortic stiffness was associated with loss of physical function over ~11 years.

Blood flow declines with aging, in part due to arterial stiffening. Consequent dysfunction in blood vessel dynamics may contribute to organ pathology and declines in muscle mass. The current study utilized data from a large cohort of 2,498 relatively healthy men and women and extends previous investigations by utilizing a longitudinal study design. The majority of previously published studies have utilized cross-sectional study designs with modest sample sizes. The authors believe that future studies should evaluate whether interventions that target vascular health may reduce age-related declines in physical function.

Link: https://www.eurekalert.org/news-releases/989047

High blood cholesterol accelerates the onset of atherosclerosis, making it easier to reach the tipping point at which localized excesses of cholesterol form in blood vessel walls. The majority of cholesterol is generated in the liver, not obtained from the diet - and yet high fat diets are well proven to accelerate atherosclerosis. Researchers here provide evidence for the mechanism to be less direct than might be expected, involving the gut microbiome and its relationship with tissues and the immune system. Certain components of dietary fat lead to a cascade of events that provoke an inflammatory response, and the more fat, the greater the chronic inflammation.

Anything that induces a lasting state of unresolved inflammatory signaling will accelerate the development of atherosclerosis. This is again a matter of shifting the tipping point at which the innate immune cells called macrophages, responsible for clearing excess cholesterol from blood vessel walls, become overwhelmed by circumstances. Inflammatory signaling shifts macrophages into a state more appropriate for defense against pathogens than for clearing up metabolic debris. Fewer macrophages clearing cholesterol means a greater deposition of cholesterol.

High-fat diet 'turns up the thermostat' on atherosclerosis

Obesity and a high-cholesterol, high-fat diet are both well-established risk factors for atherosclerosis. In fact, obese individuals are two and a half times more likely to develop heart disease. However, the mechanistic link between obesity and atherosclerosis eludes scientists. The researchers behind this new study believe the link may be in how specific derivatives of natural emulsifiers in a Western diet alter the way that cells that line the intestines interact with gut-resident bacteria. "We study natural emulsifiers in the diet called phospholipids. For example, if you look at salad dressing and shake it up, it is the phospholipids, or emulsifiers, that keeps the oil in globules. Those emulsifiers can get modified by specific enzymes in the intestinal cells into very potent pro-inflammatory molecules in the body."

Using a mouse model, researchers found that on a high-fat high-cholesterol diet, the cells that line the small intestine churn out reactive phospholipids that makes the intestinal lining more susceptible to invasion by the bacteria that live in the gut. "The normal defenses for intestinal lining cells to keep bacteria in the lumen of the intestine are reduced when they take up large amounts of cholesterol and fat. This also results in bacteria being able to come in direct contact with the cells lining your intestines called enterocytes. Without those defenses, this results in more bacterial products, like bacterial cell membranes that contain a toxin called endotoxin, getting into the bloodstream to cause inflammation."

"People who are obese and people eating high-fat, high-cholesterol diets have higher levels of endotoxin in their blood. It's not at the level of causing sepsis, but it causes a low level of inflammation. When the cholesterol and fat come into the mix, the endotoxin kind of turns up the thermostat on inflammation and that accelerates atherosclerosis and leads to increased heart attacks and strokes."

Role of enterocyte Enpp2 and autotaxin in regulating lipopolysaccharide levels, systemic inflammation, and atherosclerosis

Conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously reported that feeding Ldlr-/- mice standard mouse chow supplemented with unsaturated LPA or lysophosphatidylcholine qualitatively mimicked the dyslipidemia and atherosclerosis induced by feeding a Western diet. Here, we report that adding unsaturated LPA to standard mouse chow also increased the content of reactive oxygen species and oxidized phospholipids (OxPLs) in intestinal mucus.

We conclude that the Western diet increases the formation of intestinal OxPL, which i) induce enterocyte autotaxin resulting in higher enterocyte LPA levels; that ii) contribute to the formation of reactive oxygen species that help to maintain the high OxPL levels; iii) decrease intestinal antimicrobial activity; and iv) raise plasma lipopolysaccharide levels that promote systemic inflammation and enhance atherosclerosis.

Here I'll note an interesting effort to produce a taxonomy of companies and approaches to treatment in the longevity industry. There is a growing diversity of efforts to find ways to target various mechanisms and manifestations of aging, and since the industry is still small it remains possible for one person to walk through a list of the participants and understand what each is doing in a reasonable amount of time.

This post aims to provide a survey of all different scientific approaches in longevity biotech. Although comprehensive databases like Longevity List and AgingBiotech offer valuable information on various companies, it is still challenging to see the big picture and identify established or unexplored paths. Beginning with a broad overview of the entire landscape, we will delve deeper into each approach and scope out under-explored areas with promising potential.

There are four paradigms for longevity biotech therapeutics. (1) Reset and Repair: This paradigm focuses on targeting specific, known age-related pathways, factors, or damages identified in hallmarks of aging (with some modifications). (2) Replace: Falling within the domain of regenerative medicine, this paradigm includes the replacement of aged cells, tissues, organs, or even the whole body with younger counterparts or endogenous regeneration. (3) Reprogram: This paradigm is inspired by the natural rejuvenation process that occurs during early embryonic development, which enables the production of youthful offspring from old gametes. It aims to activate a similar embryonic-like program within aged cells, without altering their cell identity, through a process known as partial reprogramming. (4) Discover: This paradigm focuses on identifying novel targets or interventions for aging by analyzing extensive datasets using advanced machine learning techniques.

Compared to other biotech sectors such as oncology, longevity biotech is still in its infancy, both in terms of funding and the number of companies involved, despite the potential it holds to tackle the leading cause of death - aging. There is still an abundance of untapped opportunities in each paradigm, leaving several avenues for commercial development. In creating this landscape, my aim is to provide a structured approach to identify and address the lesser-known approaches within this field. As a starting point, consider which paradigm you'd like to see expanded, and go deeper there to find new opportunities for company formation or investment.

Link: https://www.adanguyenx.com/longevity

While the operation of chaperone proteins inside the cell is fairly well understood, how chaperones operate on proteins outside the cell is less well researched. Damaged and misfolded proteins exist outside the cell just as they exist inside the cell; consider amyloid-β aggregates in the context of Alzheimer's disease, for example. A greater understanding of extracellular chaperone proteins may enable novel strategies to target damaged and misfolded proteins characteristic of aging and disease, particularly in the brain.

A set of unique proteins - molecular chaperones - play an essential role in proteostasis: they target and interact with misfolded proteins, maintain their solubility, and designate them for refolding or degradation. And, while intracellular proteostasis is well understood, extracellular conditions are harsher. Mediating proteostasis in this environment requires specific extracellular molecular chaperones, and the specifics of extracellular proteostasis are yet to be fully understood. Take, for example, an extracellular chaperone, alpha 2-macroglobulin (ɑ2M), an abundant plasma protein. ɑ2M targets defective proteins and is speculated to facilitate the clearance of defective proteins. However, the exact mechanism of how this happens is unknown.

Now researchers have identified the substrates that ɑ2M targets for degradation. They also developed a novel assay that detects how ɑ2M mediates the lysosomal degradation of targeted proteins. The group also compared the substrate specificities of α2M and clusterin, another extracellular chaperone. Clusterin also plays a part in the extracellular degradation of proteins like amyloid-beta, the extracellular aggregation of which has been implicated in Alzheimer's disease. The group found that while α2M and clusterin had overlapping functions, their pathways were not redundant. α2M was seen to recognize the defective proteins more prone to aggregation. According to the researchers, this finding lends credence to the theory that an array of extracellular chaperones cooperates to protect us from the spectrum of misfolded proteins likely to be found in the body.

In the future, elucidating the molecular mechanism of protein degradation by extracellular chaperones may prove useful in treating related diseases, like Alzheimer's disease. By degrading and removing abnormal proteins that accumulate outside cells, extracellular chaperones have the potential to be a valuable therapeutic tool.

Link: https://www.eurekalert.org/news-releases/988935

The initial results from the first five patients enrolled in the STOMP-AD trial were recently published as a preprint paper. This clinical trial assesses the outcome of a (possibly too low) dose of the senolytic combination of dasatinib and quercetin in Alzheimer's patients. The hypothesis to be tested is that the age-related increase in the burden of senescent cells in the brain is important in the onset and progression of neurodegeneration. Animal models of inflammatory neurodegeneration have shown considerable improvement following clearance of senescent cells, and a range of evidence implicates senescent cells in aspect of brain aging.

Because only a few patients have completed the trial so far, there isn't too much that one can say about the results, but they do confirm that the treatment passes the blood-brain barrier as expected, and is relatively safe. The researchers observed changes in inflammatory markers consistent with a reduction in harmful senescent cell signaling, but not in a statistically robust way given the low number of patients. They did not observe any useful outcome in measures of cognitive function, which is unfortunate.

There is some thought in the community that the doses used in the Mayo Clinic sponsored trials of dasatinib and quercetin are too low (e.g. 100mg or 125mg of dastinib and 1000mg or 1250mg of quercetin). The Betterhumans clinical trial conducted a few years ago used higher doses; unfortunately nothing has yet been published on this, I believe. Nonetheless, one would have hoped to see some improvement in cognitive function in these patients if cellular senescence is a major mechanism in Alzheimer's disease and other forms of neurodegeneration. We will have to see how the rest of the trial data looks as it emerges over the next few years. These trials are not moving rapidly, and there is definitely room for independent efforts to test these senolytics in other conditions and many more patients.

Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease

Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy.

Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study.

Our study was not powered to examine target engagement, but instead designed to collect exploratory data on baseline to post-treatment changes in markers of cellular senescence and senescence-associated secretory phenotype (SASP) both in CSF and blood. Change in IL-6 was a prespecified secondary outcome. The analyses revealed a statistically significant elevation of IL-6 in CSF after treatment. Plasma levels modestly increased, but did not reach statistical significance. The treatment-induced changes in IL-6 may reflect senescent cell apoptosis whereby IL-6 was directly released from senescent cells upon their lysis; alternatively, apoptosis may have initiated an immune response to clear the cellular debris.

Recognizing that IL-6 is a pleiotropic cytokine, we simultaneously performed a broader evaluation of cytokines and chemokines to better infer the treatment effect. CSF analyses indicated baseline to post-treatment decreases in adaptive immunity markers, TARC, IL-17A, I-TAC, Eotaxin and Eotaxin-2; and chemokine, MIP-1α. A similar pattern was observed in plasma whereby treatment was associated with a decrease in adaptive immunity markers IL-23, IL-21, IL-17, IL-31, and VEGF54; and chemokines, MIP-1α and MIP-1β. Given that senescent cells secrete these molecules as SASP factors, the observed reduction support a decrease in senescent cell burden post-treatment.

In CSF, we observed a significant increase in GFAP levels from baseline to post-treatment. CSF GFAP levels are presumed to reflect reactive astrogliosis and demonstrate elevations early in the neurodegenerative disease process. In our study, it is unclear if increases in GFAP reflect or an acute response to treatment. Coupled with the elevated CSF IL-6 data, it is tempting to speculate that the concomitant increase in GFAP may reflect apoptosis of senescent astrocytes. Supporting evidence for this would require additional blood and CSF collections, weeks or months after the end of treatment, to determine if increased GFAP and IL-6 were transient or sustained responses to senolytic treatment.

Angiogenesis, the growth of new blood vessels, is a complex process of successive stages, in which numerous cell types and signal molecules play changing roles as budding and growth of the new vessel progresses. Angiogensis becomes less effective with age, for reasons that remain unclear. Here, researchers note that increased levels of PLGF, a companion signal molecule to VEGF in regulating angiogenesis, are associated with poor outcomes in cerebral small vessel disease, a dysfunction of the smaller blood vessels in the brain. They hypothesize that an increased effort to conduct angiogenesis, likely unsuccessful given the noted decline in capillary density with age, is a reaction to the damage found in these aged, inflamed blood vessels.

Cerebral small vessel disease, a common disease marked by damage to the cells lining the blood vessels in the brain, is a major driver of cognitive problems and dementia in older adults. However, it can be difficult for doctors to determine whether a patient's cognitive impairments stem predominately from Alzheimer's disease or vascular problems, the two most common causes of dementia. In new research, scientists found that patients with higher levels of placental growth factor (PLGF) - a key molecule involved in the formation of new blood vessels, or angiogenesis - were more likely to have cognitive impairment or evidence of brain injury.

Researchers identified signaling involved in angiogenesis as potential biomarkers, theorizing that the body may respond to damaged small blood vessels in the brain with intensified efforts to grow more. For this study, researchers focused on just one of those signals, PLGF, which has previously been associated with cerebral blood flow regulation. Data had also suggested this may be a useful biomarker for identifying patients with cognitive impairment and dementia due to vascular brain injury.

335 patients underwent brain imaging, cognitive testing and blood collection. Researchers found those in the top quartile for PLGF measurement were three times as likely to have cognitive impairment or dementia compared to those in the bottom quartile. Every unit increase in total PLGF in the bloodstream was also associated with a 22% increase in the likelihood of having cognitive impairment and a 16% increase in the likelihood of having neuroimaging evidence of cerebral small vessel disease.

Link: https://www.uclahealth.org/news/researchers-identify-biomarker-diagnosing-vascular-dementia

Numerous forms of deafness, including age-related hearing loss, involve either loss of hair cells in the inner ear or loss of their axonal connections to the brain. These cells do not normally regenerate in mammals, and there is some interest in finding a way to bypass the suppression mechanisms that allow growth of hair cells during development but prevent regrowth during adult life. Approaches that show promise in animal studies include stem cell transplants, gene therapies, and small molecules targeting regulatory pathways. Here, researchers report on the ability of a mix of small molecules and siRNAs to produce regeneration of hair cells; an interesting option, but clearly still at a very early stage of development.

Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of Myc and Notch1 reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the non-transgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD "rejuvenates" the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite Myc/Notch activation.

We screened and identified a combination (the cocktail) of drug-like molecules composing of small molecules and small interfering RNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. We show that the cocktail effectively replaces Myc and Notch1 transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration.

Link: https://doi.org/10.1073/pnas.2215253120

Mitochondrial function declines with age, and one of the effects of this decline is an increased production of oxidizing molecules. Delivering antioxidants specifically to mitochondria has shown some ability to modestly slow aging in animal models, and has demonstrated its worth in the treatment of a few conditions characterized by excessive oxidative stress.

Efforts to develop mitochondrially targeted antioxidants to date have largely involved small molecules, and a limited number of classes of such molecules, those capable of localizing themselves to the mitochondria, have been established to date. Given a delivery system like lipid nanoparticles (LNPs) capable of targeting mitochondria, however, one can consider many different payloads. A broader selection of antioxidants, for a start, but there are many forms of protein therapy and gene therapy that one might want to send to mitochondria, given the means to do so.

Today's open access paper is focused on the liver as a target for LNP-delivered antioxidant therapy, as LNPs tend to end up in the liver, like most injected compounds or therapies. It is, however, possible to build LNPs that have very different biodistribution characteristics, either more broadly distributed throughout the body, or much more localized to specific tissues other than the liver. We should expect to see steady innovation on this front given initial demonstrations of the ability to target the delivery of LNP payloads to the mitochondria.

A system that delivers an antioxidant to mitochondria for the treatment of drug-induced liver injury

Mitochondria function as hubs for the integration and control of metabolic and immune systems by communicating with other organelles to maintain their individual functions and provide energy and signals. This organelle produces reactive oxygen species (ROS) in the electron transport chain that produces adenosine triphosphate (ATP). ROS production is regulated by oxidoreductases and antioxidant pathways, and moderate levels of ROS that play a role in signal transmission, cell survival, apoptosis, differentiation, and the activation of the immune system.

However, when mitochondria are unable to maintain homeostasis due to external stimulation, they generate excessive levels of ROS, thus inducing oxidative damage. Increased oxidative stress leads to mitochondrial dysfunction, resulting in premature ageing and the development of various diseases. On this point, the delivery of antioxidant molecules to mitochondria would be a useful type of therapeutic strategy.

Delivering a drug or other molecule to mitochondria needs to reach the target organ, be taken up by cells and then transferred to an organelle. The use of lipid nanoparticles (LNPs) for lipid-based drug delivery have the potential to overcome these challenges. Coenzyme Q10 (CoQ10) is a well-known antioxidant molecule and also acts as an essential coenzyme for ATP production in mitochondria. We previously reported on a method for preparing a CoQ10-MITO-Porter, a mitochondria-targeted LNP encapsulating CoQ10, using a microfluidic device. The procedure had a high degree of reproducibility and could be scaled up.

This study reports on an attempt to establish a system for delivering an antioxidant molecule CoQ10 to mitochondria and the validation of its therapeutic efficacy in a model of acetaminophen liver injury caused by oxidative stress in mitochondria. A CoQ10-MITO-Porter, a mitochondrial targeting lipid nanoparticle (LNP) containing encapsulated CoQ10, was prepared using a microfluidic device. It was essential to include polyethylene glycol (PEG) in the lipid composition of this LNP to ensure stability of the CoQ10, since it is relatively insoluble in water.

Based on transmission electron microscope observations and small angle X-ray scattering measurements, the CoQ10-MITO-Porter was estimated to be a 50nm spherical particle without a regular layer structure. The use of the CoQ10-MITO-Porter improved liver function and reduced tissue injury, suggesting that it exerted a therapeutic effect on APAP liver injury.

Non-alcoholic fatty liver disease (NAFLD) is an excess of lipids in the liver, disruptive of liver function. In our modern society of cheap calories and machineries of comfort the most common way to achieve an excess of lipids in the liver is obesity. That perhaps obscures the point that aspects of aging, such as growing mitochondrial dysfunction, change liver metabolism, and metabolism in general, to increase the risk of suffering NAFLD at a given weight in later life. We might not tend to think of NAFLD as an age-related condition per se, but it is certainly influenced by aging.

Due to the decline in the regenerative ability of the liver and dysfunctions in the immune response, older people are more likely to suffer from non-alcoholic fatty liver disease (NAFLD), acute and chronic liver injury, liver fibrosis, and other diseases. Studies have reported that the prevalence of NAFLD increases in the elderly, with a prevalence of less than 30% in people under 40 years of age and more than 50% in people over 60 years of age.

Currently, it is believed that the mechanism of development of NAFLD includes increased production of fat, increased dietary free fatty acid (FFA) levels, β-oxidative damage, and dysfunction in very low density lipoprotein synthesis. However, reduced activity and changes in diet structure lead to a continuous increase in body fat in the elderly. These factors lead to the accumulation of triglycerides (TGs) in the liver and eventually cause age-related NAFLD.

Studies have reported that the accumulation of TG droplets in hepatocytes is not a harmful process in itself. On the contrary, it is considered an adaptive response to excessive lipid uptake or the production of fat, and this imbalance in TG synthesis and breakdown causes fatty degeneration of the liver. In addition, the structural and functional changes in the mitochondria have been shown to be related to the pathogenesis of NAFLD. Ultramicroscopic analyses have demonstrated a disordered morphology of hepatocyte mitochondria in elderly patients with NAFLD, and the damage to the structure and function led to fatty degeneration of the liver and other injuries.

The changes in mitosis and fusion of mitochondria during ageing lead to the inhibition of mitochondrial phagocytosis. Cell function can be affected further if the damaged mitochondria are not cleared in time. The structural and functional changes in the mitochondria have been proven to be related to the pathogenesis of NAFLD, the loss of mitochondrial DNA (mtDNA) in hepatocytes affects function, leading to hepatic steatosis and other injuries. The present study reviewed the manifestations, role and mechanism of mitochondrial dysfunction in the progression of NAFLD in the elderly. In addition, the study discusses the treatment strategies for NAFLD based on the understanding of mitochondrial dysfunction and abnormal lipid metabolism to provide new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.

Link: https://doi.org/10.3748/wjg.v29.i13.1982

One of the more noteworthy aspect of fly aging is the degree to which it is centered around intestinal dysfunction. Increasing leakage of the intestinal barrier is a feature of aging in many species, however, as noted here. When the intestinal barrier is compromised, the result is an invasion of tissues by gut microbes, provoking chronic inflammation throughout the body and further consequent dysfunction.

A major challenge in the biology of aging is to understand how specific age-onset pathologies relate to the overall health of the organism. The integrity of the intestinal epithelium is essential for the wellbeing of the organism throughout life. In recent years, intestinal barrier dysfunction has emerged as an evolutionarily conserved feature of aged organisms, as reported in worms, flies, fish, rodents, and primates. Moreover, age-onset intestinal barrier dysfunction has been linked to microbial alterations, elevated immune responses, metabolic alterations, systemic health decline, and mortality.

Here, we provide an overview of these findings. We discuss early work in the Drosophila model that sets the stage for examining the relationship between intestinal barrier integrity and systemic aging, then delve into research in other organisms. An emerging concept, supported by studies in both Drosophila and mice, is that directly targeting intestinal barrier integrity is sufficient to promote longevity. A better understanding of the causes and consequences of age-onset intestinal barrier dysfunction has significant relevance to the development of interventions to promote healthy aging.

Link: https://doi.org/10.1242/dmm.049969

The most visible symptoms of Parkinson's disease, the tremors and loss of motor control, result from the death of a small but vital population of dopamine-generating neurons in the brain. These neurons happen to be more sensitive than others to the underlying harmful biochemistry of the condition. Parkinson's disease begins with the misfolding of α-synuclein, one of the few proteins in the body that can become altered in a way that encourages other molecules of the same protein to alter in the same way, joining together to form solid aggregates. These α-synuclein aggregates are disruptive to cell function and ultimately toxic, causing cell death.

In recent years it has become clear that a sizable fraction of Parkinson's disease begins in the intestines. The initial α-synuclein misfolding occurs there, and then slowly spreads through the nervous system to the brain. In today's open access paper, researchers provide evidence for a specific bacterial species found in the gut to be responsible for producing this initial misfolded α-synuclein. It remains to be seen as to whether further human gut microbiome studies will replicate the results here and further support a role for bacteria in the origination of Parkinson's disease, or whether it is only a smaller fraction of the overall incidence of Parkinson's disease that has a bacterial origin.

To the extent that bacteria are capable of producing a sizable amount of misfolded α-synuclein in comparison to natural misfolding in human cells, one might expect to find it responsible for a majority of the incidence of Parkinson's disease. While this discovery may lead to the prevention of much of Parkinson's disease in the best case scenario, it doesn't much help those people who already have misfolded α-synuclein present in the central nervous system; at that point it is too late and other strategies will be needed.

Desulfovibrio bacteria enhance alpha-synuclein aggregation in a Caenorhabditis elegans model of Parkinson's disease

The aggregation of the neuronal protein alpha-synuclein (alpha-syn) is a key feature in the pathology of Parkinson's disease (PD). Alpha-syn aggregation has been suggested to be induced in the gut cells by pathogenic gut microbes such as Desulfovibrio bacteria, which has been shown to be associated with PD. This study aimed to investigate whether Desulfovibrio bacteria induce alpha-syn aggregation.

Fecal samples of ten PD patients and their healthy spouses were collected for molecular detection of Desulfovibrio species, followed by bacterial isolation. Isolated Desulfovibrio strains were used as diets to feed Caenorhabditis elegans nematodes which overexpress human alpha-syn fused with yellow fluorescence protein. Curli-producing Escherichia coli MC4100, which has been shown to facilitate alpha-syn aggregation in animal models, was used as a control bacterial strain, and E. coli LSR11, incapable of producing curli, was used as another control strain. The head sections of the worms were imaged using confocal microscopy. We also performed survival assay to determine the effect of Desulfovibrio bacteria on the survival of the nematodes.

Statistical analysis revealed that worms fed Desulfovibrio bacteria from PD patients harbored significantly more and larger alpha-syn aggregates than worms fed Desulfovibrio bacteria from healthy individuals or worms fed E. coli strains. In addition, during similar follow-up time, worms fed Desulfovibrio strains from PD patients died in significantly higher quantities than worms fed E. coli LSR11 bacteria. These results suggest that Desulfovibrio bacteria contribute to PD development by inducing alpha-syn aggregation.

Exercise improves health and life expectancy in humans, so it shouldn't be all that surprising to find studies in which assessments of the epigenome and transcriptome show signs of greater youth in people with greater aerobic fitness. It is in fact somewhat surprising that early epigenetic clocks were insensitive to the state of physical fitness. In the study noted here, the researchers do not use any of the existing epigenetic or transcriptomic clocks, and instead build their own assessment of the youthfulness of epigenetic and transcriptomic profiles as compared to chronological age. The findings are interesting, but specific to muscle tissue rather than the body as a whole.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3,176).

We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse.

We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

Link: https://doi.org/10.1111/acel.13859

Given the lack of compelling results to date in the search for genetic variants associated with longevity, I don't hold out a great deal of hope for the discovery of specific differences in gut microbial populations associated with longevity. A lot of small effect sizes will likely be discovered in a range of studies, but these results will not replicate between study populations. Equally, it seems clear that the gut microbiome as a whole does have a sizable effect on long-term health, and changes significantly with age in harmful ways. Rejuvenation of the gut microbiome does appear to be a viable strategy for improved health in later life, based on animal studies and very limited human data, and clinical trials should be undertaken to prove this point sooner rather than later.

Gut microbiota associated with longevity plays an important role in the adaptation to damaging stimuli accumulated during the aging process. The mechanism by which the longevity-associated microbiota protects the senescent host remains unclear, while the metabolites of the gut bacteria are of particular interest. Here, an integrated analysis of untargeted metabolomics and 16S rRNA gene sequencing was used to characterize the metabolite and microbiota profiles of long-lived individuals (aged ≥90 years) in comparison to old-elderly (aged 75-89 years), young-elderly (aged 60-74 years), and young to middle-aged (aged ≤59 years) individuals.

This novel study constructed both metabolite and microbiota trajectories across aging in populations from Jiaoling county (the seventh longevity town of the world) in China. We found that the long-lived group exhibited remarkably differential metabolomic signatures, highlighting the existence of metabolic heterogeneity with aging. Importantly, we also discovered that long-lived individuals from the familial longevity cohort harbored a microbiome distinguished from that of the general population.

Specifically, we identified that the levels of a candidate metabolite, pinane thromboxane A2 (PTA2), which is positively associated with aging, were consistently higher in individuals with familial longevity and their younger descendants than in those of the general population. Furtherly, functional analysis revealed that PTA2 potentiated the efficiency of microglial phagocytosis of β-amyloid 40 and enhanced an anti-inflammatory phenotype, indicating a protective role of PTA2 toward host health. Collectively, our results improve the understanding of the role of the gut microbiome in longevity and may facilitate the development of strategies for healthy aging.

Link: https://doi.org/10.1111/acel.13848

The present state of parabiosis studies demonstrates that diluting blood in old animals produces improved health, whether this is achieved using saline or young blood. Thus we expect there to be few beneficial factors in young blood, and many harmful factors in old blood. So far there has been mixed or little benefit noted in studies in which young plasma is transfused into old recipients, but dilution appears more promising.

As noted here, the growing burden of senescent cells in aged tissue is a significant source of those harmful factors. Senescent cells are very active, generating a mix of factors known as the senescence-associated secretory phenotype (SASP). Much of this is inflammatory signaling, which when sustained for the long term causes a broad range of disarray in the immune system and tissue function. That includes encouraging more cells to become senescent, a feedback loop of damage and signaling, like much of aging.

An Oil Change is Not a Gasket Change: Insights from the Interaction of "Old Blood" and Senolytic Therapy

Does aging damage drive the pro-aging signaling environment in old plasma? Or does old plasma cause the aging damage? Researchers chose to look at the interplay between circulating factors and senescent cells, because each of them is known to worsen the other. Could "pro-aging" factors in blood from a biologically aged organism drive aging damage in a young animal? The answer: Yes. When they bathed cells from the deep layers of mouse skin in old mouse blood, the cells began to exhibit signs of senescence.

In living, breathing mice, even a single round of old blood transfusion was enough to push a substantial number of the cells in young mice into senescence. The effect emerged within the first two days, and even more senescent cells crept into the young animals' tissues over the following two weeks. And the corrosive spread of senescent cell markers was accompanied by a surge of circulating SASP factors in the young animals' blood. Between the eruption of senescent cells in their tissues and the tainting of their blood with "pro-aging" factors, the young mice became afflicted with many of the infirmities of old age. The aged blood sapped them of strength and endurance, fat infiltrated their muscles, they suffered minor kidney damage, and their liver function declined as the organ became somewhat fibrotic.

Why does an animal's blood become fouled with these baleful proteins with age? All of this deranged "pro-aging" signaling is the agonized biochemical crying-out of a body riddled with aging damage. As cells and essential biomolecules become damaged, they increasingly function abnormally, including in the production and reception of signaling molecules.

Researchers set out to purge the tissues of aged mice of a significant number of their senescent cells using either of two different drug regimens that destroy senescent cells: Navitoclax or the cocktail dasatinib plus quercetin (D+Q). Then they would see if having removed some of that damage from the old animals' tissues would make their blood less "pro-aging." And that's exactly what happened. Pretreating an old mouse with either senolytic approach before transferring its blood into a young mouse greatly reduced the "pro-aging" effects of its blood on the young animal, driving fewer of the young mouse's cells into senescence and causing less organ dysfunction

The study that started present interest in metformin as a potential approach to modestly slow aging was problematic in a number of ways, as examined in a lengthy series of posts at the SENS Research Foundation. It appeared to show that type 2 diabetics on metformin enjoyed a small survival advantage over non-diabetics not taking metformin. Here, researchers look at survival over twenty years, and find an apparent short-term gain in life expectancy over non-diabetics that vanishes after a few years. The hypothesis is that the effects of type 2 diabetes overwhelm the benefits of metformin given time. It remains unclear as to whether metformin can have any meaningful small benefit for non-diabetics; finding out is the goal of the proposed TAME trial.

We examined longevity in type 2 diabetes (T2D) patients treated with metformin therapy and compared them to matched controls and T2D patients treated with sulphonylurea therapy. Looking at individuals over a period of up to twenty years we showed that T2D patients had shorter survival times after first treatment than matched controls. When the study period was artificially truncated, we found a statistically significant benefit of metformin therapy for longevity over matched non-diabetic controls within the first three years. However, this benefit disappeared when we looked over longer periods of time (after five years).

This suggests that benefits of metformin may be short-term only and/or the longer-term benefits of metformin are negated by the life-shortening effects of T2D and associated comorbidities. An alternative explanation is that T2D patients experience better short-term survival outcomes following treatment due to lifestyle adjustment, as recommended by doctors. However, we did not see a benefit to longevity in the short-term for sulphonylurea therapy patients who would presumably be motivated to improve their lifestyle in the same way.

Metformin has been linked to lower mortality due to cancer, and to reduced cardiovascular disease (CVD) risk. Compared to the sulphonylurea therapy group, we did see significantly lower lifetime prevalence of cancer, and lower rates of cardiovascular disease. Excluding individuals with history of cancer and CVD prior to first treatment, these differences were even larger. This finding is supportive of the protective effects of metformin for cancer and CVD compared to other diabetes treatments. However, as we used non-diabetic controls who were matched on cancer and CVD status to the diabetic cases, we are unable to distinguish if there is a benefit of this treatment.

Link: https://doi.org/10.1186/s12889-023-15764-y

This paper provides an introduction to the several different methodological approaches that can be used to assemble a measure of biological age from data sets that exhibit changes with age. In recent years, many varied aging clocks have been produced and tested. Where such clocks are derived from epigenetic, transcriptomic, proteomic, and similar data, it remains unclear as to which processes of aging they reflect, and to what level of sensitivity. Clocks that use very few data points can produce good measures in a naturally aging population, but are unlikely to be useful when assessing the outcome of a potential rejuvenation therapy that targets only one or a few specific mechanisms of aging.

Aging is accompanied by a progressive decline in physiological functions and an accumulation of damage to the body, leading to an increased risk of morbidity and mortality. Based on birth date, chronological age (CA) is the traditional criterion for assessing aging. However, the degree of aging may vary significantly between individuals with the same CA. Therefore, CA is not the best indicator for evaluating the degree of aging in human individuals.

To seek a better index to assess the degree of aging of individuals, biological age (BA) are used as alternatives to CA to estimate aging status. BA is the most popularly used model. Aging markers are the basis for constructing biological age, and in this article we summarize the markers used in constructing biological age.

There are many ways to classify markers of aging, e.g., the aging markers can classify into two categories: histology-based data (DNA methylation, metabolomics, proteomics, etc.), and clinical biomarkers obtained from blood chemistry, hematology, anthropometry, and organ function test measurements. The "aging clock" developed from omics data is another form of biological age, multiple omics data can be combined to build the clock.

Until now, omics data have rarely been used in the construction of BA because of the high cost of its application in large-scale populations. Previously built BA models commonly choose aging biomarkers in multiple organs/systems, such as blood biomarkers, genetic indicators, and physical activity data. Biomarkers from diverse organs are more reflective of the overall body state. To build the BA model, these biomarkers can be applied to different model building methods like multiple linear regression (MLR), principal component analysis (PCA), Klemera and Doubal's method (KDM), deep learning, and other methods.

Link: https://doi.org/10.3389/fpubh.2023.1074274

Today's open access paper is a tour of the better known mechanisms of post-translational modification of proteins, and their relevance to the universal age-related loss of muscle mass and strength, the onset of sarcopenia. It is a good example of the state of knowledge in much of the life sciences, where it is possible to know both a great deal and very little about an important topic such as maintenance of muscle tissue.

Thus one can find any number of papers in which specific mechanisms of post-translational modification when applied to specific proteins are investigated in connection to the regulation of muscle growth or maintenance of structures important to muscle strength, such as neuromuscular junctions. But at the end of the day, the forest obscures the trees: there is no unified, detailed understanding as to how it all comes together. Researchers cannot in fine detail describe the progression of muscle aging at the level of cellular biochemistry and show all of the relevant post-translational modifications fit into that picture.

Every paper describes a tiny part of the whole. The synthesis of present day knowledge will be a project of the century ahead. We can only point to the known causes of aging, find ways to intervene, and then reinforce those lines of development that prove to be more successful. In the case of sarcopenia, we know that stem cell function is important, and that is is impacted by causes of aging such as mitochondrial dysfunction and cellular senescence. That is perhaps a place to start, bypassing the very incomplete picture of regulation of muscle growth and maintenance in favor of simpler approaches that may credibly restore stem cell activity in aged muscle tissue.

Post-translational regulation of muscle growth, muscle aging and sarcopenia

Post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination play critical roles in regulating signalling pathways that control muscle protein synthesis and degradation during muscle growth. However, during muscle aging, PTMs such as oxidation and glycation can lead to the accumulation of damaged proteins and impair muscle function. Specifically, oxidative stress can increase protein carbonylation and reduce the activity of key muscle proteins. The role of PTMs in sarcopenia is complex. Phosphorylation, acetylation and methylation can impact the activity of crucial proteins involved in muscle protein synthesis and degradation, whereas glycation and advanced glycation endproduct (AGE) formation can contribute to the accumulation of damaged proteins and affect muscle function.

Although this review provides an overview of the role of several PTMs in muscle homeostasis, it is important to note that there may be other types of modifications that also play a significant role in regulating muscle function, such as cysteine oxidation, ADP-ribosylation, and neddylation. High-throughput profiling of protein modifications associated with muscle mass, strength and functions helps us to understand the pathogenesis of sarcopenia and explore new diagnostic and therapeutic strategies, for example, the use of serological peptide biomarkers derived from PTM of proteins in tissues of interest for diagnosing skeletal muscle injury.

In addition, crosstalk between PTMs in physio-pathological processes of muscle, such as muscle aging and sarcopenia, remains to be investigated. The order and timing of protein modifications may be important for specific cellular processes, such as signal transduction. In these cases, sequential modifications may create a molecular 'switch' that controls the downstream signalling pathway or signal output. For instance, ubiquitination followed by phosphorylation can target a protein for degradation, whereas phosphorylation followed by acetylation can alter protein-protein interactions.Therefore, elucidating PTM crosstalk based on large-scale clinical samples is important for precision medicine in muscle diseases.

Cancer is an age-related condition. With age, there is a greater background of mutational damage that spreads throughout tissues. Greater inflammatory, pro-growth signaling by lingering senescent cells makes the environment more hospitable for cancerous growth once it is underway. The aging immune system becomes ever less able to destroy precancerous and cancerous cells rapidly enough to stop a cancer in its earliest stages.

Thus we should expect people who show an accelerated biological age to exhibit a greater risk of cancer, and this is largely the case. Most measures of biological age have quirks, however, as they are based on metrics that most likely only strongly reflect one or a few of the underlying mechanisms of aging, not all of them. Thus we might also expect to find that some measures of biological age do not correlate well with the risk of some specific cancers.

We studied 308,156 UK Biobank participants with no history of cancer at enrollment. Using 18 age-associated clinical biomarkers, we computed three biological age measures (Klemera-Doubal method [KDM], PhenoAge, homeostatic dysregulation [HD]) and assessed their associations with incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, and melanoma) using Cox proportional-hazards models.

A total of 35,426 incident cancers were documented during a median follow-up of 10.9 years. Adjusting for common cancer risk factors, 1-standard deviation (SD) increment in the age-adjusted KDM (hazard ratio = 1.04), age-adjusted PhenoAge (hazard ratio = 1.09), and HD (hazard ratio = 1.02) was significantly associated with a higher risk of any cancer. All biological age measures were also associated with increased risks of lung and colorectal cancers, but only PhenoAge was associated with breast cancer risk. Furthermore, we observed an inverse association between biological age measures and prostate cancer, although it was attenuated after removing glycated hemoglobin and serum glucose from the biological age algorithms.

Link: https://doi.org/10.1038/s41416-023-02288-w

GlyNAC supplementation involves intake of comparatively large amounts of glycine and N-acetylcysteine in order to boost levels of the antioxidant glutathione, which normally decline with age. In small human trials this proved to be a surprisingly beneficial intervention for older people when it comes to reducing inflammation and improving measures of health. Animal studies still continue, of course, and here researchers demonstrate that GlyNAC supplementation slows cognitive decline in mice.

Researchers worked with three groups of mice. Two groups were aged naturally side-by-side until they were 90 weeks old, which is similar to a 70-year-old person. At 90 weeks of age, both groups of old mice were evaluated for their cognitive abilities, such as remembering the correct route in a maze that leads to a food reward. These results were compared to those of young mice, the third group. Then, one group of old mice began a GlyNAC-supplemented diet, while the other group, called the old-controls, continued their regular diet without GlyNAC supplementation.

After completing eight weeks on their respective diets, the animals' cognitive abilities were evaluated again and their brains analyzed to measure specific brain defects that had previously been associated with cognitive impairment in studies by others. The results of these analyses in old mice supplemented with GlyNAC were compared with those of the old-control group and with the corresponding data obtained from young mice.

GlyNAC supplementation in old mice corrected brain glutathione deficiency, improved brain glucose transporters, reversed mitochondrial dysfunction and improved cognition. In addition, GlyNAC supplementation reduced oxidative stress, inflammation, and genomic damage and improved neurotrophic factors. Previous rodent studies reported that GlyNAC supplementation improved similar biological defects in the heart, liver and kidneys, and also increased length of life. A recently published randomized clinical trial in older humans provided evidence of similar improvements in skeletal muscle and blood and reversal of aging hallmarks.

Link: https://www.bcm.edu/news/glynac-supplementation-improves-cognitive-decline-and-brain-health

The first batch of immunotherapies demonstrated to be capable of clearing extracellular amyloid-β from the brain have performed poorly in late stage Alzheimer's patients. Data is beginning to emerge for their ability to modestly slow down the progression of the condition at earlier stages, however. This somewhat fits with the amyloid cascade hypothesis, in that it is evidence to support the idea that amyloid-β is no longer important to disease progression once the condition has reached the stage of becoming a feedback loop involving tau aggregation, chronic inflammation, and cell death.

Unfortunately, it isn't strong evidence for amyloid-β aggregation to be the major player in early Alzheimer's, building the foundation for that late stage disease environment to exist. When we say "modestly slow down the progression", it is worth noting that the reported effect size really isn't all that impressive, and it becomes reasonable to ask whether the side-effect profile and cost of the treatment is actually worth it. If amyloid-β were the major mechanism of early phases of Alzheimer's disease, wouldn't we see a much more profound benefit from clearance?

Expensive therapies that do little for patients are, unfortunately, business as usual in the fields of neurodegeneration and cancer. Pharma companies have become adept at colluding with regulators to eke out some declaration of marginal success from what is essentially a failed avenue of research and development. Much has been learned about the biology of the brain in the course of developing immunotherapies that can clear amyloid-β, and in principle clearance of protein aggregates is desirable even if immediate and obvious benefits are not realized, but at the same time this is quite clearly the wrong direction for Alzheimer's therapies.

New Alzheimer's drug slows cognitive decline by 35%, trial results show

A new Alzheimer's drug slowed cognitive decline by 35%, according to late-stage trial results, raising the prospect of a second effective treatment for the disease. Donanemab met all goals of the trial and slowed progression of the condition by 35% to 36% compared with a placebo in 1,182 people with early-stage Alzheimer's, the drugmaker Lilly said. It comes after trial results published last year showed that lecanemab, made by Eisai and Biogen, reduced the rate of cognitive decline by 27% in patients with early Alzheimer's.

In patients on donanemab, 47% showed no signs of the disease progressing after a year, according to a statement issued by Lilly. That compared to 29% on a placebo. The drug resulted in 40% less decline in the ability to perform activities of daily living, the company said. Patients on donanemab also experienced a 39% lower risk of progressing to the next stage of disease compared to those on a placebo.

However, the company also reported side-effects. Brain swelling occurred in 24% of those on donanemab, with 6.1% experiencing symptoms, Lilly said. Brain bleeding occurred in 31.4% of the donanemab group and 13.6% of the placebo group. Lilly also said the incidence of serious brain swelling in the donanemab study was 1.6%, including two deaths attributed to the condition and a third death after an incident of serious brain swelling.

Calorie restriction, the practice of consuming fewer calories while still maintaining an optimal intake of micronutrients, improves near all aspects of health and slows the progression of aging. This outcome appears to largely result from improved autophagy, or at least it is the case that functional autophagy is required for these benefits to occur in animal models. The relative extension of life span resulting from calorie restriction is much greater in short-lived species, as much as 40% in mice, but most likely only a few additional years in humans. The short-term health benefits are quite similar between mice and humans, however. It is certainly worth investigating as a lifestyle choice.

Age-related neurobiological changes significantly affect hippocampal structure and function, such that the main cognitive impairments associated with aging are related to the integrity of this brain structure, including the deterioration in spatial object recognition (SOR) memory. Previous studies have shown that intrinsic factors such as neuroinflammation, as well as lifestyle factors such as diet, can affect aging-associated brain functions and cognitive performance. In this regard, caloric restriction (CR) produces beneficial effects on health and life expectancy, although its ability to slow down age-dependent effects on cognitive decline and hippocampus (HPC) functioning remains unclear.

Therefore, we set out to evaluate the effects of CR on SOR memory in aged male Wistar rats, as well as those on hippocampal neuron loss, neurogenesis, and inflammation. The data show that CR in aged rats attenuates the decline in SOR memory, age-associated hippocampal neuron loss, and age-dependent microglial activation. Furthermore, we found a significant reduction in neurogenesis in the dentate gyrus of the old animals relative to adult rats. These findings support the positive effect of CR on SOR memory, suggesting that it dampens hippocampal neuronal loss and reduces proinflammatory activity.

Link: https://doi.org/10.3390/nu15071572

Sabotaging antioxidant systems can shorten life span in model organisms, but that doesn't necessarily imply that one can lengthen life by improving on biological antioxidant capacity. Yes, oxidative stress rises with age, and the presence of too many oxidizing molecules is harmful to a cell, but the presence of those oxidizing molecules and the damage they cause to cellular machinery is also a signal that produces greater cell maintenance and other beneficial outcomes. Cellular biochemistry is complicated, and it is rarely the case that relationships are simple and linear. General delivery of antioxidants as supplements has been shown to have no effect, or even mildly negative effects, on long-term health. Targeting antioxidants to the mitochondria on the other hand appears modestly beneficial.

Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. The role of the cytoplasmic and mitochondrial thioredoxin systems in determining lifespan has been examined in multiple genetic model organisms through increasing or decreasing the expression of thioredoxin or thioredoxin reductase.

While there is evidence for a contribution of the thioredoxin systems to longevity in yeast, worms, flies, mice, and humans, the relative importance of each component of these systems varies between species. In yeast and C. elegans, disruption of the cytoplasmic thioredoxin system results in the largest detrimental effect on longevity, while disruption of the mitochondrial thioredoxin system has minimal impact on lifespan. In Drosophila, both the cytoplasmic and mitochondrial thioredoxin systems affect lifespan, with the largest effect observed with the cytoplasmic thioredoxin reductase.

In mice, both the cytoplasmic and mitochondrial thioredoxin systems are essential for life as disruption of any of the components results in embryonic lethality. Thus, it appears that in more complex organisms, there is a greater reliance on thioredoxin systems for survival and an increased importance of the mitochondrial thioredoxin system compared to less complex organisms.

While it is not possible to genetically manipulate the expression levels of thioredoxin system genes in humans, multiple studies have identified genetic variants that are associated with extended longevity. In a study comparing oldest-old individuals (age 92-93) with middle-aged individuals, an allele of the cytoplasmic thioredoxin reductase gene TXNRD1 was found to be associated with longevity. These results suggest that the thioredoxin system may also contribute to longevity in humans.

Link: https://doi.org/10.3390/antiox12040944

Cells are each packed with hundreds of the organelles called mitochondria, the distant descendants of ancient symbiotic bacteria, constantly dividing, fusing, and passing around component parts. Mitochondria are the power plants of the cell, conducting energetic reactions to produce the chemical energy store molecule adenosine triphosphate. As a side-effect, these reactions produce a flux of oxidative molecules that can react with other cell components to damage them. This damage is constantly repaired in a healthy cell, and even acts as a hormetic signal under some circumstances. It is involved in the beneficial response to exercise, for example.

With age, however, mitochondria become less efficient and generate more oxidative molecules, putting stress on the cell. The proximate causes of this decline involves changes in gene expression relating to mitochondrial quality control (the process of mitophagy) and mitochondrial dynamics and structure, as well as damage to mitochondrial DNA. These two issues interact, in that mitochondria in a cell can become resistant to mitophagy, allowing worn and damaged organelles to accumulate. Links to the deeper causes of aging remain to be firmly established. As noted here, researchers are interested in finding ways to improve mitochondrial function in aged tissues, or at the very least soak up the harmful excess of oxidative molecules.

Targeting Mitochondrial Oxidative Stress as a Strategy to Treat Aging and Age-Related Diseases

Changes in organelle morphology or function are a characteristic of aging, among which mitochondrial degeneration is most prominent. Mitochondria exhibit structural changes such as significant increases in volume and size due to the buildup of defective mitochondria. Defective mitochondria generate reactive oxygen species (ROS) as a byproduct of electron leakage from the electron transport chain (ETC). Not only are defective mitochondria ROS generators, but they are also targets of mitochondrial oxidative stress, which then boosts mitochondrial ROS production.

Mitochondrial ROS generated by defective mitochondria deteriorate the morphology and function of organelles, consequently leading to aging and age-related diseases. Therefore, strategies to reduce mitochondrial oxidative stress may be beneficial as therapeutic approaches to aging and age-related diseases. The finding that treatment of senescent cells with ROS scavengers restored the senescent phenotype supports the usefulness of this strategy. Mitochondrial oxidative stress is a major cause of senescence and the consequent development of age-related diseases, so a deeper comprehension of the mechanisms that target and control mitochondrial oxidative stress is needed.

In this review, we investigated and discussed mitochondrial alterations and the consequent increase in mitochondrial oxidative stress. In addition, by examining the process through which mitochondrial oxidative stress progresses aging and aging-related diseases, we found that mitochondrial oxidative stress acts as a vicious feedback loop for aging. Here, we suggested mitochondrial oxidative stress as a potential target for aging. Therapeutic approaches to reduce mitochondrial oxidative stress have proven to be an important factor in treating aging and age-related diseases. However, clinical trials using non-mitochondria-targeted antioxidants have shown that non-mitochondria-targeted antioxidant therapies are not effective in the treatment of aging and age-related diseases. To complement these clinical findings, mitochondria-targeting antioxidants have recently been applied to various animal models, and there is growing evidence that mitochondria-targeting antioxidants have beneficial effects on aging and age-related diseases.

The use of immunotherapies will most likely replace chemotherapy and radiation therapy for the treatment near all cancers over the next twenty years, and has already done so for many types of cancer. We should expect immunotherapies to in turn be replaced by approaches that target the telomere lengthening essential to all cancers. The wheel turns slowly, but this progress will lead steadily to an end to the suffering and loss of life accompanying cancer. Cancer will become a mild, annoying but controllable condition within a matter of decades, within the lifetimes of most of those reading this now. The review paper noted here looks over the state of T cell immunotherapies, a subset of the broader category that has seen growing success in the treatment of a range of different cancers.

T cells are critical in destroying cancer cells by recognizing antigens presented by MHC molecules on cancer cells or antigen-presenting cells. Identifying and targeting cancer-specific or overexpressed self-antigens is essential for redirecting T cells against tumors, leading to tumor regression. This is achieved through the identification of mutated or overexpressed self-proteins in cancer cells, which guide the recognition of cancer cells by T-cell receptors.

There are two main approaches to T cell-based immunotherapy: HLA-restricted and HLA-non-restricted immunotherapy. Significant progress has been made in T cell-based immunotherapy over the past decade, using naturally occurring or genetically engineered T cells to target cancer antigens in hematological malignancies and solid tumors. However, limited specificity, longevity, and toxicity have limited success rates.

This review provides an overview of T cells as a therapeutic tool for cancer, highlighting the advantages and future strategies for developing effective T cell cancer immunotherapy. The challenges associated with identifying T cells and their corresponding antigens, such as their low frequency, are also discussed. The review further examines the current state of T cell-based immunotherapy and potential future strategies, such as the use of combination therapy and the optimization of T cell properties, to overcome current limitations and improve clinical outcomes.

Link: https://doi.org/10.3390/vaccines11040835

Chronic inflammation and oxidative stress go hand in hand, both disruptive of tissue function and health. This is in part because mitochondrial dysfunction, which generates an increased amount of oxidative molecules, can provoke inflammation via the innate immune sensing of damage-associated molecular patterns, such as mislocated mitochondrial DNA fragments. Further, broad mitochondrial dysfunction can push a greater number of cells into a senescent state, in which they produce pro-inflammatory signaling. Other links also exist between these two harmful states.

Both frailty and metabolic syndromes lead to the following consequences: poorer response to physical and/or mental stressors, increased risk of hospitalization, adverse outcomes, institutionalization and premature death. A similar pathogenesis underlies the development of the metabolic as well as the frailty syndrome in the context of oxidative stress and acceleration of inflammation. The disturbance of various metabolic processes on the cellular, tissue, and organ level have demonstrated that the syndromes represent two faces of the same coin.

Through the human lifespan, unfavorable biochemical phenomena accumulate, including increased inflammation and the progression of oxidative stress, which result in the manifestation of clinical dysfunctions and, as a result, premature death. Thus, aging is complicated by disorders such as decreased insulin sensitivity, hyperglycemia, hyperlipidemia or civilization diseases such as diabetes, hypertension, and cardiovascular diseases. Gathered clinical and metabolic conditions are seen in the metabolic syndrome. The main mechanism of pathology in the metabolic syndrome is insulin resistance.

Enhanced inflammation, increased reactive oxygen species (ROS) production and faint antioxidant defense systems are responsible for the improper synthesis, secretion and action of insulin leading to insulin resistance. Moreover, lower insulin sensitivity causes an imbalance toward muscle mass density, relative handgrip force, and decreased level of physical activity with an outcome of sarcopenia and thus leads to the clinical face of frailty syndrome. The aim of this narrative review is to pay attention to the interrelationships between the impact of inflammation, oxidative stress markers, and various metabolic pathways in the development of frailty and metabolic syndromes in elderly individuals, which underlie the pathogenesis of these syndromes.

Link: https://doi.org/10.3390/metabo13040475

In mammalian tissues, cells become senescent constantly as a result of reaching the Hayflick limit on cell replication. Telomeres, lengths of repeated DNA sequences at the ends of chromosomes, are reduced in length with each cell division. When too short, or otherwise damaged, cellular senescence or programmed cell death is the outcome. In youth, senescent cells don't tend to last long: they secrete a potent mix of pro-inflammatory signals that attracts the attention of the immune system, and are consequently destroyed by immune cells. With advancing age, this clearance slows down and senescent cells accumulate to cause harm.

Matters are somewhat different in the exceptionally long-lived naked mole-rat and blind mole-rat species, however, both species in which individuals exhibit very little age-related decline until very late in life. Their senescent cells are nowhere near as active and pro-inflammatory as is the case in other mammals, for one thing, and thus senescent cell accumulation has nowhere near the same detrimental contribution to long-term health. Secondly, as noted in today's open access paper, the relationship between telomeres and replicative senescence appears to be quite different, and their version of the Hayflick limit may function in ways that have yet to be explored.

The existence of the Hayflick limit on cell replication is fundamental to multicellular life. We are made up of (a) a tiny number of stem cells are are privileged, maintaining long telomeres via the use of telomerase and capable of continued replication, and (b) a vastly greater number of somatic cells that are limited in their ability to replicate. This arrangement is how the risk of cancer is kept low enough for evolutionary success; most potentially cancerous mutational damage has no lasting impact because it occurs in somatic cells that will soon enough be replaced, and cannot spread the mutation to many descendants.

In this context, it is worth recalling that mole-rats exhibit minimal cancer incidence, for reasons still under investigation, but which certainly include highly efficient cancer suppression mechanisms. It may well be the case that this cancer suppression has allowed evolution to take the use of telomeres and the Hayflick limit in a different direction than is the norm for mammals.

Damage-Free Shortening of Telomeres Is a Potential Strategy Supporting Blind Mole-Rat Longevity

In this study, we examined the average telomere length and telomerase activity, as well as the formation of telomere associated foci (TAFs) and the mRNA expression levels of the shelterin components in cultured primary cells of Spalax, a long-lived, hypoxia-tolerant, and cancer-resistant blind mole-rat species.

We showed that with cell passages, Spalax fibroblasts demonstrated significant shortening in telomere length, similar to rat cells, and in line with the processes observed earlier in tissues. We also demonstrated that the average telomere length in Spalax fibroblasts was significantly higher than the average length in rats, similar to previously reported results in Spalax muscles. Long telomeres are controversially described in the literature by their association with cancer risk, aging, or longevity. Extremely long telomeres in mice were reported to produce beneficial metabolic effects, low cancer risks, and longevity. Whether the long, seemingly guarded telomeres are one of the driving forces in Spalax longevity and healthy aging remains unclear.

It may be speculated that longer telomeres are attributed to telomerase overexpression, which presumably prolongs cell survival; however, we found that Spalax fibroblast telomerase activity was, in fact, lower than that of its counterpart in rats, which further supports our hypothesis that integrity maintenance of the telomeres (such as via shelterin activity), rather than telomere elongation, is characteristic of Spalax cells as a strategy that contributes to its long lifespan and supports its unique mode of cellular senescence.

It was suggested that long-lived animals have adopted a mechanism whereby the pace of telomere attrition and the activity of the telomerase is the same as that in other, short-lived animals. However, since initially, Spalax exhibits longer and potentially safeguarded telomeres, it seems tempting to speculate that the time it takes to reach critical length/damage that ignites the senescence machinery is longer and therefore, may contribute to their profoundly unique mode of replicative senescence lacking the canonical inflammatory response known to accompany the senescent phenotype in all studied species.

In summary, our results support that Spalax have evolved strategies for genome protection that apparently include telomere maintenance machinery, together contributing to its longevity and healthy aging. These strategies include a unique mode of senescence not induced by persistent DNA damage response (DDR) or telomere attrition, but which rather seems to be an independent cell program driven by other types of 'clocks'. The precise mechanisms of telomere maintenance and the apparently 'non-canonical senescence clock' require further investigation in Spalax and other long-lived species as possible requisites for long lifespan and healthy aging.

Increasing dysfunction of mitochondria, the power plants of the cell, is a feature of aging. It is also strongly connected to neurodegenerative conditions. The brain is an energy-hungry organ, and anything that interferes with the supply of nutrients and their processing to power cellular operations is going to cause issues. In this review paper, researchers discuss the link between mitochondrial dysfunction and neurodegeneration, and go on to note a few of the efforts underway to produce pharmacological treatments capable of restoring greater mitochondrial function in aged tissues. Sadly all too few of these treatments can outpace the beneficial effects of exercise on mitochondrial function. More and better approaches are needed, such as transplantation of functional mitochondria.

The decline in mitochondrial function during aging and associated disorders like neurodegeneration has received much attention, and there are extensive efforts underway to develop pharmacological treatments that can restore the potential and integrity of these crucial organelles. A large number of pharmacological modulators, both natural and synthetic, are being studied for their ability to reduce mitochondrial stress by targeting different pathways, including mitochondrial OXPHOS, ROS homeostasis, and metabolic processes. Furthermore, several other pathways, such as mitochondrial biogenesis, dynamics, and degradation, are also considered in developing therapeutics against mitochondria-associated disorders.

The depleted energy production by mitochondria due to various cellular stresses such as increased ROS levels and calcium dyshomeostasis, significantly affects energy-intensive cells like neurons. Scientists have explored various molecules that could potentially improve the functioning of the electron transport chain (ETC). For example, riboflavin and idebenone enhance the transfer of electrons, while others, such as thiamine and dichloroacetate, increase the availability of ETC substrates.

In addition, researchers have studied various natural compounds for their ability to regulate mitochondrial oxidative stress. For example, saponins derived from Panax japonicus and Panax notoginseng show neuroprotective effects by reducing mitochondrial damage through the induction of antioxidant responses. Besides this, several mitochondrial antioxidants, including MitoQ, Mitotempo, and Mito apocynin, protects mitochondria from oxidative damage.

Another approach to address energy deficiency involves increasing the number of mitochondria in cells by targeting transcription factors participating in formation of new mitochondria, such as PGC-1α. Pioglitazone, a type of thiazolidinedione, has been shown to have protective effects in several neurological diseases by targeting transcription factors such as PGC-1α. Furthermore, various studies show the protective effects of directly or indirectly activating mitochondrial biogenesis with compounds such as bezafibrate, resveratrol, and AICAR. It is evident that mitochondrial dynamics are altered in various neurodegenerative diseases, and different pharmacological interventions that can modulate the proteins involved in this process are investigated. Echinacoside (ECH) treatment shows neuroprotective effects by inducing mitochondrial fusion via increased transcription of Mfn2. Treatment with liquiritigenin, a flavonoid, has been found to induce mitochondrial fusion and protects against amyloid-β cytotoxicity.

Various modulators of mitophagy that have shown beneficial effects by removing damaged or altered mitochondria are identified. Urolithin A induces autophagic removal of altered mitochondria and extended lifespan in C. elegans. Spermidine treatment was found to induce both the mitophagy as well as biogenesis of mitochondria in aged mice heart cells. Metformin, a drug used in treating type 2 diabetes, has been found to enhance mitochondrial function by restoring ETC proteins and promoting mitophagy.

Link: https://doi.org/10.3389/fcell.2023.1146564

Researchers here demonstrate an approach to inhibiting miR-141-3p that leads to improved health in old mice following twelve weeks of treatment. It appears that this microRNA is involved in the at least the inflammatory signaling characteristic of old age, but potentially a range of other mechanisms as well, such as mitochondrial function, and tendency for cells to become senescent. Since every aspect of cellular biochemistry influences every other aspect, one can produce benefits in this way and still be left with an unclear understanding of exactly why the results are positive.

We previously demonstrated elevated levels of miR-141-3p with age in human and murine bone marrow environments. We have also reported that miR-141-3p inhibits the osteogenic differentiation of bone marrow stromal cells. Several other groups have shown elevated levels of miR-141-3p in age-related diseases, such as neurodegenerative disorders, and cardiovascular diseases. The current study was designed to answer the critical question whether by inhibiting miR-141-3p during aging can we improve overall health, specifically systemic and musculoskeletal health. For this study, we treated mice at 15 months of age subcutaneously twice a week for three months.

Overall health depends on oxidative and inflammatory stress levels in tissue and organs. With advanced age, pro-inflammatory cytokines tend to be higher. In our study, we found that serum pro-inflammatory cytokine levels (TNF-α, IL-1β, IFN-γ) declined in the Anti-miR-141-3p treatment. Moreover, we found decreased M1 and increased M2 macrophage in splenocytes in the treated group. This suggested that Anti-miR-141-3p treatment helps in maintaining better immune health.

Maintaining musculoskeletal health is an important contributing factor to healthy aging and longevity. We, therefore, analyzed the effects of Anti-miR-141-3p on muscle and bone microstructure. We observed muscle fiber size was increased in the mice treated with Anti-miR-141-3p compared to the vehicle-treated group. As expected, we also observed better bone microstructure in Anti-miR-141-3p treated animals. Ours is the first study to demonstrate the treatment with Anti-miR-141-3p decreases systemic inflammation and improves musculoskeletal health in aged mice.

We hypothesized that miR-141-3p induces a determinate effect on aging cells through multiple signaling pathways, specifically by promoting a pro-inflammatory environment and inducing premature senescence. Our data demonstrated that treatment of cells in vitro with miR-141-3p elevated the expression of pro-inflammatory cytokines (TNF-α, IL-1β) and senescence markers (p16, p21) and Anti-miR-141-3p reversed the effect.

Link: https://doi.org/10.14336/AD.2023.0310-1

Is epigenetic change a cause or consequence of aging, and are epigenetic clocks measuring a cause or consequence of aging? In today's open access preprint, researchers build a model of the epigenetic contribution to aging, and propose that the answer is "both", with different epigenetic marks on the genome being either cause or consequence of aging.

Epigenetic marks such as DNA methylation, the attachment of methyl groups to the genome at specific locations called CpG sites, alter gene expression. They do so by altering the structure of packaged DNA, either hiding regions from transcriptional machinery or exposing those same regions to allow RNA to be produced. The activity of RNA and proteins in a cell in turn alters epigenetic marks, a feedback loop that integrates contributions of the epigenome, cell machinery, and the impact of the surrounding extracellular environment.

A cell is thus a dynamic system, but nonetheless the advent of epigenetic clocks has demonstrated that certain epigenetic marks are characteristic of aging. Why is this the case? It was widely thought that the epigenome reacted to the accumulating damage and dysfunction of aging, and thus was much more a downstream consequence than an important contributing cause of aging. In recent years, however, new studies have suggested that at least some epigenetic change may be closer to the fundamental causes of aging. For example, recall the research indicating that repeated cycles of DNA double strand break repair directly provoke age-related epigenetic changes.

Given (a) the present popularity of intervening at the epigenetic level, (b) the billions in funding for organizations attempting to do this, and (c) the demonstrated ability to rejuvenate the aged epigenome via partial reprogramming technologies, it seems clear that hypotheses and models regarding epigenetic aging will be earnestly tested in the years ahead. While epigenetic rejuvenation clearly cannot fix issues that a young body cannot fix, such as aggregation of persistent metabolic waste, cross-links that cannot be broken down effectively by our biochemistry, or localized excess cholesterol, these are nonetheless exciting times.

Epigenetic fidelity in complex biological systems and implications for ageing

It has been proposed that epigenetic changes are causative in ageing, and a recent study has suggested that DNA damage response-induced loss of epigenetic information drives ageing. More broadly, the information theory of ageing has suggested that loss of epigenetic information with age is a major driver of the ageing process. It has also been suggested that pre-programmed shifts in epigenetic information states with age are a major determinant of ageing phenotypes. As such, understanding the basis of epigenetic clocks, and how epigenetic changes could impact ageing is a major and important open question. Moreover, despite efforts to understand the informatic character of ageing, there has been comparatively little research on what makes mammalian ageing inevitable.

In this work, we develop a conceptual model to explain the ageing process based on first principles. We demonstrate that the epigenetic system has unique inherent informatic properties that progressively acquire informatic corruption, meaning that with age epigenetic information fidelity cannot be maintained. In this work we set out to break down the nature of epigenetic damage and characterise biological ageing as a failure of repair fidelity.

To do this, we began by showing that chronological age correlates to the progressive deviation within certain classes of CpG loci. It seems that there are three variables that control the correlation to age: those values representing fluke correlation to cellular regulation, those representing genes that are being regulated increasingly as age increases (senescence, DNA repair, stress response, etc) and those peaks describing epigenetic systems becoming deregulated with age. We suggest that epigenetic clocks are measuring both of the latter classes of CpG and that the answer to the question 'Are epigenetic clocks measuring cause or consequence' is 'both', depending on the CpGs used.

Genes that change in response to age represent the effect of age and the epigenetic stochastic noise represents biological age itself. We propose that this epigenetic damage would result in a feedback cycle, in which deregulation would lead to further deregulation through the disruption of maintenance and repair of the epigenetic regions, and to the phenotype of age through the general deregulation of cellular systems. This would fit the profile of ageing as a robust, gradual process, with slow, reliable progress made as deregulation accumulates, accelerating toward network failure as the feedback cycle picks up pace.

We can see in the gene ontology results that in all organisms and tissues, those genes regulated by the loci in which deregulation correlates to age are genes governing promotors and enhancers. We suggest that this is because promotors and enhancers have a unique feature that precludes polarising their regional control for regulation: they need to regularly reconfigure the local methylation state consequent to the current state of transcription.

We suggest this makes them tautologically defined, in that the definition of the epigenetic signal of a promotor/enhancer modulator relies in part on its own current state (such that any damage results in damage to any rule from which the signal could be corrected), and thus representing a class of loci in which epigenetic regional control cannot be correctly defined once epigenetic damage has occurred. We suggest damage accrues in these regions and the global deregulation of transcription that occurs consequent to this gives rise to the general phenotype of age.

Sepsis is not, strictly speaking, an age-related condition. It can occur at any age, the result of bacterial infection leading to a feedback loop of runaway inflammatory signaling. Older individuals exhibit greater risk and greater severity of sepsis, however. The aged tissue environment and immune system is biased towards greater inflammation, and the immune system is less able to control bacterial infections. Given an infection leading towards sepsis, an older individual is less able to resist suffering a worse outcome. Senescent cells provide one contribution to the chronic inflammation of aging, but as noted here, changes in the gut microbiome are also a factor.

Older adults suffer more frequent and worse outcomes from sepsis, a critical illness secondary to infection. The reasons underlying this unique susceptibility are incompletely understood. Prior work in this area has focused on how the immune response changes with age. The current study, however, focuses instead on alterations in the community of bacteria that humans live with within their gut (i.e., the gut microbiome). The central concept of this paper is that the bacteria in our gut evolve along with the host and "age," making them more efficient at causing sepsis.

Prior research has focused on host factors as mediators of exaggerated sepsis-associated morbidity and mortality in older adults. This focus on the host, however, has failed to identify therapies that improve sepsis outcomes in the elderly. We hypothesized that the increased susceptibility of the aging population to sepsis is not only a function of the host but also reflects longevity-associated changes in the virulence of gut pathobionts.

We utilized two complementary models of gut microbiota-induced experimental sepsis to establish the aged gut microbiome as a key pathophysiologic driver of heightened disease severity. Further murine and human investigations into these polymicrobial bacterial communities demonstrated that age was associated with only subtle shifts in ecological composition but also an overabundance of genomic virulence factors that have functional consequence on host immune evasion. Escape of these age-conditioned pathogens from the intestinal lumen therefore leads to exaggerated sepsis severity.

Link: https://doi.org/10.1128/mbio.00052-23

Cardiovascular aging is greatly influenced by exercise and physical fitness, to the point at which one can point to physically active hunter-gatherer populations that exhibit very few of the common cardiovascular issues present in wealthier first world populations. Researchers here report on a study of cardiovascular aging in competitive athletic individuals, noting that they exhibit less than half of the risk of hypertension observed in the general population. This is one of many examples of the way in which athletes tend to be healthier than the average.

Master athlete is a term applied to individuals typically aged 35 years and older, who exercise and compete on a regular basis in organized sports competitions with similar-aged individuals. Master athletes have been reported to be significantly healthier than the general population in a number of health outcomes, including numerous chronic diseases such as asthma, coronary heart disease, stroke, cancer (all types combined), depression, diabetes (type 1 diabetes mellitus, type 2 diabetes mellitus), hypercholesterolemia, hypothyroidism, osteoporosis, Parkinson's' disease, and peripheral arterial disease.

We assessed resting blood pressure (BP) in male and female World Masters Games (WMG) athletes. This was a cross-sectional, observational study which utilized an online survey to assess the blood pressure (BP) and other physiological parameters. A total of 2,793 participants were involved in this study. Significant differences were identified when comparing WMG athletes' resting BP results to the general Australian population with WMG athletes having a lower systolic BP and diastolic BP. Only 8.1% of the WMG athletes were found to be hypertensive compared to 17.2% in the general Australian population.

Link: https://doi.org/10.3390/sports11040085

Visceral fat tissue generates inflammation through a range of mechanisms, and this only becomes worse with advancing age. The more visceral fat tissue, the worse the long-term consequences for metabolism, driven by inflammatory signaling. One of these mechanisms is that fat tissue provokes a greater burden of cellular senescence, cells that shut down replication and focus their energies on generating disruptive pro-inflammatory signals. This tendency increases with age.

Today's open access paper focuses on the regulation of macrophage senescence in fat tissue, and identifies rising levels of osteopontin with age as an important contributing factor. Macrophages are innate immune cells found throughout the body, responsible for a broad portfolio of tasks that go beyond chasing down pathogens and destroying errant cells to include assisting in tissue maintenance and regeneration. Their activities are important to the state of chronic inflammation.

Increased osteopontin levels are implicated in a range of degenerative processes observed in aged tissues. Researchers have considered using osteopontin as a biomarker of aging. Much of this may be due to effects on stem cell function, as in muscle tissue and the hematopoietic system in bone marrow. That in turn may be mediated by inflammatory signaling, given effects on macrophage function noted here.

Osteopontin promotes age-related adipose tissue remodeling through senescence-associated macrophage dysfunction

In obesity, adipose tissue (AT) undergoes cellular senescence involving activation of adipose tissue macrophages (ATMs), which enhances AT remodeling through proinflammatory and profibrotic signaling. Macrophages play a pivotal role in both the induction and resolution of inflammation that results in cellular dysfunction and AT damage. Notably, increased infiltration of proinflammatory macrophages in AT impairs the secreted adipokine profile and contributes to insulin resistance through a senescence-associated secretory phenotype (SASP). Indeed, ATMs are an important source of chemokines, matrix metalloproteinases, and other profibrotic and inflammatory mediators that collectively constitute the SASP.

Macrophages are also critically involved in AT remodeling because they are key to the clearance of obesity-associated senescent or damaged AT cells. Recent observations suggest that senescence initiates tissue remodeling by recruiting immune cells through SASP to allow clearance and regeneration of the damaged tissue. With persistent damage, as occurs in obesity and aging, however, clearance and regeneration may be compromised by senescence-associated macrophage dysfunction.

Interestingly, we have recently established visceral AT (VAT) as the major source of osteopontin (OPN) during aging. OPN is a matricellular protein involved in intracellular and extracellular signaling mediating cell-to-cell interactions, immune cell function, inflammation, and tissue remodeling. Beyond the reported role of OPN in AT proinflammatory status, we identified OPN as an important SASP component among a variety of growth factors, proinflammatory cytokines/chemokines, and adipokines, with a major role in inducing remote cardiac tissue remodeling by modulating fibroblast function. However, the link among age-related OPN production, VAT senescence, and impairment of ATM function is elusive.

Here we show that during chronological aging ATMs acquire several features of senescent cells, which impair ATM function, and contribute to age-related VAT remodeling and dysfunction, a process mediated by OPN. Our findings highlight OPN inhibition as a potential therapeutic intervention to rejuvenate VAT, thus promoting healthy aging.

As noted in this open access paper, protein misfolding and aggregation is a body-wide feature of aging, not only associated with the brain and neurodegenerative conditions. In the case of the heart, it is becoming apparent that misfolding of transthyretin to form amyloid can play a role in heart disease, and this form of amyloidosis may grow to be the majority cause of death for supercentenarians. The paper here is a more general tour of relevant mechanisms rather than a focus on any one specific protein, but is nonetheless interesting.

Protein homeostasis, the balance between protein synthesis and degradation, requires the clearance of misfolded and aggregated proteins and is therefore considered to be an essential aspect of establishing a physiologically effective proteome. Aging alters this balance, termed "proteostasis", resulting in the progressive accumulation of misfolded and aggregated proteins. Defective proteostasis leads to the functional deterioration of diverse regulatory processes during aging and is implicated in the etiology of multiple pathological conditions underlying a variety of neurodegenerative diseases and in age-dependent cardiovascular disease.

Detergent-insoluble protein aggregates have been reported by us in both aged and hypertensive hearts. The protein constituents were found to overlap with protein aggregates seen in neurodegenerative diseases such as Alzheimer's disease. Therefore, targeting these protein components of aggregates may be a promising therapeutic strategy for cardiovascular pathologies associated with aging, ischemia, and/or hypertension.

Link: https://doi.org/10.20517/jca.2023.4

To what degree can the current panoply of stem cell therapies slow the progression of aging? A great many trials have been conducted, largely of cell therapies wherein the principle mode of action is reduction of chronic inflammatory signaling. This has value, but it remains the case that the original vision of greatly enhanced regeneration and transplanted cells surviving to support tissue for the long term has yet to be realized. The paper here provides a concrete list of trials and various different strategies for the production of first generation stem cell therapies; good reading for those interested in seeking out this form of treatment.

Aging is associated with a decline in the regenerative potential of stem cells. In recent years, several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions).

Information concerning those clinical trials was extracted from national and international databases (United States, EU, China, Japan, and World Health Organization). Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging. With regard to physical frailty, positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation), and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed. With regard to facial skin aging, positive results have been obtained with an autologous preparation of adipose-derived stem cells.

A further sixteen clinical trials for physical frailty and facial skin aging are currently underway. Reducing physical frailty with intravenous mesenchymal stem cell administration can increase healthy life expectancy and decrease costs to the public health system. However, intravenous administration runs the risk of entrapment of the stem cells in the lungs (and could raise safety concerns). In addition to aesthetic purposes, clinical research on facial skin aging allows direct evaluation of tissue regeneration using sophisticated and precise methods. Therefore, research on both conditions is complementary, which facilitates a global vision.

Link: https://doi.org/10.3389/fragi.2023.1148926

How much optimization of exercise is a reasonable goal, given what is presently known? Today's open access paper makes the fair point that our hunter-gatherer evolution matches us to a certain strategy, meaning a lot of moderate exercise leavened with a smaller amount of intermittent vigorous exercise. Epidemiological evidence supports the merits of a lot of moderate exercise, while suggesting that a lot of vigorous exercise doesn't add that much to the benefits, and it is actually possible to exercise too much.

The dose-response curve for exercise is one in which small amounts of effort are a great improvement over being sedentary, but after one hits a reasonable amount of moderate effort (maybe twice the recommended 150 minutes per week), further benefits taper off. Still, a great deal of thought and effort presently goes into the question of whether one can optimize type, timing, and degree of physical activity. One has to think that much of this is wasted effort, even while somewhere in there are a few grains of sense.

Training Strategies to Optimize Cardiovascular Durability and Life Expectancy

A landmark, long-term, prospective, cohort study evaluated the links between leisure-time physical activity duration and intensity with all-cause mortality and cause-specific mortality. The relationships between dose of exercise and risk of death during follow up were distinctly different for vigorous physical activity (VPA) than for moderate physical activity (MPA). First and foremost, very high levels of MPA reduced risk of cardiovascular disease (CVD) mortality and all-cause mortality substantially better than very high levels of VPA. Secondly, the reductions in CVD mortality and all-cause mortality were maximized at ~150 minutes/week of VPA; doses >150 minutes/week of VPA were associated with a plateau in all-cause mortality, and a modest but progressive loss of CVD mortality reduction at higher doses. In contrast, MPA reduced CVD mortality and all-cause mortality in dose-dependent, inverse relationships - the higher the dose of MPA the lower the number of deaths during the study.

For an individual whose goal is to decrease the risk of CVD and boost life expectancy, a routine of MPA appears to be adequate. Although chronically performing very high doses of VPA may attenuate some of the benefits bestowed by less extreme efforts, this is relevant for only about 2.5% of the US adult population. This is not to say that VPA is harmful; it substantially reduces all-cause mortality and CVD mortality compared to a sedentary lifestyle. Yet, the magnitude of the mortality and CVD risk reductions with high doses of VPA do not appear to be as substantial as for high doses of MPA. Chronically doing very high doses of moderate exercise reduced risks of all-cause mortality and CVD mortality at least two-fold better compared to chronically performing very high doses of vigorous exercise.

At the other extreme, a sedentary lifestyle - which affects about half of the U.S. adult population - is associated with worse health outcomes and diminished life expectancy. After sitting more than 60 minutes, the levels of blood glucose, triglycerides, and inflammatory markers begin to rise. Even light or moderate activity mitigates these adverse effects of sedentary behavior without unduly increasing orthopedic injuries or cardiac risks.

Throughout the last three million years of hominin evolution, our ancestors' existence necessitated a very physically active lifestyle. Adults would usually accumulate 14,000 to 16,000 steps/day, mostly in the form of walking three to eight miles, often while carrying objects such as wood, food, water, and children. Hunter-gatherer humans' daily subsistence required large amounts of MPA with smaller doses of interspersed VPA - this is the activity pattern for which we remain genetically adapted. This evolutionary template would seem to be a logical guide to structuring an ideal activity pattern for promoting optimum health and longevity.

To the degree that regular exercise and maintenance physical fitness preserve health in later life, it must be slowing the fundamental mechanisms of aging. One of those mechanisms is the accumulation of senescent cells, which emerges due to a growing imbalance between the pace of creation and pace of destruction. Exercise is known to improve autophagy, and this in turn slows the pace of creation of senescent cells. Exercise also improves immune function. Which of these effects are more important in the case of the age-related burden of senescent cells is an open question.

Blood vessels are key conduits for the transport of blood and circulating factors. Abnormalities in blood vessels promote cardiovascular disease (CVD), which has become the most common disease as human lifespans extend. Aging itself is not pathogenic; however, the decline of physiological and biological function owing to aging has been linked to CVD. Although aging is a complex phenomenon that has not been comprehensively investigated, there is accumulating evidence that cellular senescence aggravates various pathological changes associated with aging.

Emerging evidence shows that approaches that suppress or eliminate cellular senescence preserve vascular function in aging-related CVD. However, most pharmacological therapies for treating age-related CVD are inefficient. Therefore, effective approaches to treat CVD are urgently required. The benefits of exercise for the cardiovascular system have been well documented in basic research and clinical studies; however, the mechanisms and optimal frequency of exercise for promoting cardiovascular health remain unknown.

Accordingly, in this review, we have discussed the changes in senescent endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) that occur in the progress of CVD and the roles of physical activity in CVD prevention and treatment.

Link: https://doi.org/10.3389/fphys.2023.1138162

One of the more noted figures in the senolytics industry has founded a think-tank institute to promote longevity science, and is organizing a senotherapeutics conference to take place later this year. This seems a good thing, and I encourage more of those in the industry to step outside the bounds of their company research and development programs to consider the bigger picture and what they might do to cultivate faster progress towards greater human longevity.

The Phaedon Institute was envisioned by a group of distinguished scientists and entrepreneurs to promote a greater degree of synergy, efficient cooperation, and discussion among longevity industry stakeholders that could set rigorous standards and guidance to support the growing community of the emerging field of longevity sciences. The Phaedon Institute is aimed to distill solid and sound science, support the leaders and talents, recognize the proper regulatory environment and investment opportunities, and transform the aging and longevity industry.

In the past 100 years, we have achieved groundbreaking milestones in disease diagnosis and treatment and extended a healthy life span. A step change in life expectancy will have vast implications for individuals, governments, and society. To ensure that increases in longevity benefit all, a collaborative approach among different stakeholders is required to drive change and create solutions to equip us for this new reality.

The Phaedon Summit is a platform to offer space to the key opinion leaders in the science and therapeutic development to support the growing community of the emerging field of longevity sciences. Phaedon Institute is pleased to introduce the inaugural Seno-Therapeutics Summit 2023 to be held in November 2023 at the beautiful Buck Institute For Research On Aging, Novato, California.

Link: https://www.phaedon.institute/

Microglia are innate immune cells of the brain. They are analogous to macrophages elsewhere in the body, responsible for clearing up debris, destroying pathogens and problem cells, and participating in regeneration. They also undertake an arguably larger portfolio of tissue maintenance tasks that are related to neural function and synaptic connections.

With advancing age, the microglial population of the brain becomes more activated and inflammatory in response to a tissue environment that contains more signs of damage and cell stress. As is true of senescent cells, this microglial contribution to the chronic inflammation of aging appears to be a significant aspect of age-related neurodegeneration. There is thus an increasing interest in the research community in targeting microglia as a basis for therapies to treat neurodegenerative conditions.

Aging microglia

Microglia are the resident immune cells of the central nervous system (CNS), a tissue-resident macrophage population with specific characteristics to support the CNS environment and health. Microglia have a mesodermal origin and originate from yolk-sac progenitors during embryogenesis; after their early migration and proliferation, they colonize the CNS and self-renew throughout the lifespan.

Microglia perform a variety of critical functions; (a) they support neurogenesis and ensure correct neuronal circuitry by pruning synapses; (b) phagocytose apoptotic neurons; (c) defend against infectious and non-infectious insults; (d) produce extracellular matrix (ECM) components and control its remodeling by secreting ECM-degrading enzymes; (e) maintain myelin health; (f) and remove extracellular protein aggregates, which accumulate in neurodegenerative diseases. Homeostatic adult microglia have a highly ramified morphology, with extended and arborized processes and a small body. However, when responding to stimulation or during aging and CNS pathology, their morphology changes.

With age, microglia alter their function, morphology and phenotype; however, there are still many gaps in our knowledge of how microglia age. Both rodent and human aging microglia are characterized by alterations in morphology, phagocytosis, metabolism, and inflammatory phenotype, which appear to play protective and detrimental roles in maintaining brain homeostasis and preserving their ability to respond to non-sterile and sterile insults.

Furthermore, more recent evidence indicates that environmental factors, such as meningeal lymphatics health and production of metabolites from the gut microbiome, can affect brain homeostasis by affecting microglia reactivity and phenotype. Recent single cell RNA-seq studies suggest that different subsets of microglia already exist in young adults; however, they expand in aging and even more so in neurodegeneration. Nonetheless, we still do not know the full extent of microglia plasticity and how firm these phenotypes are.

An aging clock can be built from near any collection of data that changes with age. The first epigenetic clocks used DNA methylation status for many different locations on the genome, but just about any biochemical or physiological measure can be incorporated into a clock algorithm. Since early epigenetic clocks were insensitive to physical fitness, it is interesting to see an attempt to extend a later epigenetic clock by adding assessments of physical fitness. Can there be a hypothetical best clock, one that accurately reflects the result of any intervention in aging, or will it always be the case that clocks will only approximate the complex reality, and there will always be issues in which a clock is too sensitive or not sensitive enough to one or more mechanisms of aging? That is the question.

Physical fitness is a well-known correlate of health and the aging process and DNA methylation (DNAm) data can capture aging via epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance fitness in their construction. We develop blood-based DNAm biomarkers for fitness parameters gait speed (walking speed), maximum handgrip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max) which have modest correlation with fitness parameters in five large-scale validation datasets.

We then use these DNAm fitness parameter biomarkers with DNAmGrimAge, a DNAm mortality risk estimate, to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness. DNAmFitAge is associated with low-intermediate physical activity levels across validation datasets, and younger/fitter DNAmFitAge corresponds to stronger DNAm fitness parameters in both males and females. DNAmFitAge is lower and DNAmVO2max is higher in male body builders compared to controls.

Physically fit people have a younger DNAmFitAge and experience better age-related outcomes: lower mortality risk, coronary heart disease risk, and increased disease-free status. These new DNAm biomarkers provide researchers a new method to incorporate physical fitness into epigenetic clocks.

Link: https://doi.org/10.18632/aging.204538

Researchers here report on a correlation between accelerated biological age, as measured by two very different clocks, and risk of depression and anxiety disorders. To the extent that one believes that the presentation of these disorders is made worse by negative events taking place in life, it makes sense that a worse state of physical health, as tends to accompany accelerated biological age, would tend to increase reported incidence of depression and anxiety. Otherwise, there is a growing body of evidence for mechanisms of brain aging to contribute to mood disorders, and range of data on correlations between specific aspects of brain aging and mood disorders.

In this study, we tested associations of blood-chemistry measures of biological aging with prevalent and incident depression and anxiety among a half-million midlife and older adults in the UK Biobank. The main findings were that adults with more advanced biological age were more likely to experience depression and anxiety at baseline and were at higher risk of depression/anxiety over eight years of follow-up, as compared with peers who were the same chronological age, but who were tested to be biologically younger.

The risk associated with biological age was independent of and additive to genetic risk. The risk was also independent of self-reported history of childhood adversity. This study contributes evidence from a large biobank cohort to support the hypothesis that biological aging might represent a risk factor for depression/anxiety in midlife and older adults.

There is accumulating evidence for a link between mental health problems and biological aging. However, most studies have focused on poor mental health as a risk factor for accelerated aging. The reverse process may also occur. For example, white matter hyperintensities, neuroimaging signatures of small cerebral infarcts, are associated with aging and with the risk of depression, and recently have been linked to measurements of biological aging. The same is true of low-grade systemic inflammation and mitochondrial dysfunction.

Link: https://doi.org/10.1038/s41467-023-38013-7

Variations in the APOE gene correlate with risk of Alzheimer's disease. This has long been thought to relate to mechanisms promoting amyloid-β aggregation, given the centrality of the amyloid cascade hypothesis to Alzheimer's research. Scientists have recently provided evidence to suggest that increased inflammatory behavior of the innate immune cells called microglia in the brain is an important mechanism linking APOE variant and Alzheimer's risk, however. So this is not a completely settled area of research.

Separately, evidence exists for Alzheimer's disease patients to tend to exhibit a distinct and more harmful gut microbiome. The microbial populations of the intestinal tract are demonstrated to shift in relative abundance with advancing age. Microbes that provoke inflammation and tissue dysfunction grow in number, while beneficial microbes that produce needed metabolites are lost. Immune dysfunction is thought to be an important cause of this change, as the immune system is responsible for gardening the gut microbiome, but equally it is also the case that chronic inflammatory stimuli are to some degree a cause of immune aging.

The immune systems of the body and brain are somewhat distinct: different cell populations, different environments separated by the blood-brain barrier. They are connected by inflammatory signaling and a very limited degree of passage of cells back and forth, however. If one is roused to chronic inflammation, the other will be as well. Thus one might consider that microglial inflammation and an inflammatory gut microbiome are both manifestations of the same issue. It is interesting that this issue, however it might arise, whatever the ordering of cause and effect, appears to be affected by subtle changes in the behavior of APOE. What is clear, both here and in a great deal of other research relating to age-related neurodegenerative conditions, is that chronic inflammation is something to be avoided.

Genetic correlations between Alzheimer's disease and gut microbiome genera

A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer's disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual's risk for the disease.

Using the largest genome-wide association study of gut microbiota genera from the MiBioGen consortium, we used polygenic risk score (PRS) analyses and determined the genetic correlation between 119 genera and AD in a discovery sample (ADc12 case/control: 1278/1293). To confirm the results from the discovery sample, we next repeated the PRS analysis in a replication sample (GenADA case/control: 799/778) and then performed a meta-analysis with the PRS results from both samples. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes.

In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (Eubacterium fissicatena as a protective factor, Collinsella, and Veillonella as a risk factor) were independently significant in the replication sample. Meta-analysis with discovery and replication samples confirmed that ten genera had a significant correlation with AD, four of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples.

Overall, the host genetic factors influencing the abundance of ten genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE. Larger datasets and functional studies are required to understand their causal relationships.

Given a continued slow upward trend in life expectancy, accompanied by improved health at a given age, it makes some sense for impressions of subjective age to also exhibit change over time. Older people compare their present experience with that shown in literature and film of past generations, and memories of their parents and grandparents. Ask someone how old they feel in an era in which aging is steadily, modestly slowed over time, and they will feel younger than their age, as their points of comparison aged more rapidly than is now the case.

Subjective age describes how old people feel, in comparison with how old they actually are chronologically. It is usually assessed with a single-item question (such as "How old do you feel?"). Evidence from nearly 300 studies using this item has shown that most middle-age and older people feel younger than they are, including very old individuals. This phenomenon has been labeled subjective age bias and might reflect an age-group dissociation process ("They are old, but I feel younger") that helps individuals cope with ageism.

Little is known about historical shifts in subjective age. Moving beyond the very few time-lagged cross-sectional cohort comparisons, we examined historical shifts in within-person trajectories of subjective age from midlife to advanced old age. We used cohort-comparative longitudinal data from middle-age and older adults in the German Ageing Survey (N = 14,928; ~50% female) who lived in Germany and were between 40 and 85 years old when entering the study. They provided up to seven observations over 24 years.

Results revealed that being born later in historical time is associated with feeling younger by 2% every birth-year decade and with less intraindividual change toward an older subjective age. Women reported feeling younger than men; this gender gap widened across cohorts. The association of higher education with younger subjective age became weaker across cohorts. This historical trend of feeling younger was observable across all ages in the second half of life, also - contrary to our expectations - in very old age.

Link: https://doi.org/10.1177/09567976231164553

Senescent cells accumulate with age, and disrupt tissue function via the signaling that they generate, the senescence-associated secretory phenotype (SASP). In bone tissue, the SASP contributes to breaking the balance between the activities of osteoblast cells, constantly building bone, and osteoclast cells, constantly deconstructing bone. Osteoclast activity in older people outweighs osteoblast activity, leading to a progressive loss of bone mineral density and eventual osteoporosis.

Maintaining lifelong mobility is one aim of healthy aging that allows independence and autonomy. However, falls and fragility fractures, which tend to occur in clusters toward the end of life, represent common hazards for the mobility of the aging population. This period comes with a substantial loss of quality of life and causes an enormous socioeconomic burden for patients and their families. While there has been tremendous progress in our understanding of osteoporosis due to sex hormone deficiency or medications, insights into how cell-intrinsic mechanisms contribute to the aging process of the skeletal system are still limited.

Over the past decade, emerging bone research has focused on the biology of osteocytes, the least accessible yet most common bone-resident cell type. Osteocytes are specialized bone cells that orchestrate skeletal remodeling. Senescent osteocytes are characterized by an activation of cyclin-dependent kinase inhibitor p16Ink4a and have been implicated in the pathogenesis of several bone loss disorders.

Researchers have now shown that systemic removal of senescent cells (termed senolysis) prevented age-related bone loss at the spine and femur and mitigated bone marrow adiposity through a robust effect on osteoblasts and osteoclasts, whereas cell-specific senolysis in osteocytes alone was only partially effective. Surprisingly, transplantation of senescent fibroblasts into the peritoneum of young mice caused host osteocyte senescence associated with bone loss. This refined concept of osteocyte senescence and the effects of remote senolysis may help to develop improved senolytic strategies against multisystem aging in bone and beyond.

Link: https://doi.org/10.1172/JCI169069

Today's open access paper, with more than 120 contributing authors, is a tour of the broad topic of biomarkers of aging, an attempt to say at least something about every aspect of cellular biochemistry and functional capacity that is either used or proposed to be used to measure biological age, from grip strength to epigenetic clocks. Biological age is in one sense an aspirational concept, a way to measure the progression of aging that will accurately reflect mortality and disease risk. In another sense, biological age is self-evidently real. Different people age at different rates, and exhibit very different risk levels for age-related disease at a given chronological age. In this sense, biological age is a very complicated state of a very complicated system, a state that we cannot measure comprehensively, even setting aside the presently incomplete understanding of cellular biology and the systems of the body.

Thus scientists search for shortcuts, measurements that are practical and attainable, but nonetheless do a fair job of reflecting the highly complex state of aging. These options are what is usually meant by biomarkers of aging. The challenge with all such approaches is that we'd like to use them to assess the performance of potential rejuvenation therapies. A given rejuvenation therapy will only influence a subset of the important mechanisms that drive degenerative aging, usually a narrow subset. That in turn means that any given biomarker of aging will likely place too little weight or too much weight on specific mechanisms of aging, and it is rarely clear in advance as to which of these is likely to be the case. This makes it hard to use biomarkers of aging as we would like to use them, and suggests that a great deal of work will be needed to make any given set of biomarkers useful in this way.

Biomarkers of aging

Do we truly know how old we are biologically, that is, more accurately describing the status of our body than our chronological ages? Are some people at higher risk of certain types of age-related diseases, i.e., cardiovascular disorders or neurodegenerative diseases, and how can they be identified? Or how do we know if any of the claimed geroprotective treatments are effective? To answer these questions, we need to establish biomarkers for aging. In a broad aspect, these biomarkers are defined as scientifically measured parameters of the physiological aging process, to measure age-related changes and to predict the transition into a pathological status.

As a biological measurement to qualify aging, a biomarker must be specific, systemic, and serviceable. (i) Specific: aging is such a heterogeneous process that it proceeds at different rates in different individuals and varies in different organs, even in the same individual. Therefore, it is impossible to have one biomarker for the entire organism but different ones or even different sets of biomarkers for different organs for evaluation; vice versa, each biomarker should be able to capture a unique aging signal of the relevant organ. Moreover, aging biomarkers should be predictive of the risk of disease development, which requires a specific threshold for the transition from physiological aging to pathological disorder. (ii) Systemic: aging involves almost very organ system, comprising numerous interconnected biological processes. Moreover, changes in one organ may elicit compensatory mechanisms or systemic feedback across the body. Therefore, biomarkers should be able to reflect such systemic changes with age, and a collection of biomarkers from multiple dimensions is required for this aspect. (iii) Serviceable: biomarkers collected through non-invasive or minimally invasive methods are particularly suited for translation into clinical practice. As aging is a gradually deteriorating process over time, longitudinal studies are needed, and again, non-invasive measurements are preferred. In larger cohort studies, cost and convenience should be considered when choosing biomarkers. In all, being specific, systemic, and serviceable are as critical to the broad spectrum of aging biomarkers as the three primary colors.

Over the years, various data types and modeling techniques have been used to develop a broad spectrum of aging biomarkers. Based on the nature of these parameters used for aging biomarkers, the collection of alterations with age can be categorized into 6 classes, or 6 pillars, although biomarkers in different categories are often interconnected with each other. There are higher-order types of changes that reflect physiological and functional changes, such as physiological characteristics, imaging traits, and histological features. Additionally, there are more causal or mechanistic driver types of biomarkers, such as cellular alterations and molecular changes. Finally, there are biomarkers serving in between, such as hormones and secretory factors that are detectable in body fluids, such as blood, urine, saliva, and cerebrospinal fluid (CSF), among which those act in a paracrine manner are of particular interest. The latter three types, as they may also serve as hallmarks or drivers of aging, may be targeted to intervene in the aging process.

Aging biomarkers are critical to answer the three major questions in the field of aging: how old are we? Why do we get old? And how can we age slower? In this comprehensive review, we provided an encyclopedia summary of aging biomarkers covering a hierarchy of dimensions at cellular, organ, organismal, and populational aging levels, along with associated ethical and social implications. We hope this re- view serves as a resource for readers in academia, industry and medical practice, broadening our understanding of not only what biomarkers can be used to monitor aging, but also how to use them to assess novel therapies to slow, modify or even reverse aging. As such, we can accelerate the journey of basic science discoveries in the aging field from bench to bedside.

Early applications of in vivo cellular reprogramming to medicine are cautiously focused on retinal regeneration. The eye is as close to an isolated system as one is going to find in the body, and only small amounts of a gene therapy vector are required for effective delivery. This very localized, comparatively isolated therapy bypasses or minimizes many of the technical concerns and areas of uncertainty regarding reprogramming, allowing those who are focused on pushing applications to the clinical to forge ahead. The more interesting applications remain those in which reprogramming factors are delivered systemically to much of the body, but a good deal of work remains to answer questions about safety, dosing, and effective delivery systems. Fortunately this part of the industry is very well funded, so answers seem likely to emerge in the years ahead.

Life Biosciences (Life Bio), a biotechnology company advancing innovative cellular rejuvenation technologies to reverse diseases of aging and injury and ultimately restore health for patients, today announced preclinical data in nonhuman primates (NHP) for its novel gene therapy candidate which uses a partial epigenetic reprogramming approach to restore visual function. Life Bio's therapy significantly restored visual function in an NHP model of non-arteritic anterior ischemic optic neuropathy (NAION), a disorder similar to a stroke of the eye that is characterized by painless yet sudden loss of vision.

Life Bio's lead platform reprograms the epigenome of older animals to resemble that of younger animals via expression of three Yamanaka factors, Oct4, Sox2, and Klf4, collectively known as OSK. The approach partially reprograms cells to resemble a more youthful state while retaining their original cellular identity. Previous data have shown that treatment with OSK reverses retinal aging and restores vision in old mice in a mouse model of glaucoma. Now, the company has demonstrated restoration of visual function and increased nerve axon survival in an NHP model that mimics human NAION deficits in retinal ganglion cells.

Link: https://www.globenewswire.com/news-release/2023/04/23/2652317/0/en/Life-Biosciences-Presents-Groundbreaking-Data-at-ARVO-Demonstrating-Restoration-of-Visual-Function-in-Nonhuman-Primates.html

With advancing age, the balance of microbial populations in the intestinal tract changes to favor harmful, pro-inflammatory species at the expense of those that produce beneficial metabolites. This contributes to the onset and progression of age-related conditions. Here find an interesting example of adjustment of the aging gut microbiome in mice, promoting beneficial microbial populations to result in extended life span. We'd expect mouse life span to be more plastic to this class of intervention than human life span, but nonetheless, work on preventing detrimental age-related changes to the gut microbiome is demonstrating its worth in animal models. Researchers should now focus on obtaining more human data on the effects of fecal microbiota transplant from young to old individuals, as this is the most clearly effective approach to date, with the greatest amount of existing human safety data.

Dietary oligosaccharides can impact the gut microbiota and confer tremendous health benefits. The aim of this study was to determine the impact of a novel functional oligosaccharide, neoagarotetraose (NAT), on aging in mice. 8-month-old C57BL/6J mice as the natural aging mice model were orally administered with NAT for 12 months. The preventive effect of NAT in Alzheimer's disease (AD) mice was further evaluated. Aging related indicators, neuropathology, gut microbiota and short-chain fatty acids (SCFAs) in cecal contents were analyzed.

NAT treatment extended the lifespan of these mice by up to 33.3%. Furthermore, these mice showed the improved aging characteristics and decreased injuries in cerebral neurons. Dietary NAT significantly delayed DNA damage in the brain, and inhibited reduction of tight junction protein in the colon. A significant increase at gut bacterial genus level (such as Lactobacillus, Butyricimonas, and Akkermansia) accompanied by increasing concentrations of SCFAs in cecal contents was observed after NAT treatment. Functional profiling of gut microbiota composition indicated that NAT treatment regulated the glucolipid and bile acid-related metabolic pathways. Interestingly, NAT treatment ameliorated cognitive impairment, attenuated amyloid-β (Aβ) and Tau pathology, and regulated the gut microbiota composition and SCFAs receptor-related pathway of Alzheimer's disease (AD) mice.

In conclusion, NAT mitigated age-associated cerebral injury in mice through gut-brain axis. The findings provide novel evidence for the effect of NAT on anti-aging, and highlight the potential application of NAT as an effective intervention against age-related diseases.

Link: https://doi.org/10.1016/j.jare.2023.04.014