Fight Aging!

The practice of calorie restriction alters near all aspects of cellular biochemistry throughout the body. The result is improved function and modestly slowed aging, an evolved response to low nutrient levels that serves to increase the odds of surviving a famine to reproduce once plenty returns. Seasonal famine is the most common such circumstance, and while the calorie restriction response appears to be near universal across all forms of life, short-lived species exhibit a much greater extension of life span as a result than is the case for long-lived species. A season is a sizable fraction of a mouse life span, but not of a human life span. So mice can live up to 40% longer on a low calorie diet, while humans likely gain only a few years.

Since calorie restriction changes just about everything for the better in the aging body, one can find any number of papers examining one very specific aspect of the calorie restriction response. Today's open access paper, for example, is focused on how beta cells are improved, and their functional decline with aging is slowed, in calorie restricted mice. Beta cells reside in the pancreas, produce insulin, and are thus of central importance in insulin metabolism and glucose metabolism. This portion of overall metabolism affects the pace of aging, as illustrated by the accelerated aging exhibited by diabetic patients.

Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice

Beta cells secrete insulin in response to increases in blood glucose levels to sustain normal glucose homeostasis for an entire lifetime. Several studies have investigated the impact of aging on beta cells and established that aging beta cells have compromised expression of transcription factors (TFs) and re-organization of gene regulatory networks (GRNs) that maintain beta cell identity, accumulation of islet fibrosis, inflammation, and ER stress, reduced KATP channel conductance, loss of coordinated beta cell calcium dynamics, impaired beta cell autophagy and accumulation of beta cell DNA damage, and/or beta cell senescence. When combined with an unhealthy lifestyle during old age, these aging signatures could pre-dispose beta cells to failure and lead to type 2 diabetes (T2D) onset.

Caloric restriction (CR) and CR-mimicking approaches (e.g., time-restricted feeding (TRF)) can prolong organismal longevity and delay aging from yeast to non-human primates. These beneficial effects are associated with improved glucose homeostasis due to prolonged fasting and enhanced peripheral insulin sensitivity, enhanced insulin signaling, lower adiposity, enhanced mitochondrial homeostasis and lower ATP generation, increased autophagy, enhanced protein homeostasis and reduced ER stress and inflammation. In the pancreas, 20-40% CR or CR achieved via TRF are linked to lower islet cell mass in lean mice, whereas in pre-diabetic mice, CR restores normal beta cell secretory function, identity, and preserves beta cell mass in a process dependent on activation of beta cell autophagy via Beclin-2. In patients with a recent T2D diagnosis, the efficacy of extreme CR (average of 835 kcal/day or greater than 50% CR based on a 2000 kcal/day diet) to reverse T2D depends on the capacity of beta cells to recover from previous exposure to a T2D metabolic state. However, how beta cells adapt during CR, and whether CR can delay the hallmarks of beta cell aging remains largely unknown.

We investigated these questions by exposing adult male mice to mild CR (i.e., 20% restriction) for up to 12 months and applied comprehensive in vivo and in vitro metabolic phenotyping of beta cell function followed by single-cell multiomics and multi-modal high-resolution microscopy pipelines. Our data reveals that CR reduces the demand for beta cell insulin release necessary to sustain euglycemia by increasing peripheral insulin sensitivity. Ad-libitum (AL) consumption of a diet with reduced caloric intake failed to trigger a similar phenotype, thus indicating that CR and CR-associated fasting periods are required for this adaptive metabolic response. During CR, the transcriptional architecture of beta cells is re-organized to promote a largely post-mitotic and long-lived phenotype with enhanced cell homeostasis and mitochondrial structure-function. This is associated with reduced onset and/or expression of beta cell aging and senescence signatures. When exposed to a high-fat diet (HFD), CR beta cells upregulate insulin release, however they have a compromised adaptive response due to limited cell proliferation resulting in reduced beta cell mass. Therefore, our results provide a molecular footprint of how CR modulates adult beta cell function and insulin sensitivity to promote beta cell longevity and delay aging in mice.

Lower animals that are essentially tiny blobs of stem cells are in principle capable of immortality, as illustrated by hydra and the jellyfish Turritopsis dohrnii that cycles from immaturity to adulthood and back again. Even if not actually immortal, their potential life spans absent predation are too long to be experimentally confirmed in any practical way. These species are so very different from higher animals with complex nervous systems that store data that it is quite possible there is little of practical use to medicine to be learned here. A blob of stem cells can continually regrow and replace all of its component parts, or change its shape and state of maturity as needed, whereas a vertebrate is more vulnerable, more locked in to its structure and the state of that structure. We might think that aging has the look of an inevitable consequence of having a nervous system that stores data, coming to rely on the structural state of that tissue, no longer being able to easily discard cells and replace them.

To date, the capacity of one life cycle stage to transform back to the preceding stage by morphological reorganization has been regarded as a distinctive and unparallelled feature of cnidarians. This ability for reverse development known for a few cnidarian species was first reported over a century ago and gained wide renown with the discovery of the peculiar life cycle of the so-called immortal jellyfish, Turritopsis dohrnii. This hydrozoan is currently considered the only animal able to repeatedly rejuvenate after sexual reproduction, challenging our understanding of aging and suggesting a potential for biological immortality.

Ctenophores (or comb jellies) are one of the oldest extant animal lineages. Accumulated evidence supporting their phylogenetic position as the sister group to all other animals place them as a pivotal model to study unique evolutionary innovations potentially rooted within the deepest branches of the animal tree of life. Here, we demonstrate that the ctenophore Mnemiopsis leidyi is capable of reversal from mature lobate to early cydippid when fed following a period of stress. Our findings illuminate central aspects of ctenophore development, ecology, and evolution and show the high potential of M. leidyi as a unique model system to study reverse development and rejuvenation.

Link: https://doi.org/10.1073/pnas.2411499121

The tricarboxylic acid (TCA) cycle is an important part of the process by which mitochondria generate chemical energy store molecules to power the cells. With age, mitochondrial function diminishes throughout the body. This produces disruption to cell and tissue function, particularly in energy-hungry tissues such as the brain and muscles. This loss of mitochondrial function is thought to be the consequence of some combination of damage to mitochondrial DNA and maladaptive changes in the expression of relevant genes, such as those coding for proteins necessary to mitochondrial energy production. For example, researchers here point out the reduced production of TCA cycle proteins in aged tissues, and note it as as a contribution to age-related mitochondrial dysfunction.

Aging is associated with a decline in physiological functions and an increased risk of metabolic disorders. The liver, a key organ in metabolism, undergoes significant changes during aging that can contribute to systemic metabolic dysfunction. This study investigates the expression of genes involved in the tricarboxylic acid (TCA) cycle, a critical pathway for energy production, in the aging liver. We analyzed RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to assess age-related changes in gene expression in the human liver. To validate our findings, we conducted complementary studies in young and old mice, examining the expression of key TCA cycle genes using quantitative real-time PCR.

Our analysis of the GTEx dataset revealed a significant reduction in the expression of many genes that are critical for metabolism, including fat mass and obesity associated (FTO) and adiponectin receptor 1 (ADIPOR1). The most overrepresented pathway among the statistically enriched ones was the TCA cycle, with multiple genes exhibiting downregulation in older humans. This reduction was consistent with findings in aging mice, which also showed decreased expression of several TCA cycle genes. These results suggest a conserved pattern of age-related downregulation of TCA cycle, potentially leading to diminished mitochondrial function and energy production in the liver. The reduced expression of TCA cycle genes in the aging liver may contribute to metabolic dysfunction and increased susceptibility to age-related diseases. Understanding the molecular basis of these changes provides new insights into the aging process and highlights potential targets for interventions aimed at promoting healthy aging and preventing metabolic disorders.

Link: https://doi.org/10.1016/j.bbrc.2024.150917

The enormous cost of medical regulation ensures that natural compounds that may be useful receive little rigorous attention in the form of clinical trials and correspondingly little adoption in the mainstream medical community. Since the use of these compounds cannot be patented in a way that prevents competition, companies focused on these compounds cannot become valuable enough to raise the funding needed to conduct extensive development and formal clinical trials. Thus little tends to be known in certain about even quite widely used natural compounds, far less than is known about the average small molecule drug.

We can see these incentives at work in the case of the senolytic flavonoid fisetin; despite the existence of animal data suggesting it to be as good at clearing senescent cells from aged tissues as the combination of dasatinib and quercetin, we still don't know if it works in the same way in humans, what the optimal dose might be, how delivery is best improved given its low bioavailability, and so forth. No-one is putting significant funds into answering any of those questions, and it is unlikely that anyone ever will. What does tend to happen, as illustrated by today's open access research, is that groups attempt the slow process of producing patentable variants of the molecule in question and move ahead with those into the regulatory system.

Development of novel flavonoid senolytics through phenotypic drug screening and drug design

Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging.

Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.

The more visceral fat you have, and the longer you have it for, the worse off you are. Visceral fat contributes to chronic inflammation and metabolic dysfunction, accelerating the onset and progression of age-related conditions. This is well understood in the case of obesity, but even lesser degrees of being overweight are harmful to long-term health, as the data here illustrates.

Visceral fat tissue, interspersed with resident immune cells, when activated, increases local or systemic inflammation, leading to the production of cytokines and other immune and pro-inflammatory mediators, promoting insulin resistance, oxidative stress, and altered cell metabolism. Abdominal fat accumulation is associated with changes in glucose metabolism and lipid metabolism, primarily due to insulin resistance, resulting in hyperlipidemia, hypertension, glucose intolerance, and mitochondrial abnormalities in skeletal muscle.

An individual's leanness or corpulence is commonly assessed using the Body Mass Index (BMI), but this measure does not account for fat distribution or differentiate between fat and muscle mass. Therefore, clinicians have explored alternative anthropometric measurements that better reflect body composition and mortality risk, such as waist circumference (WC) and waist-to-hip and waist-to-height ratios. Most of these measures fail to reflect body composition effectively or are easily affected by variations in other body measurements. A new body shape index (A Body Shape Index, ABSI) has been introduced as an anthropometric measure unrelated to BMI, based on waist circumference adjusted for weight and height. ABSI offers a better explanation of how central abdominal adiposity is strongly associated with mortality than other anthropometric measurements, and it captures additional harmful effects not captured by BMI.

This prospective cohort study included 159 volunteers (94 women, aged 60-80 years), recruited in the frame of the "Physical Activity and Nutrition for Great Ageing" (PANGeA) Cross-border Cooperation Program Slovenia-Italy 2007-2013, and followed for 10 years. During the 10-year follow-up, 10 deaths (6.7%) were recorded. ABSI (adjusted for age, smoking, comorbidities, and therapy) was an independent predictor of mortality (hazard ratio = 4.65). Higher ABSI scores were linked to reduced VO2max (r = -0.190) and increased systolic blood pressure (r = 0.262). An ABSI-based predictive model showed strong discriminatory power, and thus ABSI is a reliable predictor of 10-year mortality in active, non-obese elderly individuals and may improve risk stratification in clinical practice.

Link: https://doi.org/10.3390/jcm13206155

Researchers can measure a great many facets of aging in the brain and elsewhere in the body, ranging across structural changes, gene expression changes, cell behavior changes, and so forth ad infinitum. The challenge lies in establishing cause and effect, and the relative importance of different possible mechanisms of damage and dysfunction. So, as researchers point out here, there is a compelling picture to be painted of the way in which the innate immune cells called microglia change in biochemistry and behavior in the aging brain, but no concrete certainty that these changes are the major contribution to neurodegenerative conditions that many researchers argue them to be. Inflammatory microglia may well be an important proximate cause of dysfunction in the brain, and a range of animal studies strongly suggest this to be the case, but as ever solid proof lags somewhat behind inference.

Microglia signatures refer to specific profiles of microglia activity or gene expression. Through a comprehensive analysis of gene and protein expression profiles, we can identify specific genes and proteins that characterize different states of microglial activation, including those associated with pro-inflammatory and anti-inflammatory states. This approach contributes to the knowledge base regarding the dynamics of microglial activation in both physiological and pathological conditions. The question of whether these signatures are a cause or a consequence of microglia-related brain disorders is highly relevant since understanding whether alterations in microglia are a primary cause of brain pathologies (e.g., neurodegenerative diseases such as Alzheimer's disease) or whether they are a secondary response to such pathologies can significantly influence therapeutic strategies.

Microglia can become hyperactive or dysfunctional, releasing inflammatory cytokines and neurotoxic factors that can damage neurons and the extracellular matrix. This may contribute to the pathogenesis of diseases such as Alzheimer's disease and Parkinson's disease. Microglia can have a proactive role in shaping the neuronal environment. If altered, they can negatively affect synaptogenesis, synaptic plasticity, and clearance of cellular debris, leading to brain dysfunction. Microglia interact closely with neurons, astrocytes, and other cell types in the brain. Alterations in these interactions caused by primary diseases may lead to changes in microglia signatures as an adaptive response, which could exacerbate the disease. Microglia may be activated in response to brain damage or other pathologies. In this scenario, alterations in their signatures could be a consequence of the presence of pathogens, abnormal protein deposits, or neuronal damage. In neurodegenerative disorders, neuroinflammation may be a secondary response to primary pathological processes. For example, in Alzheimer's disease, microglia may be activated by amyloid-β deposits.

The relationship between microglia signatures and brain disorders is likely to be bidirectional and dynamic. In some conditions, dysfunctional microglia may actively contribute to disease onset and progression (cause), while in other situations, they may represent an adaptive or maladaptive response to pre-existing damage or pathology (consequence). Understanding this complex interaction requires further research, including longitudinal studies and experimental models that can isolate the various factors involved. Unraveling these dynamics may lead to new and more effective therapeutic strategies for microglia-related brain diseases.

Link: https://doi.org/10.3390/ijms252010951

Here are two interesting points about the gut microbiome that have become clear in recent years: (a) the composition of the gut microbiome, the relative sizes of microbial populations, changes with age in ways that contribute to inflammation and tissue dysfunction throughout the body; and (b) it is possible to produce lasting change in the composition of the gut microbiome through either engineering of an immune response against target microbes or the procedure of fecal microbiota transplantation from a donor with a very different microbiome.

A simple example of the immune engineering approach is to inject small amounts of flagellin, the protein making up bacterial flagellae, to rouse the immune system into greater efforts to destroy anything it can find equipped with a flagellum. In the gut, most such bacteria are undesirable. Like fecal microbiota transplantation from a younger donor, the effects are unknowable in advance, generally in the direction of producing benefit, but these are not precision approaches to therapy. One can't yet engineer the exact gut microbiome one desires. Unfortunately strategies involving oral probiotics, which seem the most obvious path towards obtaining more of the specific microbes desired in the gut, have yet to advance to the point at which they are capable of producing lasting change; their effects are very transient.

As today's open access paper illustrates, the aged gut microbiome is clearly harmful. It is harmful in ways that even a young body and immune system cannot escape from. Just as fecal microbiota transplantation from young to old animals produces a lasting change to a young-looking microbiome in an old body and consequent benefits to health, the reverse produces a lasting change to an old-looking microbiome in a young body and consequent damage and dysfunction to tissues throughout the body. This is a good argument for replacement of the microbiome to be the primary thrust of development when it comes to finding ways to remove this aspect of aging. It seems unlikely that rousing the aged immune system is going to solve enough of the problem if a young immune system cannot wrestle an aged gut microbiome into shape.

Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice

The aging vasculature is associated with endothelial dysfunction, arterial stiffness, increased oxidative stress and chronic inflammation, contributory to higher risks of cardiovascular diseases, such as heart failure and coronary artery disease. 'Dysbiosis' is considered as a new integrative hallmark of aging. During aging, the microbial composition in intestine varies that the homeostatic relationship between the host and gut microbiome deteriorates, contributory to altered immune and inflammatory responses in the elderly. Age-associated dysbiosis also increases the risks of various diseases, particularly cancers, cardiovascular diseases (CVDs), and diabetes, potentially through shift in intestinal microbial composition from providing benefits to causing chronic inflammation, and through alterations in the production of gut-derived substances to influence host nutrient-sensing pathways. However, the comprehensive mechanism of how age-related dysbiosis promotes other recognized hallmarks of aging remains elusive.

Of note, the vasculature serves as the first-line barrier vulnerable to the changes in gut microbiome due to close proximity between the intestine and blood circulation. Besides, the increased intestinal permeability, known as 'leaky gut', during aging further aggravates the vulnerability of vasculature towards dysbiosis. However, whether age-associated dysbiosis promotes host premature aging remains unclear. Previous studies showed that gut microbiome suppression by antibiotics ameliorates endothelial dysfunction in aged mice, and age-associated hyperproduction of harmful gut-derived metabolite (e.g., trimethylamine-N-oxide) drives endothelial dysfunction. It is therefore reasonable to hypothesize that age-associated dysbiosis shall promote vascular aging by triggering aging hallmarks in the vasculature, such as telomere attrition, endothelial dysfunction, and vascular inflammation and oxidative stress.

In this study, we performed fecal microbiome transfer (FMT) from aged to young mice to (i) study whether age-associated dysbiosis causes premature vascular and intestinal dysfunction; (ii) unveil whether such transfer changes the metabolic profiles; (iii) uncover microbiome alterations and underlying mechanism that are potentially critical; and (iv) identify potential interventions that might partially reverse age-related harmful effects. We demonstrated that age-associated dysbiosis, achieved by aged-to-young FMT, caused endothelial dysfunction, telomere dysfunction, inflammation, and oxidative stress in vascular tissues, partially reflective of premature vascular aging. Moreover, aged-to-young FMT also caused metabolic impairment and altered gut microbial profiles in young mice, along with disrupted intestinal integrity. Interestingly, aged-to-young FMT caused telomere dysfunction in both intestinal and aortic tissues. These findings highlight the harmful effects of aged microbiome on intestine and vasculature, providing important insight that gut-vascular connection represents a potential intervention target against age-related cardiometabolic complications.

Mifepristone is known to slow aging in flies. While mifepristone is not a drug that one should take to slow aging, as it has complex, sizeable effects on hormone levels that would tend to outweigh any benefits obtained, it is interesting to see that it has some of the same effects as rapamycin on life span and aspects of autophagy. Autophagy recycles damaged cell structures, and improved autophagy is a feature of many of the interventions known to slow aging in short-lived laboratory species, such as the flies used in this study. The researchers focused on measuring autophagy targeting mitochondria, known as mitophagy. Given the importance of mitochondrial dysfunction to aging, that is a reasonable choice. Nonetheless, it is hard to imagine much in the way of further research emerging based on the use of mifepristone or other near analog small molecules because of the effects on hormonal metabolism.

The drugs mifepristone and rapamycin were compared for their relative ability to increase the life span of mated female Drosophila melanogaster. Titration of rapamycin indicated an optimal concentration of approximately 50 μM, which increased median life span here by average +81%. Meta-analysis of previous mifepristone titrations indicated an optimal concentration of approximately 466 μM, which increased median life span here by average +114%. Combining mifepristone with various concentrations of rapamycin did not produce further increases in life span, and instead reduced life span relative to either drug alone.

Assay of maximum midgut diameter indicated that rapamycin was equally efficacious as mifepristone in reducing mating-induced midgut hypertrophy. The mito-QC mitophagy reporter is a previously described green fluorescent protein (GFP)-mCherry fusion protein targeted to the outer mitochondrial membrane. Inhibition of GFP fluorescence by the acidic environment of the autophagolysosome yields an increased red/green fluorescence ratio indicative of increased mitophagy. Creation of a multi-copy mito-QC reporter strain facilitated assay in live adult flies, as well as in dissected midgut tissue. Mifepristone was equally efficacious as rapamycin in activating the mito-QC mitophagy reporter in the adult female fat-body and midgut. The data suggest that mifepristone and rapamycin act through a common pathway to increase mated female Drosophila life span, and implicate increased mitophagy and decreased midgut hypertrophy in that pathway.

Link: https://doi.org/10.1080/19336934.2024.2419151

Researchers here report on an interesting mechanism by which the cell maintenance processes of autophagy are inhibited in the aging brain, in flies at least. Changes in the maintenance of the actin cytoskeleton inside a cell cause this reduction in autophagy, but can be blocked via small molecules in order to restore a more youthful function in brain tissue. In general, approaches to improve autophagy in aging tissue have been shown to produce a slowing of aging and improved function of aged tissues in short-lived species. From what we know of interventions such as exercise and calorie restriction, both of which improve autophagy, the effects on life span are not as large in long-lived species such as our own, even if some of the short term benefits are similar.

The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Actin can be found in two forms: monomeric (G-actin) and filamentous (F-actin). Assembly and disassembly of actin filaments are regulated by a large number of actin-interacting proteins, making maintenance of the actin cytoskeleton highly susceptible to disruption caused by aging. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions.

Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.

Link: https://doi.org/10.1038/s41467-024-53389-w

Bats are a popular choice in the study of the comparative biology of aging because there is considerable variation in life span between closely related species, a good place to start looking for specific genes that might be important in determining species differences in life span. Further, some bat species are particularly long-lived for their small size, which is again a place to start if seeking to understand how genetics determines life span. While some inroads have been made, these are still early days in the process of building a robust set of bridges between the islands represented by the present understanding of (a) genetics, (b) cell metabolism, and (c) aspects of aging. Much remains unknown.

As is the case for investigations of the biochemistry of naked mole-rats, elephants, and whales, some fraction of research into the genetics of long-lived bat species is motivated by their resistance to cancer. Cancer is a numbers game; either a greater number of cells or a given number of cells existing for a longer period of time implies an increased risk of cancerous mutation. Larger species and long-lived species can only be large or long-lived because they have evolved means of cancer suppression that do not exist in their smaller or short-lived relatives. Will study of the comparative biology of aging find mechanisms that can be used to produce therapies to treat and prevent cancer in humans in the near future? At this point it is too early to tell whether discoveries will be amenable to therapeutic development in this way, but this is the hope.

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats

Bats are widely known for their long lifespan, cancer resistance, and viral tolerance. As highly complex and pleiotropic processes, the genes and mechanisms underlying these phenotypes can be challenging to identify. Here we outline an approach that enables functional comparative biology by generating cell lines from wing punches of wild caught bats for genome assembly, comparative genomics, and functional follow up. Cell lines are generated from minimally-invasive biopsies collected in the field thus avoiding disturbing natural populations. Given the high density of bat species concentrated at single locations world-wide, it is feasible to collect wing punches from a large number of individuals across a wide phylogenetic range; these wing punches can be used to generate cell lines and sequencing libraries for reference genomes in a matter of weeks.

By explicitly modeling the evolution of lifespan separately from body size, we recapitulate the extant relationship between body size and lifespan across mammals in evolutionary time. Contrary to prior work, we show that overall bats exhibit allometric lifespan scaling, comparable to other mammals. However, two bat clades - Myotis and Phyllostomidae - exhibit distinct trends with Myotis demonstrating an increased rate of change in lifespan given body size compared to other mammals. This altered scaling of longevity in Myotis has dramatic consequences for their intrinsic, per-cell cancer risk and for the evolution of tumor-suppressor genes and pathways.

We found a number of genes under selection across multiple longevity-associated pathways, consistent with the pleiotropic nature of the aging process. These include members of canonical longevity pathways such as mTOR-IGF signaling, DNA damage repair, oxidative stress, and the senescence-associated secretory phenotype. We additionally identified selection in various pathways that have likely emerged as a result of the unique biology of bats, including genes at the intersection of immunity and senescence, such as Serpin-family genes; genes in metabolic pathways including amino acid metabolism; and pervasive selection observed in the ferroptosis pathway, which sits at the intersection of bats' extreme oxidative challenges, metabolic demands, immune function, and cancer resistance.

By quantifying the relative contributions of genes under selection to cancer-related pathways at each node, we found significant enrichment of these processes across the phylogeny, especially at nodes undergoing the greatest changes in lifespan and cancer risk. While cancer risk scales linearly with body size, it scales over time as a power law of 6. Unlike other systems where the evolution of cancer resistance has been driven by rapid changes in body size, the body size of Myotis has not significantly changed since their common ancestor. Instead, the rapid and repeated changes in lifespan across an order of magnitude in Myotis lead to some of the most significant changes in intrinsic cancer risk seen across mammals.

While no reports or studies of neoplasia rates have been published in Myotis, the use of in vitro models of carcinogenesis provides a promising avenue for comparative studies of cancer resistance under controlled conditions. In agreement with our results, in vitro and xenograft transplant models have shown that cells of long-lived bats, including M. lucifugus, are more resistant to carcinogenesis than shorter-lived bats and other mammals.

Efforts to produce therapies based on cellular reprogramming aim to restore cell function without changing cell state. The original reprogramming research involved the production of induced pluripotent stem cells from somatic cells via expression of the Yamanaka factors, recapturing a process that takes place in early embryonic development. Since then, researchers have found that transient, partial reprogramming can restore youthful epigenetic patterns and behaviors in aged cells without the change of state, and the question is now how to constrain this partial reprogramming activity in a useful way in a living organism. A perhaps surprisingly large fraction of the work currently taking place on cellular reprogramming is aimed at the brain and nervous system. As an example of this sort of work, researchers here show that expression of the Yamanaka factors in the adult mouse hippocampus is protective against the pathology induced in a mouse model of Alzheimer's disease.

Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we employed a controlled spatiotemporal induction of YFs in the mouse brain across two distinct scenarios: during brain development and in adult stages within the context of neurodegeneration. Our focus on the impact of YFs on neurogenesis during development was influenced by recent findings that a subset of these factors is expressed in various neural progenitors early in this phase.

Here, we report that transient, low-level expression of YFs increased proliferation, resulting in an augmented output of neurons and glia, which led to an enlarged neocortex. This expansion was functionally reflected in enhanced motor and social behavior in adult mice. Because this induction protocol enhanced cognitive skills, we hypothesized that it could exert a similar effect in the context of a neurodegenerative disorder. Thus, we expressed YFs only in mature hippocampal neurons, using the 5xFAD mouse model of Alzheimer's disease. We show that these neurons tolerate intermittent YF expression while preserving their identity. This safe approach led to cognitive, molecular, and histological improvements in the 5xFAD mice.

Our results establish transient YF induction as a powerful tool for modulating neural proliferation, and it may open new therapeutic strategies for brain disorders.

Link: https://doi.org/10.1016/j.stem.2024.09.013

The SENS Research Foundation staff here continue their series of posts on the problems with studies of metformin as a potential means to modestly slow aging. Taken as a whole, the animal data for metformin is dismal, and the human data often touted as a rationale for use of metformin is problematic. If one feels motivated to make use a small molecule drug that may act to modestly slow aging, and which has extensive existing safety data for human use in other contexts, then look to rapamycin instead, where the animal data is robust.

Serious scientists have championed the diabetes drug metformin as a potential longevity therapeutic for more than two decades, but more careful scientific testing of the hypothesis over the last ten years has soured many critical thinkers on this use of the drug. Notable evidence against the idea include that metformin failed to extend lifespan in rodents in the National Institute on Aging (NIA)'s Interventions Testing Program and other well-done lifespan studies, and the debunking of the human epidemiological study that appeared to show that people with diabetes who took metformin lived longer than nondiabetics who didn't.

But interest was rekindled by a new study of metformin in aging cynomolgus monkeys. The authors claim to have shown that metformin preserved brain structure, "enhanced" cognitive function, and slowed biological aging by more than six years after less than three and a half years of treatment, as measured on a new species-specific aging clock. So like gamblers who have lost their shirt but can't stop themselves from playing, the conviction that this time it's different has set into the longevity community.

The monkeys in the metformin trial began the study at a body mass index (BMI) of 28, which is in the "overweight" category, and remarkably, the control animals ballooned to BMI 32 (obese) just three months later. By contrast, the monkeys on metformin remained 3 to 5 BMI points lighter than the controls through most of the experiment, up until the control animals began their late-life decline. That's a quite profound weight-protective effect, comparable to the new GLP-1 receptor agonist drugs.

So the first two interrelated problems with the study are that the control animals were obese throughout almost the entire study and that metformin had such a profound protective effect against weight gain in these animals. Why would metformin have made these monkeys so much lighter than their untreated labmates? Metformin is known to cause modest weight loss in humans, especially when it is "enhanced" by common side effects like indigestion or diarrhea. But the weight-buffering effect in these monkeys is much greater than you'll typically see in humans on the drug. Whatever the mechanism, the protective effect against the substantial weight gain seen in the control animals seems highly likely to be responsible for much or all of the benefits in the metformin-treated monkeys, for reasons that have nothing to do with a direct effect on aging processes.

Link: https://www.sens.org/monkeying-with-clocks-metformin/

Why are long-lived individuals long-lived? While some evidence suggests that cultural transmission of beneficial lifestyle choices across generations might explain much or all of the phenomenon of long-lived families, and continued examination of large databases of genetic information has tended to reduce the estimated contribution of genetic variants to life expectancy, there continue to be studies demonstrating that older cohorts exhibit fewer of the long list of mutations and variants known to be disadvantageous. The implication here is that small reductions in mortality add up over time and over large populations. The older the population, the greater the odds that any given member will have more beneficial gene variants and fewer harmful gene variants. The effect size for any given variant when it comes to mortality risk does not have to be large for this to be the case.

Given that the effect size for a given gene variant is typically small, and indeed the discovery of a variant that moves average life expectancy by a year or more is big news, is there really much to be gained from the exploration of the genetics of extremely long-lived people? So far the results seem to bear out the pessimistic viewpoint: that this is probably helpful to those working on the long, long road ahead to a complete map of metabolism, how it changes with age, and how that all maps to health outcomes, but that we should not expect useful therapies to slow aging to emerge from this part of the field.

Depletion of loss-of-function germline mutations in centenarians reveals longevity genes

While previous studies identified common genetic variants associated with longevity in centenarians, the role of the rare loss-of-function (LOF) mutation burden remains largely unexplored. Here, we investigated the burden of rare LOF mutations in Ashkenazi Jewish individuals from the Longevity Genes Project and LonGenity study cohorts using whole-exome sequencing data.

In this study, we have discovered that centenarians, within the large cohort we examined, possess a significantly lower burden of predicted deleterious LOF variants compared to controls. This finding suggests that a protective genetic background, characterized by the depletion of damaging coding mutations, contributes to the exceptional longevity of centenarians. Notably, we also observed a lower mutation burden in centenarian offspring, although the effect was less pronounced. These findings support the notion of a heritable component to longevity outside of protective and common variants and suggest that the combined genetic background, including protective variants and depletion of damaging variants, may be transmitted across generations to support exceptional longevity.

Our pathway analysis revealed that centenarian exomes are depleted of LOF variants in several pathways related to aging and disease, including Class A/1 (Rhodopsin-like receptors), hyaluronan metabolism, post-translational protein modification, and mitochondrial translation. Class A/1 (Rhodopsin-like) receptors are involved in various physiological processes and have been implicated in age-related diseases, suggesting their potential role in longevity. Hyaluronan is a key component of the extracellular matrix that has been shown to decline with age, and its increase contributes to the extension of lifespan. Variants that maintain hyaluronan homeostasis may, therefore, promote healthy aging in humans. Post-translational protein modifications play crucial roles in protein function and stability, and their dysregulation has been associated with various age-related diseases. Mitochondrial translation has also been linked to lifespan extension in model organisms.

To complement our analysis of rare LOF variants, we also investigated the causal role of identified longevity genes in aging-related traits using Mendelian randomization (MR) analyzes. This approach allows us to infer potential causal relationships between gene expression and phenotypes of interest by using expression quantitative trait loci, eQTLs (common variants that are associated with gene expression) as instrumental variables. Our MR analyzes provided evidence for the causal effects of several longevity-associated genes, including RGP1, PCNX2, and ANO9, on multiple aging-related traits. PCNX2 was identified to be associated with longevity in an independent genome-wide association study, while ANO9 was associated with various cancers. These findings suggest that these genes may directly influence the aging process and contribute to the extended healthspan and lifespan. The consistent causal effect estimates across different aging-related traits further support the robustness of these associations.

Inadvertent and deliberate breeding programs in domesticated animals have engineered great diversity into single species. Different breeds of dogs exhibit radically different life spans, for example, and this natural experiment may allow some insight into the relative importance of various mechanisms of aging. Research suggests that transposon activity is an important factor in determining the longevity of a dog breed, as outlined here. Transposons are relics of ancient viral infections, DNA sequences capable of hijacking cell machinery to copy themselves across the genome. In youth, transposon activity is suppressed, but with advancing age their activity increases as a consequence of epigenetic changes, acting as a source of mutational damage and disruption of cell activities.

Within a species, larger individuals often have shorter lives and higher rates of age-related disease. Despite this well-known link, we still know little about underlying age-related epigenetic differences, which could help us better understand inter-individual variation in aging and the etiology, onset, and progression of age-associated disease. Dogs exhibit this negative correlation between size, health, and longevity and thus represent an excellent system in which to test the underlying mechanisms. Here, we quantified genome-wide DNA methylation in a cohort of 864 dogs in the Dog Aging Project.

Age strongly patterned the dog epigenome, with the majority (66% of age-associated loci) of regions associating age-related loss of methylation. These age effects were non-randomly distributed in the genome and differed depending on genomic context. We found the LINE1 (long interspersed elements) class of TEs (transposable elements) were the most frequently hypomethylated with age. This LINE1 pattern differed in magnitude across breeds of different sizes - the largest dogs lost 0.26% more LINE1 methylation per year than the smallest dogs. This suggests that epigenetic regulation of TEs, particularly LINE1s, may contribute to accelerated age and disease phenotypes within a species.

Since our study focused on the methylome of immune cells, we looked at LINE1 methylation changes in golden retrievers, a breed highly susceptible to hematopoietic cancers, and found they have accelerated age-related LINE1 hypomethylation compared to other breeds. We also found many of the LINE1s hypomethylated with age are located on the X chromosome and are, when considering X chromosome inactivation, counter-intuitively more methylated in males. These results have revealed the demethylation of LINE1 transposons as a potential driver of inter-species, demographic-dependent aging variation.

Link: https://doi.org/10.1101/2024.10.08.617286

Near all patients exhibiting type 2 diabetes have the condition as a result of being overweight. Losing weight will improve the diabetic metabolism; studies have shown that type 2 diabetes is reversible even into fairly late stages. The primary outcome of taking GLP-1 receptor agonists such as semaglutide is weight loss. Excess visceral fat in individuals who are overweight or obese contributes to chronic inflammation and a variety of other mechanisms that are known to accelerate the onset and progression of age-related disease. The brace of recent papers lauding GLP-1 receptor agonists as treatments for age-related disease, focusing heavily on changes in cellular biochemistry in their discussions of the topic, are really just a new way of advocating for the evident benefits of weight loss in those who are overweight.

Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior Alzheimer's disease (AD) diagnosis by comparing semaglutide with seven other antidiabetic medications.

Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33) and most weakly compared with other GLP-1RAs (HR, 0.59). Similar results were seen across obesity status, gender, and age groups. Semaglutide was associated with significantly lower AD-related medication prescriptions. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM.

Link: https://doi.org/10.1002/alz.14313