Fight Aging!

Animal studies suggest that the composition and activities of the gut microbiome are as influential on long-term health and the progression of degenerative aging as is the case for lifestyle choices such as degree of physical fitness and level of physical activity. The gut microbiome changes with age: microbial populations delivering harmful metabolites or that otherwise provoke the immune system into a state of chronic inflammation grow in number, while microbial populations delivering beneficial metabolites necessary for tissue function are reduced in number. Rejuvenation of the gut microbiome, which can be achieved via fecal microbiota transplantation from a young donor to old recipient, has been shown to improve health and extend life in aged animals.

In the matters of health and aging, untangling the contribution of the gut microbiome from the contributions of diet and exercise is a challenge. The function of diverse tissues, the composition and activities of the gut microbiome, and lifestyle choices are all components of a single system, linked together and influencing one another. Today's open access paper is a discussion along these lines, focused on what is known of the ways in which exercise and the gut microbiome interact with one another to affect the aging of muscle tissue. Muscle mass and strength declines with age, and in this age of comfort and engines of transport there is a widespread lack of the physical fitness that is needed to slow muscle aging. But even the fittest people become frail eventually. A better understanding of the mechanisms involved in muscle aging may lead to therapies better able to do something about that.

The exercise-gut-muscle axis in physical frailty: A narrative review

Frailty is characterized by a decline in physiological reserve across multiple organ systems. Individuals with frailty are vulnerable to stressors, leading to an increased risk of falls, functional impairment, and death. A key biological factor underlying frailty is sarcopenia, which involves the progressive deterioration of skeletal muscle mass and function during aging. Sarcopenia involves a gradual loss of muscle mass, strength, and physical performance over time. Given the central role of skeletal muscle in physical function and metabolic health, muscle health must be maintained to sustain a healthy life.

Regular exercise is considered a highly effective non-pharmacological strategy for preserving skeletal muscle function during aging. In older adults, both aerobic and resistance exercise have been shown to enhance muscle strength, physical performance, and metabolic health. Regular physical activity is also associated with improved mitochondrial function, enhanced insulin sensitivity, increased muscle protein metabolism, and reduced chronic inflammation. Accordingly, exercise plays a central role in reducing frailty risk and preserving physical independence among older adults.

Despite abundant clinical evidence of the benefits of exercise, the biological mechanisms through which physical activity promotes health in older adults remain unclear. Recent evidence suggests that the gut microbiome may serve as an important link between lifestyle factors and host physiological function. The gut microbiome consists of trillions of microorganisms, including bacteria, viruses, and fungi. These microorganisms influence host physiology through complex metabolic and signaling pathways; they play crucial roles in nutrient metabolism, immune regulation, and energy homeostasis.

Human cohort studies have linked age-related alterations in the gut microbiome to frailty, reduced physical function, and poorer overall health in older populations. Large cohort studies have demonstrated that variations in gut microbiota composition are closely linked to dietary patterns and overall health status in older adults, and further reported microbial signatures associated with early frailty. Among community-dwelling older adults, physical fitness has been associated with dietary patterns, gut microbial composition, and metabolomic profiles. These observations suggest that the gut microbiome may be associated with physical function and frailty during aging, although causal relationships remain unclear.

One plausible mechanism involves microbial metabolites. Gut bacteria produce numerous biologically active metabolites, such as short-chain fatty acids (SCFAs), bile acid metabolites, indole-derived compounds, and products of amino acid metabolism. SCFAs such as acetate, propionate, and butyrate have considerable effects on inflammation, mitochondrial metabolism, glucose homeostasis, and insulin sensitivity. Importantly, exercise has been shown to influence the microbial composition of the gut as well as its metabolic function. Animal and human studies indicates that habitual physical activity may enhance microbial diversity in certain settings and enriches bacterial taxa associated with beneficial metabolic functions, including SCFA production.

Researchers here assess the present animal study evidence for first generation stem cell therapies to produce benefits in the most common neurodegenerative conditions, and also the consequences of stroke. The results are promising. While these therapies have been fairly widely deployed in patients via medical tourism, that data will never be available for analysis in any useful way. A few formal clinical trials have taken place, with unfortunately mixed results, which suggests that the details of manufacturing process, source of cells, and other logistical factors are important to outcomes. In general, these stem cell therapies appear to reliably modulate chronic inflammation, but all other desired outcomes are quite unreliable where they have been assessed rigorously in human patients. This is one of the reasons why factions within the research community are interested in identifying the most influential signals secreted by transplanted stem cells and using those signal molecules instead of cells as a basis for therapy.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the two most prevalent neurodegenerative disorders. Neurodegenerative diseases are conditions characterized by the progressive dysfunction of nerve cells. This process is primarily associated with cellular aging, which advances with the patient's age. In turn, stroke is caused by vascular factors. Although it is not classified as a neurodegenerative disease, it leads to the degeneration of brain cells. These are severe disorders that frequently impair independent functioning.

As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke.

A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models.

Link: https://doi.org/10.1007/s12035-026-06247-3

Transposable elements are DNA sequences that can copy themselves. The remnants of ancient viral infections, they encode viral-like particles that act to insert DNA into the genome. Transposable elements are suppressed in youth, but with age the epigenetic control over DNA structure and gene expression is altered, and one of the consequences is that transposable elements are exposed to translation machinery and begin to copy themselves. This produces a form of DNA damage where that haphazard insertion of new sequences breaks existing genes, but perhaps more importantly generates an inflammatory response to the viral-like particles that innate immune sensors recognize as foreign. Some fraction of the harmful chronic inflammation results from transposable element activity, and thus suppression may form a useful basis for therapy.

The reactivation of transposable elements (TEs) is a recurrent molecular event across cancer, neurodegeneration, autoimmune disease, and aging, yet its therapeutic implications remain largely unexplored. Normally repressed under strict epigenetic surveillance, reactivated transposable elements can generate immunostimulatory nucleic acids that engage cytosolic pattern-recognition receptors, converging on type I interferon signaling and driving chronic sterile inflammation. Yet this inflammatory potential is inherently dual: the same reactivation that drives pathology in some contexts can be harnessed to prime immunity in others.

Here, we review two complementary strategies that exploit this duality. Suppressive approaches, including nucleoside reverse transcriptase inhibitors, antisense oligonucleotides, and epigenetic silencing agents, aim to quench pathological TE-driven inflammation in diseases and restore other adaptive mechanisms governing homeostasis. Conversely, controlled TE reactivation through epigenetic priming can induce a viral mimicry state in tumor cells, sensitizing them to immune checkpoint blockade. In parallel, TE-derived peptides presented on MHC class I molecules are emerging as a largely unexploited reservoir of shared tumor antigens for next-generation vaccines and engineered T cell therapies.

Together, these observations reframe transposable elements not as mere viral relics to be tolerated, but as a tunable immunological switch whose therapeutic modulation holds promise across some of the most challenging diseases of our time.

Link: https://doi.org/10.1038/s44321-026-00528-z

Humanity is poorly supported by its vasculature. Vascular aging is the primary cause of human mortality, giving rise to atherosclerosis, the formation of fatty plaques that narrow vessels and eventually rupture to produce a fatal blockage and thus a heart attack or stroke. The quality of the vasculature suffers in other ways along the road to old age: vessels become leaky where they should not be, allowing the passage of disruptive cells and molecules into tissues; the network of capillaries becomes less dense, reducing delivery of necessary nutrients into tissues; the smooth muscle surrounding vessels becomes less capable of constriction and relaxation, leading to a range of issues relating to blood pressure and pulsatile flow; and so forth. One can find dozens of scientific papers in which Thomas Sydenham's most famous maxim is quoted, that "a man is as old as his arteries." There is of course more to aging that the decline of one important system, but the vasculture is an important system, and its dysfunction does include the single largest cause of mortality, atherosclerosis.

The authors of today's open access paper cast a summary view over the aging of the vasculature, taking the Hallmarks of Aging as their theme, and discussing each hallmark as it aligns with what is known of age-related dysfunction in vascular tissues. Of the hallmarks, study of the age-related accumulation of senescent cells is perhaps the most well advanced when it comes to the construction of therapies and preclinical evidence for rejuvenation following treatment. The parts of this review covering the role of senescent cells and the potential application of senotherapeutics to the treatment of vascular aging are thus the least speculative. Nonetheless, there remains a way to go yet if the goal is the widespread availability of senotherapies in old people; much of the system of medical regulation has yet to be convinced, and large, slow, and expensive clinical trials remain the only practical way to carry out that process of persuasion. This is unfortunately, given that many of the first, readily available senotherapeutics cost very little, but must sit on the sidelines until the regulators and physicians are more engaged on this topic.

Decoding Vascular Senescence: Cellular Insights and Therapeutic Strategies

The vascular system, an intricate network spanning the entire human body, serves as the primary conduit for nutrient delivery, gas exchange, and metabolic waste removal. With advancing age, the vascular wall undergoes a series of degenerative transitions that compromise these vital functions, laying the pathological groundwork for systemic organ decay. The arterial wall is composed of three anatomical layers: the tunica intima, a single layer of endothelial cells (ECs); the tunica media, composed of multiple layers of vascular smooth muscle cells (VSMCs) interspersed with elastic fibers; and the tunica adventitia, containing adipocytes, fibrous connective tissue, and extracellular matrix (ECM). Although each layer has distinct physiological properties, their collective integrity relies on a delicate balance between cellular homeostasis and microenvironmental stability. During aging, this homeostasis is disrupted as the specialized cells within these layers-including ECs, VSMCs, and pericytes-undergo profound phenotypic and functional shifts. Furthermore, exhaustion of the endothelial progenitor cells (EPCs) reservoir and the progressive remodeling of the ECM redefine the vascular niche, shifting it from a regenerative environment toward one characterized by chronic inflammation and structural decay.

In the process of aging in humans, senescent cells tend to accumulate at divergent rates in numerous tissues. Cellular senescence is defined as a terminal state of cell cycle arrest characterized by the irreversible loss of proliferative capacity. This program is primarily executed through the p53/p21WAF1/Cip1 and p16INK4A/pRB axes, which inhibit cyclin-dependent kinases to prevent E2F-mediated DNA replication. While initially a tumor-suppressive mechanism, the excessive accumulation of senescent cells drives vascular aging. In elderly individuals, p53, p21, and p16 levels are significantly elevated in the endothelium, an effect that is attenuated by regular physical activity. Mechanistically, p53 hyperactivation drives capillary rarefaction, whereas its downstream effector p21 (encoded by Cdkn1a) functions as a complicated regulator of vascular homeostasis. Moderate p21 expression is essential for maintaining the quiescence of EPCs and supporting angiogenesis. Furthermore, p16-INK4A (encoded by Cdkn2a) serves as a definitive marker of the senescent state. Although the clearance of p16-positive cells has been shown to delay age-associated disorders, subsequent studies have revealed that age-induced p16 accumulation is a gradual process and that the majority of p16-high cells are vascular ECs. Ultimately, the progressive accumulation of these senescent populations results in a systemic decay in vascular compliance and the functional collapse of capillary networks.

Senolytics represent a specialized class of pharmacological agents that selectively eliminate senescent cells. Intermittent oral administration of the representative senolytic cocktails, dasatinib and quercetin, significantly decreases the burden of senescent cells within the aortic inner layer of aged mice, thereby remarkably improving vasodilatory function. Mechanistically, these agents achieve selectivity by disabling distinct nodes of senescent cell anti-apoptotic pathways (SCAPs). Dasatinib predominantly inhibits ephrin receptors and tyrosine kinases, whereas quercetin targets the PI3K/AKT, p21, and BCL-2 protein families. This targeted elimination holds pivotal therapeutic potential to diminish macrovascular and microvascular morbidity.

Since stem cell therapies produce beneficial effects via a short burst of signaling from the transplanted cells rather than via any long-lasting survival and engraftment of those cells, researchers are attempting to build therapies that deliver the signals instead of the cells. Manufacture involves culturing stem cells and harvesting the culture medium in order to obtain the molecules or extracellular vesicles secreted by the stem cells, and then introducing that material into patients. The signaling produced by different stem cell populations will likely prove to be more versus less useful in different contexts, and so some experimentation is needed. Here, researchers show that the secreted signals generated by dental pulp stem cells help to improve the outcome following stroke in mice.

Ischemic stroke induces oxidative stress, neuroinflammation, neuronal death, and synaptic dysfunction, leading to persistent motor and cognitive deficits. The human dental pulp stem cell (hDPSC) secretome is a promising cell-free therapeutic candidate containing neurotrophic, antioxidant, and immunomodulatory factors. Here, we investigated its therapeutic effects in a photothrombotic mouse model of ischemic stroke and CoCl2-induced hypoxic BV2 microglial cells.

Proteomic profiling identified antioxidant-associated proteins, including SOD2, GSR, and GSTP1, and microglial phenotype-related candidates, including GRN, CSF1, and LRP1. hDPSC secretome treatment reduced stroke-induced infarct volume and attenuated stroke-increased neuronal apoptosis, neuronal reactive oxygen species (ROS) accumulation, and NF-κB-associated inflammatory signaling in the cortex and hippocampus. It also shifted microglial marker expression toward an M2-associated profile and improved stroke-impaired hippocampal neurogenesis, vascular remodeling, and synaptic organization. Proteomic analyses further identified coordinated changes in pathways related to oxidative phosphorylation, inflammatory responses, calcium signaling, SNARE-associated vesicular transport, and ROBO-Rho-associated cytoskeletal remodeling. These molecular and cellular changes were associated with improved motor coordination, spatial learning and memory, contextual memory, and anxiety-like behavior.

These findings support the hDPSC secretome as a cell-free therapeutic candidate for post-stroke functional recovery linked to redox, inflammatory, neurovascular, and synaptic remodeling.

Link: https://doi.org/10.1002/advs.76717

That the calorie restriction imposed by GLP-1 receptor agonists induces loss of muscle mass has proved a boon for research into ways to address the loss of muscle mass that occurs with age, contributing to frailty. Suddenly a relatively large amount of funding and industry attention is available for programs that might result in a drug to prevent muscle loss in GLP-1 receptor agonist patients, and most of those options can at least in principle be used to treat age-related muscle loss. Here, researchers demonstrate a novel approach to inducing muscle growth in aged mice, by inhibiting a relevant microRNA; the technology is developed by Elenae Therapeutics which, as is usual, targets more severe and less common indications at the outset, such as improving outcomes for heart muscle following a heart attack. Given an approved drug at some point in the future, then it becomes possible to discuss other applications.

Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy.

Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.

Link: https://doi.org/10.64898/2026.09.03.749250

The gut microbiome changes with age in ways that are not favorable to health. Microbes that provoke inflammation and tissue dysfunction grow in number, replacing those microbes that generate beneficial metabolites. There are many plausible contributions to this process of change, and as is usually the case for anything to do with aging, it is hard to determine which are more or less important than the others. This is particularly the case here, as studies suggest that meaningful change in the composition of the gut microbiome begins as early as the mid-30s, a point in adult life at which very little is concretely known regarding which mechanisms of aging are dominant.

The authors of today's open access paper surveyed the literature to identify human studies that report specific differences in gut microbiome composition between various groups at different ages. Some of the studies specifically included long-lived populations such as centenarians. If interested in the results, skip ahead to table 2, which lists microbial taxons found to be increased or decreased with age, or in long-lived populations. A fair number of studies are listed, and some commonalities emerge.

This sort of data, taken in the aggregate, will form the basis for later efforts to favorably adjust the composition of the gut microbiome in specific ways in order to slow or reverse aspects of aging and age-related disease. Altering the composition of the gut microbiome can at present be achieved temporarily via probiotics, with some degree of control over the outcome, or permanently via approaches such as fecal microbiota transplantation, but with little control over the specifics of the outcome. It is to be hoped that future approaches can combine permanence of the changes following a single treatment with good control over the resulting mix of populations.

Gut microbiome and healthy ageing: a systematic review of literature

The gut microbiota comprises a diverse community of micro-organisms, including bacteria, archaea, viruses, parasites, and fungi, which inhabit the large intestine. These microbes play a crucial role in various physiological processes, including facilitating digestion, modulating immune responses, protecting against pathogens and synthesizing neurotransmitters and essential metabolites, such as vitamins, amino acids, secondary bile acids and short-chain fatty acids (SCFAs).

In 2023, researchers expanded the hallmarks of ageing framework by introducing three additional hallmarks, one of which is gut microbiome dysbiosis. This condition is characterized by reduced microbial diversity and an increased abundance of pro-inflammatory species. However, in the context of healthy ageing, the gut microbiome tends to maintain relative stability and contributes to systemic homeostasis. Studies have shown that the gut microbiome undergoes physiological changes throughout the ageing process. However, the direction and magnitude of these changes, including shifts in microbial diversity, are highly variable. These changes depend on several factors such as health status, diet, lifestyle, medication use, and population cohort. Microbial alterations often reflect a transition from a diverse and stable adult microbiome to a less balanced state in later life, marked by increased inflammation, reduced production of beneficial metabolites and disrupted immune function, changes that may contribute to the progression of age-related diseases

This systematic review aimed to identify compositional and functional features of the gut microbiome associated with healthy ageing. A total of 41 studies met the eligibility criteria and were included in this review. The included studies represented several regions, including recognized longevity hotspots, although geographic representation remained limited. Most studies used 16S rRNA gene sequencing (n=24; 58.5%), followed by shotgun metagenomics (n=13; 31.7%), both (n=3; 7.4%) or metaproteomics (n=1; 2.4%). Enrichment of specific taxa such as Akkermansia, Alistipes, and Parabacteroides was consistently reported in centenarians, alongside distinct patterns in older adults and long-lived individuals. Functional profiling suggested differences in pathways related to amino acid catabolism, vitamin biosynthesis, and pathways potentially linked to immune modulation, inflammatory processes, and gut barrier support.

It is always good to see a diversification in non-profit efforts to advance the state of research and development in the matter of treating aging as a medical condition. Given the vast costs imposed by aging, humanitarian and fiscal, we stand a long way removed from the deployment of an adequate amount of funding for aging research. New advocates and new organizations are very welcome, to add to existing efforts to induce more funding for necessary research, and more capital into the longevity industry.

We started Second Century Foundation to fulfill our childhood dream of a world where no one has to suffer or die from aging. Second Century Foundation is a 501(c)(3) private operating foundation focused on accelerating breakthroughs in human longevity. Much of the work needed to achieve these breakthroughs isn't fundable today. If it doesn't lead to a publication, the NIH won't fund it. If it doesn't enable an exit in ten years, venture capital can't fund it. We exist to fill those gaps.

Among present projects, we're writing a memo targeting for-profit investors and operators laying out the financial case for longevity biotech: the path to a successful IPO or M&A exit; top funding sources and messaging to Wall Street; a rigorous framework to project the expected NPV (net present value) of a therapeutic product; areas that we believe are overfunded relative to their financial (and lifespan) return; areas where we believe the potential return is highest. Additionally, We're creating a comprehensive map on the flow of capital in the longevity space, across academia, industry, and the government. Our goals are to: quantify and catalogue spending by organization and approach; spotlight research areas that we believe to be underfunded relative to their promise; identify top talent in the field and connect them with funding opportunities.

Which will give you a longer, healthier life: curing cancer, or slowing aging by 20%? (It's the second one, by a huge margin.) The longevity simulator is a free, open-source, browser-based tool that shows how the medicine of the future could change healthspan and lifespan. The tool is meant to demonstrate the enormous benefit of targeting aging itself, rather than playing whack-a-mole with individual diseases of aging.

Have an idea, want to collaborate, or want to help solve aging? We'd love to hear from you, especially students looking to start something: a longevity club, a research project, or a startup.

Link: https://www.secondcentury.org/

Cells become senescent in response to various forms of damage and stress, including the stress induced by reaching the Hayflick limit on replication. This was first described in the context of replicative senescence in cell cultures, and from there cellular senescence became a topic of interest in cancer research. In more recent years, the accumulation of senescent cells in aged tissues was demonstrated to be an important contribution to degenerative aging, and a small industry of biotech companies has emerged to develop a variety of therapies to either selectively destroy or modulate the behavior of senescent cells.

The history of cellular senescence is, in many ways, a history of expanding biological complexity. What began as an observation of finite proliferative capacity in cultured cells has progressively evolved through a series of conceptual transitions that have fundamentally reshaped the field. Senescence was first understood as a consequence of replicative exhaustion, then as a potent tumor-suppressive mechanism, later as a regulator of tissue remodeling through the senescence-associated secretory phenotype, and ultimately as a causal contributor to aging and age-related disease. More recently, the emergence of senotherapeutics has transformed senescence from a biological phenomenon into a clinically actionable target.

A major contemporary shift is the recognition that senescence is not a single cellular state. Advances in single-cell transcriptomics, spatial profiling, and lineage-specific genetic models have revealed extensive heterogeneity among senescent cells across different tissues, stimuli, and biological contexts. This emerging view is reshaping experimental design, biomarker discovery, and therapeutic development, while challenging many of the assumptions that historically treated senescence as a uniform biological process.

More than six decades after the original observations made by Hayflick, one of the most important lessons from the field is that senescence is neither inherently beneficial nor inherently detrimental. Rather, its biological consequences are determined by context. Senescent cells can promote tissue repair, regeneration, and tumor suppression, yet can also drive chronic inflammation, fibrosis, functional decline, and disease progression. Understanding this duality has become central to modern senescence biology.

Link: https://doi.org/10.1038/s44318-026-00922-w

Cells become senescent in response to stress and damage, in response to tissue injury, but most commonly upon reaching the Hayflick limit to replication. A senescent cell ceases to replicate, grows in size, and generates a potent mix of pro-growth, pro-inflammatory signals. Senescent cells are created throughout life in tissues throughout the body, but an established population of lingering senescent cells only begins to accumulate in later life. In youth, the immune system efficiently clears senescent cells, allowing senescence to be a beneficial state in the coordination of regeneration and in drawing the attention of the immune system to potentially cancerous cells. In later life, the immune system falters in this task. An established population of senescent cells that generates signaling constantly, even in relatively small numbers compared to the overall count of cells in a tissue, is highly disruptive to tissue structure and function.

To what degree is the age-related failure of immune clearance of senescent cells a consequence of harmful changes in the immune system versus harmful changes in the senescent cells themselves? This is an interesting and unresolved question, though there is at least some degree of evidence for contributions from both sides. Today's open access paper from a research group with a long history of work on the cellular maintenance processes of autophagy provides evidence for a loss of capacity in chaperone-mediated autophagy in aged senescent cells to induce a loss of chaperone-mediated autophagy in aged innate immune cells, which contributes to the inability of the immune system to efficiently clear senescent cells. In chaperone-mediated autophagy, an target unwanted or damaged protein is bound by a chaperone protein, and that chaperone protein facilitates the entry of the target into a lysosome for disassembly. It is a complex business, and so it seems likely there will be many possible targets for future drug candidates intended to improve this form of autophagy in senescent cells or immune cells.

Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells

Here we focus on the role of chaperone-mediated autophagy (CMA) during establishment, maintenance, and immune resolution of senescence in the aging context. CMA selectively degrades in lysosomes proteins containing a KFERQ-like motif, recognized by the cytosolic chaperone heat shock cognate protein of 71 kDa (HSC70). Substrate delivery to the CMA receptor, the lysosome-associated membrane protein 2A (LAMP2A), triggers its multimerization into a translocation complex for substrate entry into the lysosomal lumen. CMA declines with age in most tissues, and its malfunction is linked to neurodegenerative conditions, metabolic syndrome of aging, and atherosclerosis.

Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic, and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells.

Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.

Functional connectivity is a measure of neuronal activity over time in different parts of the brain, assessed using MRI to detect the increased blood flow that accompanies increased neuronal activity. Researchers here demonstrate that changes in functional connectivity observed in Alzheimer's disease patients differ from age-related changes observed in individuals without dementia. As is the case for many measures of aging, there is some debate within the scientific community with regard to whether any specific change is dysfunction or an adaptive, compensatory reaction to dysfunction. This will likely remain the case until effective rejuvenation therapies or effective treatments for specific neurodegenerative conditions such as Alzheimer's exist, can be used in sizable patient populations, and the results measured.

Aging and Alzheimer's disease (AD) are both associated with changes in functional brain networks - groups of regions that typically communicate with one another and support cognition. However, the precise nature of these changes - their spatio-temporal dynamics and whether they reflect compensatory adaptations, pathological disruptions, or both - remains a topic of active debate. Functional connectivity (FC), the temporal synchrony of activity between brain regions, may be a mechanism facilitating the spread of pathology, a system affected by pathology, or an interplay of both.

Here, in two independent cohorts (BioFINDER-2, N = 973; Alzheimer's Disease Neuroimaging Initiative, N = 129), we show that functional connectivity changes associated with aging and AD are strongly aligned with separate fundamental axes of hierarchical brain communication. Early accumulation of AD pathology and subsequent cognitive decline are both linked to functional change along the sensory-association axis. Meanwhile, age-related functional changes occur along the representation-executive axis consistently throughout the adult lifespan. These findings together suggest that both AD and aging alter major but orthogonal functional pathways in the brain.

Link: https://doi.org/10.1038/s41593-026-02402-0

A great deal of drug discovery starts by screening compounds from the vast libraries of molecules that exist. The libraries are too large to screen everything (and even then the scope of the libraries is only a sampling of the space of the possible). Thus even unbiased screening starts with some hypothesis to cut down the number of molecules being screened to a tractable number for the time and budget at hand. Here, researchers discuss the use of existing transcriptomic data to guide drug screening approaches intended to uncover geroprotective compounds that adjust metabolism to modestly slow aging. Based on results to date, this side of aging research seems unlikely to produce exciting outcomes, as near all of what has been discovered in this way triggers the same array of known beneficial stress responses, and thus doesn't improve on the present state of the art.

To date, invertebrate-based screens have identified hundreds of life span-extending compounds. However, relatively few have been validated across multiple species, and most of the geroprotectors belong to extensively studied classes like mechanistic target of rapamycin (mTOR) inhibitors, AMPK activators, or histone deacetylase (HDAC) inhibitors. Because these pathways regulate broad cellular processes, direct pharmacological modulation of their core components may produce pleiotropic effects. This reliance on a limited set of well-studied targets and drug classes underscores the need for unbiased tools that can prioritize diverse candidate geroprotectors.

Currently, several strategies have been developed to identify small-molecule geroprotectors, ranging from unbiased screening to transcriptomic-based drug prediction. The latter, which infers the geroprotective effects of drugs based on drug-induced transcriptomic changes, is an emerging method and has gained traction thanks to availability of large-scale transcriptomic resources. Several methodologies have been developed within this framework. One widely used strategy is the "reversal approach," which identifies drugs that counteract aging-associated gene expression changes. This approach has led to discoveries such as oridonin, an AKT inhibitor extending life span in yeast and mice. However, the reversal approach assumes that all age-related changes are detrimental despite evidence that some may be adaptive.

Another strategy, the "mimic approach," matches drug-induced transcriptomic profiles to those of known antiaging interventions. This method has been applied to identify compounds like allantoin and rilmenidine, which extend life span in Caenorhabditis elegans. However, this method tends to rediscover drugs similar to known interventions, limiting its capacity to reveal novel mechanisms.

Here, we used C. elegans and mice to explore transcriptomic strategies for geroprotector discovery. Applying transcriptomic clocks and coexpression network analysis, we found that many aging-associated changes in C. elegans are adaptive - some transcriptomic changes that resemble aging may contribute to longevity. We identified conserved coexpression modules associated with life span: "aging modules" enriched in translation and mitochondrial genes and "longevity modules" enriched in stress response genes, including daf-16 targets. Several of these longevity-associated modules are preserved in specific mouse tissues and are associated with mouse health span. Last, we conducted a small-scale screen and identify seven novel geroprotectors using the module gene expressions as our transcriptomic signatures. Our findings demonstrate that expression profiles of conserved aging-related processes can serve as predictive signatures for finding effective geroprotective compounds.

Link: https://doi.org/10.1126/sciadv.aee3657

A reduced intake of calories triggers protective responses to low nutrient availability, dramatically altering the operation of cellular metabolism. For so long as adequate levels micronutrients are still ingested, this response to calorie restriction is beneficial. The cell maintenance processes of autophagy operate more efficiently, for example, and this improved autophagy is thought to be the primary mechanism by which calorie restriction improves health and slows aging. This response to calorie restriction is triggered by a variety of independent sensors that assess the availability of various components of the diet, where essential amino acids are one of the more important components in this respect. Researchers have assessed the metabolic response to diets low in the essential amino acid methionine, and found it to produce broadly similar effects to overall calorie restriction in laboratory animals.

The authors of today's open access paper argue that methionine restriction is likely misnamed, as: (a) low methionine diets are also low in the non-essential amino acid cysteine; (b) in a low cysteine environment, methionine is consumed to produce cysteine, meaning one can't really distinguish between the effects of low methionine and low cysteine easily; (c) given a suitably engineered animal, with the methionine to cysteine pathway disabled, one can show that in fact the important metabolic response occurs as a result of low cysteine levels and not as a result of low methionine levels.

Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging

Cysteine is a dietary non-essential yet biochemically irreplaceable amino acid. Methionine, the other sole proteinogenic sulfur amino acid (SAA), lacks a thiol group and hence cannot form complexes with metals, including disulfide bond formation, nucleophilic catalysis, and redox signaling. Typically, cysteine and methionine contents are high in animal-based diets, while plant-based vegetarian foods are lower in SAA. It is now recognized that cysteine is essential for organismal metabolism through pleiotropic effects, including regulation of coenzyme A (CoA) and glutathione (GSH)-mediated redox balance. Creation of forced cysteine depletion by deletion of cystathionine γ-lyase (CTH) and feeding a cysteine-free diet causes rapid, progressive 30% weight loss. In addition, cysteine depletion induces activation of central nervous system nuclei that control sympathetic nervous system (SNS)-derived norepinephrine, which causes rapid adipose tissue browning and thermogenesis through β3-adrenergic receptors.

However, an important underappreciated issue is that methionine restriction (MR) is erroneously called MR because this diet also lacks cystine. Interestingly, it has been well established that an 80% reduction of methionine content (in a diet with 0% cystine) in adult rats resulted in robust 40% increases in median and maximum lifespan. Additional independent studies confirmed that MR, which in fact lacks both methionine and cysteine, robustly enhances lifespan in mice despite an increase in food intake, without restriction of calories. Moreover, using methionine-and cysteine-titrated diets in wild-type mice, the anti-adiposity effects of SAA restriction have been linked to cysteine restriction.

When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via CTH in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged CTH knockout mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.

Dental follicle stem cells can be used as a basis for regenerative cell therapy in the treatment of periodontitis, the prevalent form of gum disease, and a condition that becomes more common with age. Researchers here note that IGFBP5 expression is reduced in senescent dental follicle stem cells, and find that increased expression of IGFBP5 reduces the pace at which these cells become senescent. Cellular senescence in the cultured cells used in cell therapy is a problem that the regenerative medicine community is becoming increasingly aware of, and various efforts have been made in various contexts to try to mitigate the issue. Here, researchers employ this new knowledge regarding the role of IGFBP5 to design a better cell therapy to promote periodontal regeneration, and carry out a proof of principle study in a rat model of periodontitis.

The improvement of health and the delay of aging represent pivotal goals in medical research. Bone aging contributes to various age-related disorders, including periodontitis. Dental follicle stem cells (DFSCs) serve as ideal seed cells for periodontal regenerative therapy. Insulin-like growth factor binding protein 5 (IGFBP5) has been reported to exert complex and context-dependent effects. However, its role in DFSC senescence remains undefined. In this study, we observed a significant decrease in IGFBP5 expression in DFSCs undergoing replicative or H2O2-induced senescence.

Functional experiments demonstrated that IGFBP5 overexpression alleviated cellular senescence and enhanced osteogenic potential, a process linked to the modulation of non-canonical Wnt signaling. WNT5B was then identified as a potential downstream regulator involved in mediating the pro-osteogenic effects of IGFBP5. To translate these findings clinically, we developed Gel-vHA@oe-DFSC, a nanoparticle-embedded hydrogel system for cell delivery, which enhanced the therapeutic efficacy of DFSCs and promoted periodontal regeneration in a rat model. Collectively, our study reveals a novel function of IGFBP5 in mitigating DFSC senescence and presents a promising strategy for combating periodontal bone loss.

Link: https://doi.org/10.1038/s41368-026-00463-2

Cancers are primarily age-related conditions for a range of reasons, such as the decline of the immune system's ability to find and destroy cancerous cells, a rising burden of senescent cells providing a more hospitable environment for cancerous growth, and the fact that the cells of older people have a greater burden of somatic mutations than younger people. The interesting part of this paper is that normal cells in cancer patients exhibit a higher burden of somatic mutations than normal cells in healthy individuals, thus suggesting that random mutational damage, and particularly that occurring in stem cells that can spread out into tissues over time to form the patterned outcome over overlapping mutations known as somatic mosaicism, raises the odds of a cancerous combination of mutations occurring.

Self-renewing normal tissues generate several somatic mutations at each division. Previous studies have reported that cancer cells have more mutations than their normal counterparts. It is not obvious why dramatic differences in mutational burdens between normal tissues and cancers should exist. To fully understand human tumorigenesis, the increase in mutational burden across cancers will have to be understood. In this study, we provided a systematic comparison of mutational burdens in normal and cancer cells from 5 different organs, revealing a 4-fold increase in mutational burden in cancerous versus noncancerous cells.

Three proposed hypotheses could account for the increased mutational burdens in cancer: the classical hypothesis, in which driver gene mutations explain the higher mutational burden; the catastrophic hypothesis, in which extreme mutational events lead to large-scale genomic alterations; and the tail hypothesis, in which differences in baseline mutation rates among individuals account for the differences. Testing through orthogonal observations showed that the observed medians and distributions of mutational burdens in cancers could be explained by the hypotheses to various degrees of significance, and only the tail hypothesis could easily explain the increase in median mutational burdens in the normal tissues of patients with cancer compared with the normal tissues of noncancer patients.

Overall, this study characterizes an increased mutational burden across multiple types of cancer compared with normal tissue and provides insights into the contributing factors. A tenable hypothesis proposed in this study involving fundamental differences in baseline mutation rates among individuals could have implications for cancer prevention strategies.

Link: https://doi.org/10.1158/0008-5472.CAN-26-0117

The tissues of the mammalian body span a broad range of regenerative capacity, from the highly regenerative liver to the minimal regenerative capabilities of the brain and the heart. We might speculate that the evolutionary road to a reduced capability of regeneration in the central nervous system results need to retain structure that stores memory. The heart incorporates a complex electrical system, and the need to retain the structure of this system may also place constraints on the level of regeneration that can take place following injury. Heart damage, such as that resulting from a heart attack and consequent transient loss of blood supply to regions of the heart, heals poorly, and is typically characterized by fibrosis that is disruptive to heart tissue structure and function. It sets the patient on a downward course towards mortality.

Here, researchers investigate one small part of the regulatory system that determines heart cell activities following injury. They uncover a possible way to improve mitochondrial function and reduce the formation of fibrotic structures in injured heart tissue. Notably, they also demonstrate that it is insufficient to enhance the replication of heart muscle cells if the goal is improved function. More than only this is needed. Regeneration is a complex time and space dependent interplay between multiple cell types in injured tissue; it should not be surprising to find a lack of very straightforward single protein interventions that can improve matters.

A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition

The adult mammalian heart exhibits only a negligible capacity for regeneration following injury. Metabolic reprogramming has emerged as a promising strategy to enhance regenerative capacity in the adult heart. Succinate dehydrogenase (SDH), a protein complex which links the tricarboxylic acid (TCA) cycle and electron transport chain, has been extensively studied in ischemia-reperfusion injury, where malonate reduces succinate accumulation, mitochondrial reactive oxygen species and tissue injury following reperfusion across multiple mammalian models. Moreover, mutations in SDH drive profound metabolic reprogramming in multiple cancers characterized by enhanced glycolysis and Warburg-like metabolic states. Therefore, we hypothesized that transient SDH inhibition could metabolically reprogram the adult heart toward a more regenerative state.

We previously demonstrated that transient pharmacological inhibition of SDH with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific deletion of the Sdhb subunit of SDH dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function.

SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked and H3K27me3-marked chromatin states in cardiomyocytes and fibroblasts. Integration of CUT&RUN, chromatin accessibility and transcriptional profiling identified regulatory targets linking metabolic and epigenetic remodeling to regenerative responses. Together, these findings establish SDH as a multicellular regulator of cardiac regeneration and define distinct cell-specific mechanisms contributing to the regenerative effects of transient pharmacological SDH inhibition.

Any sufficiently complex set of biological data that changes with age can be used as the basis for an aging clock. Well established machine learning techniques can identify patterns and find optimal correlations between algorithmic combinations of measurements taken from the data and outcomes of interest, such as age, mortality risk, risk of age-related disease, and so forth. For all that we are now many years into the development of aging clocks as a technology, it still remains to determine how best to use them to accelerate research and development of therapies to treat aging. In principle, a rapid measure of the state of aging should allow better progress towards rejuvenation therapies. In practice, it is impossible to trust that any given clock will react in the right way to efforts to treat aging, and the only sure way to find out is to run long and expensive life span studies. Until this core challenge is solved, clocks cannot add much to the pace of development.

Biological aging clocks offer estimations of aging and dementia, yet scalability is limited. We introduce a large-scale, cross-national speech clock derived from 2928 individuals across five Latin American countries, spanning healthy controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-language/language-dominant frontotemporal dementia (nldFTD/ldFTD). Multimodal acoustic and linguistic features were trained with supervised models to estimate chronological age, generating speech age gaps (SAGs) as cross-sectional markers of deviations from chronological age, with positive values interpreted as relatively older-appearing speech profiles.

SAGs differentiated diagnostic groups (HCs < patient groups, with AD < nldFTD < ldFTD). This pattern was associated with clinical/cognitive domains. SAGs correlated with phosphorylated tau (p-Tau217) in AD and social exposome in HCs and AD. Brain clocks (structural/functional/combined) were associated with SAG in AD, nldFTD, and ldFTD. Epigenetic age correlated with SAGs in HCs and AD across Hannum, Retroclock, and OMICmAge, whereas ldFTD associations were limited to Retroclock and OMICmAge. These results indicate that SAGs capture cross-sectional multilevel aging-related variation and may offer a scalable, culturally adaptable, low-cost biomarker candidate for research in underrepresented global settings.

Link: https://doi.org/10.1126/sciadv.aef9864

Added to the growing list of specific ways in which the gut microbiome can contribute to degenerative aging, researchers here note that indole produced by gut microbiobes provokes a chain of events that worsens the maladaptive inflammatory immune response to the damage of an ischemic stroke, increasing the overall harm done. Like many of these recent single metabolite discoveries, there is a single point of intervention that may be used to reduce the impact of indole on the immune system, and thereby improve stroke outcomes.

The gut microbiota modulates systemic immunity and neurological diseases, yet the underlying mechanisms remain unclear. Here, we identify the enrichment of indole-producing Escherichia coli being associated with worse outcomes in mice and patients with ischemic stroke. Microbial indole triggers an aryl hydrocarbon receptor (AHR)-dependent response in dendritic cells (DCs). DC-specific AHR deletion improves stroke outcomes and preserves intestinal conventional type 1 DCs. AHR deletion also promotes immunoregulatory and migratory transcriptional signatures and enhances CCR7-dependent migration in vitro.

Pharmacological AHR inhibition favors gut-derived DC accumulation in the meninges, accompanied by increased regulatory T cells (Tregs) and reduced neuroinflammation, while Treg depletion abolishes the neuroprotection conferred by AHR inhibition. Detrimental effects of indole-producing Escherichia coli, indole administration, and microbiota transplantation from patients with stroke are attenuated in DC-specific AHR-deficient mice. These findings define a microbiota-AHR axis that programs intestinal immune responses before brain injury and highlight microbial tryptophan metabolism as a tractable therapeutic target.

Link: https://doi.org/10.1016/j.cell.2026.09.013

Cancer survivors who underwent chemotherapy or radiotherapy in the course of putting their cancer into remission have been shown to exhibit an increased burden of senescent cells relative to healthy peers. This is thought to explain the observed reduction in life expectancy and increased odds of unrelated cancers in cancer survivors. In general, these individuals are aging more rapidly than would be the case with a lesser burden of senescent cells, as these errant cells generate inflammatory signaling that is disruptive to tissue structure and function throughout the body.

Evidence suggests that interventions like exercise that upregulate the cellular maintenance processes of autophagy can reduce the pace at which cells become senescent, and perhaps help to spur greater immune mediated clearance of lingering senescent cells over time. This is one of the mechanisms by which exercise can improve late life health and reduce mortality risk, though of course it is challenging to identify the relative importance of the many and varied plausible mechanisms at work. Exercise changes a great deal of the operation of cellular biochemistry for the better.

Cancer survivors make a good natural experiment: how well exercise works to improve health in these individuals provides a point of comparison with the extensive data on the aged population in general, one that might help pinpoint the importance of cellular senescence in human aging. Today's open access paper is a report of such a study conducted in cancer survivors, and one might compare the results with any number of similarly structured studies conducted in similarly aged people without cancer.

Exercise slows biological aging in breast cancer survivors: secondary analysis of a randomized trial

Sedentary breast cancer survivors within 5 years of diagnosis were randomized to a remotely delivered exercise intervention or a contact-matched health and wellness condition. Whole blood samples and cognitive assessments were obtained at baseline, 6, and 12 months. Epigenetic ages and differential methylation were calculated. A subsample of 124 participants with complete data was analyzed.

The Exercise arm showed slower epigenetic aging than the Health and Wellness arm over the 12-month study, according to GrimAge2 and DNAmFitAge clocks. Changes in epigenetic aging were significantly correlated with alterations in attention and self-reported cognition, with faster epigenetic aging associated with greater cognitive decline. Furthermore, genome-wide analysis of the blood epigenome identified differentially methylated CpG sites, some mapping to genes enriched for brain-derived neurotrophic factor (BDNF) signaling pathways.

The first human application of partial epigenetic reprogramming of aged tissues, using adeno-associated viral (AAV) vectors, was not in fact the first patient dosed in the recently launched Life Biosciences clinical trial for optic neuropathy. Instead, a few older and entrepreneurial individuals in the longevity community made use of the AAV gene therapy experience accumulated in recent years by organizations in the more reputable end of the medical tourism industry (e.g. Triple Helix Science in particular, but also BioViva and others with lower profiles) in order to responsibly manufacture and use reprogramming therapy. The medical tourism community tends not to generate formally published and peer-reviewed data, sadly, but in this case some of those involved may choose to share data further along the line, given enough time to see results.

AAV is something of a special case among modes of advanced therapy. Many of the good AAV serotypes with well defined behavior are in the public domain, there is broad, ongoing industry experience in manufacture and use in clinical trials to draw upon, and manufacture is relatively straightforward. Other forms of gene therapy vector remain locked down by patent holders, or are much harder to work with safely, or have relatively little of a manufacturing and development community. That will change over time. That AAV gene therapy is now more democratized, more accessible, and spreading into the medical tourism community is a preview of how things will be in the future for a much larger range of advanced medicine: both more accessible, but at the same point in time robust data on effects and effectiveness will be harder to uncover.

Kenneth Scott was born in 1942 and Helga Sands was born in 1938. Their KHL Foundation works with scientists, physicians, and biotechnology developers to help develop and adapt promising rejuvenation technologies for practical human application, beginning with the generation that needs them now. To this end a small number of people have received an experimental 11-gene therapy containing reprogramming factors OCT4, SOX2, and KLF4 (OSK) developed through a Triple Helix Science initiative. One of those recipients, Christine Scott, received the treatment on March 11, 2026. The therapy was administered submucosally with cognitive function as its principal target. Expression of the OSK components is controlled through a doxycycline activation regimen.

The underlying gene-therapy initiative is led by Patrick Sewell, MD, and Triple Helix Science. KHL is supporting the initiative, including through the participation and monitoring of Christine Scott, who in prior years had experienced substantial cognitive and neurological decline following a severe adverse reaction attributed to ciprofloxacin. To the best knowledge of Sewell, Scott, and Sands, these treatments represent the first administrations of OSK to humans. KHL has identified no publicly documented earlier human OSK administration and is continuing to assemble and review the treatment chronology before making an unqualified worldwide-first claim.

"This is not an announcement that we have proved that OSK reverses cognitive decline. It is an announcement that human application has begun. Now we can monitor what actually happens, learn from it and adapt. Gene therapy is becoming increasingly practical. I've already seen the cost of the technology fall dramatically. The next challenge is moving credible science into responsible human application and learning from what happens."

Link: https://khlfoundation.com/resources-center/madrid-2026-press-release/

AMPK is the target of a range of interventions known to modestly slow aging in short-lived species. Like much of the complex array of evolved machinery that responds to various forms of cellular stress with improved maintenance, repair of damage, and a consequent slowing of aging, AMPK is involved in the regulation of energy metabolism. Many of these interventions, such as metformin, are far from robust. The animal data is mixed. One might argue that this is in part because the effects on the behavior of AMPK are indirect, as researchers do in this paper. Still, their direct approach to activating AMPK still produces only a modest effect on life span, and does so in species known to be far more receptive to life extension via metabolic alteration than is the case for humans. One wouldn't expect great things to emerge from attempting this in our species.

AMP-activated protein kinase (AMPK) is a fundamental sensor of metabolic status and stress, which is universal throughout eukaryotes. AMPK plays a central role in energy homeostasis and is therefore an attractive therapeutic target in health and disease. AMPK consists of a heterotrimer, with a catalytic α subunit and regulatory β and γ subunits, and displays strong evolutionary conservation across eukaryotes, as evident from sequence alignments between the human, fly, worm, and yeast orthologues. Maximal kinase activity of AMPK requires phosphorylation of a conserved threonine in the α subunit.

Many studies utilise pharmacological targeting of AMPK, for instance by the anti-diabetic drug metformin, which activates AMPK indirectly by altering the cellular AMP/ADP:ATP ratio. To overcome the complexity and non-specificity of metformin, studies with direct AMPK activators are essential to fully appreciate the therapeutic potential of AMPK in health and ageing. Here, we apply the direct AMPK activator compound 991 in yeast, worms, flies and mice to investigate its potential pro-longevity effects. We demonstrate that direct activation of AMPK with the compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans, and Schizosaccharomyces pombe. In mice, 991 treatment induces a pro-longevity proteomic profile, highlighting the potential for translation to mammals. Overall, our study provides important proof-of-principle for AMPK as a pharmacological target with longevity benefits.

Link: https://doi.org/10.1111/acel.70721

Hundreds of mitochondria in every cell work to produce adenosine triphosphate (ATP), a chemical energy store molecule needed to power cell activities. Mitochondria evolved from symbiotic bacteria, and are now fully integrated as components of the cell, with much of their original DNA moved into the cell nucleus. Mitochondria become dysfunctional with age, reducing their production of ATP, increasing oxidative byproducts, and causing maladaptive inflammatory reactions. This is an important contribution to the disruption of cell and tissue function that takes place in aged tissues.

Unfortunately, mitochondrial dysfunction, while well established and readily measured, is also enormously complex and incompletely understood. Many different contributing mechanisms are plausible, but it is a challenge to determine which of them are more or less important than the others. So far, attempts to improve mitochondrial function in older individuals via pharmacology and supplements have struggled to improve on the effects of exercise, suggesting that the mechanisms targeted are not those with the largest effects on function, or at least are not in and of themselves sufficient to improve function.

In today's open access paper, researchers outline one of the many contributing issues to mitochondrial dysfunction. Their focus is on muscle tissue, but much of the underlying problem generalizes to other tissues. The structure of the inner mitochondrial membrane relies upon the presence of cardiolipin, but cardiolipin production declines with age. This triggers changes in mitochondrial function that muscle tissue reacts to with remodeling of the distribution of fiber type in additional to any other issues that arise. Experiments in a mouse lineage engineered to lack cardiolipin suggests that replacing lost cardiolipin can help to restore function, but one would want to see that same study repeated in aged mice before taking it at face value.

Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ

Skeletal muscle is composed of fiber types that span a continuum of contractile and metabolic properties, enabling the tissue to meet diverse functional demands. Along this spectrum, slow-twitch (type I) fibers show high mitochondrial oxidative capacity, whereas fast-twitch fibers comprise both oxidative (type IIa) and glycolytic (type IIx and IIb) subtypes that rely differently on oxidative versus glycolytic metabolism for force generation. Diminished mitochondrial function disrupts systemic energy homeostasis and is a hallmark of myopathies and aging. Yet, seemingly paradoxically, myopathies and aging also lead to selective atrophy of glycolytic fibers and a shift toward oxidative metabolism. The timing and mechanisms driving this fiber-type-specific shift remain unclear. Whether diminished mitochondrial function has a causal role in eliciting adaptive measures or is merely a marker of age- and disease-related decline is unknown.

Mitochondrial function is heavily shaped by the inner mitochondrial membrane (IMM), which coordinates cellular and organismal homeostasis by modulating macronutrient exchange, bioenergetic capacity, fusion and fission, and interactions with other organelles. The IMM's distinct curvature is conferred by a unique lipid composition, most notably the phospholipid cardiolipin (CL). Here we show that synthesis of cardiolipin causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle.

By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell-autonomously orchestrate fiber-type adaptations in aging and myopathies.

The immune system of the brain and body are distinct from one another, separated by the blood-brain barrier that lines blood vessels passing through the central nervous system. In health and youth, only small numbers of immune cells from the body pass in the brain, but this number increases considerably with advancing age and the presence of neurodegenerative disease. The blood-brain barrier leaks, and immune cells from the body finding their way into the brain in ever greater numbers are thought to maladaptively promote inflammation, causing dysfunction and damage in brain tissue. Here, researchers find an approach to slowing down this passage of immune cells into the brain, producing benefits in a mouse model of neurodegeneration.

CXCR3 is a well-defined chemokine receptor expressed by T cells, predominantly on activated T helper 1 (Th1)-polarized CD4+ and cytotoxic CD8+ T cells. Its canonical chemokine ligands, CXCL9, CXCL10, and CXCL11, are induced by interferon gamma (IFNγ) and are abundant during chronic inflammation. Upon homing to tissues, activated T cells amplify immune responses by secreting chemokines and cytokines such as IFNγ to facilitate cellular damage. In peripheral tissues, CXCR3-ligand interactions orchestrate T cell recruitment and infiltration into tissues, and some lines of evidence suggest a role in neuroinflammatory conditions.

We hypothesized that the CXCR3 axis is an important chemotactic gradient for brain-infiltrating T cells in tauopathy, thereby linking peripheral immune activation to tau-driven brain injury. To address this, we established an acute model of brain T cell infiltration via stereotaxic injections of recombinant IFNγ into the hippocampus. Using this model allowed us to confirm that antibody-mediated blockade of CXCR3 and genetic deletion of Cxcr3 or Cxcl10 prevented brain T cell infiltration. This confirmed that acute central nervous system injection of IFNγ could result in brain T cell infiltration and a putative role for CXCL10 and CXCR3 in this infiltration.

In a mouse model of tauopathy and neurodegeneration, chronic systemic anti-CXCR3 treatment markedly reduced parenchymal CD4+ and CD8+ T cell accumulation, attenuated neurodegeneration, and improved aspects of cognition. CXCR3 blockade decreased microglial major histocompatibility complex (MHC)-II expression without broadly suppressing classical disease-associated inflammatory phenotypes. Single-cell RNA sequencing and flow cytometry further revealed a reduction in the proportion of activated CD4+ T cell populations and elevated CD8+ T cell terminal exhaustion in the brain.

Link: https://doi.org/10.1016/j.neuron.2026.08.030

Researchers here discuss the chronic inflammation of aging as a contribution to the bidirectional relationship between the loss of bone mineral density leading to osteoporosis and neurodegenerative pathology leading to cognitive impairment. As they point out, the best interpretation of the correlation between these two aspects of aging is that underlying processes contribute to both forms of degenerative aging. The chronic inflammatory signaling characteristic of aging is one of the best candidate mechanisms, given what is known of its effects on bone tissue and brain tissue at the detail level.

This review consolidates existing evidence into an integrative immunopathological framework in which inflammaging - the chronic, low-grade, sterile systemic inflammatory state driven by senescent cells and their senescence-associated secretory phenotype (SASP) - is examined as a shared upstream driver that concurrently reconfigures skeletal remodeling and central neuroimmune dynamics through the bone-brain axis. Meta-analytical evidence indicates that osteoporosis is associated with a substantially elevated risk of cognitive impairment (odds ratio = 2.01), and that cognitive impairment carries a reciprocally increased risk of osteoporosis (risk ratio = 1.56) - with Alzheimer's disease conferring a particularly high risk (risk ratio = 1.70). This bidirectional association is best interpreted as the shared output of multiple interlocking aging mechanisms rather than as a direct causal relationship between the two conditions.

At the molecular level, persistently elevated SASP-derived cytokines (IL-6, IL-1β, TNF-α) engage RANKL-dependent osteoclastogenesis in bone and prime microglial neuroinflammation in the central nervous system. Chronic NF-κB signaling and NLRP3 inflammasome activation, amplified in preclinical models by mitochondrial DNA release via the cGAS-STING axis, sustain this dual pathological output. Within the bone-brain axis, bone-derived endocrine signaling is remodeled during aging: osteocalcin (OCN) secretion declines, while osteocyte-derived sclerostin (SOST) rises and may antagonize Wnt/β-catenin signaling in both compartments. Blood-brain barrier disruption and peripheral immune-cell infiltration further amplify central neuroinflammation.

Candidate bone-brain dual-targeting interventions - senolytics (dasatinib plus quercetin), NLRP3 inhibitors, cGAS-STING blockade, GLP-1 receptor agonists, and microbiota-targeted strategies - are discussed with explicit reference to current evidence level, safety concerns, and translational limitations, rather than as established co-therapies. Dual-endpoint randomized trials enriched for elevated inflammaging biomarkers are needed before any of these agents can be positioned for clinical use in bone-brain comorbidity.

Link: https://doi.org/10.3389/fimmu.2026.1874465

An important goal in the research community is to build a robust measure of biological age, the burden of age-related damage and dysfunction contributing to disease and mortality, that can be used to rapidly assess the quality of any potential intervention to slow or reverse aging. One of the reasons why the longevity field moves slowly is that, in the absence of a robust measure of biological age, it takes a long time to assess any given therapy by running life span studies in mice, and repeating such studies in humans is infeasible. So there is relatively little drive to compare, contrast, and optimize approaches shown to slow or reverse aging in laboratory species. One might hope that a robust measure of biological age would speed up the research community's efforts to build a basis for greater human longevity.

There are obviously a great many existing biomarkers of aging, some of which are very straightforward to measure. Grip strength is a popular one, and today's open access paper advocates for imaging of the degree of fat infiltration into muscle tissue. The issue is that these measures are not known to be robust. Either their relationship with outcomes in aging varies greatly from individual to individual, or they cannot be trusted to accurately reflect effects on outcomes produced by interventions. Any measure of aging can be calibrated against any specific form of treatment for aging, to determine whether or not it is helpful in that case, but then one is back to needing long-running, expensive studies to make progress. It doesn't help the bigger picture because it doesn't accelerate the field.

Myosteatosis: an emerging biomarker of aging

Adipose tissue infiltration into skeletal muscle (i.e., myosteatosis) has emerged as an independent contributor to metabolic disorders and declines in skeletal muscle function with age. It remains unclear whether myosteatosis is a marker of aging or simply a consequence of disease or disuse. This review summarizes evidence from population-based epidemiologic studies that utilized non-invasive imaging to measure myosteatosis and to evaluate age-related changes among community-dwelling middle aged and older adults.

Myosteatosis consistently increased with age, independent of weight change, and the burden of myosteatosis was greater among women, and non-White racial and Hispanic ethnic groups after accounting for physical activity levels, chronic disease burden, and overall body size. Myosteatosis accumulation is not uniform throughout the body and is differentially associated with clinically meaningful age-related outcomes, including changes to gait, balance, muscle strength, and physical function. Hormonal, cellular, genetic, and lifestyle differences comprise the biological pathways that may lead to age-related increases in myosteatosis.

Future work in diverse populations using standardized imaging methodologies could include longitudinal measures of biological markers to better understand the biological precursors that accompany the phenotypic change. In conclusion, while myosteatosis does not accumulate uniformly with age across sex, race, or anatomical location, evidence from several well-characterized epidemiologic studies supports myosteatosis as a potential marker of aging, independent of weight change, body size, activity level, or chronic disease burden.

Any sufficiently complex biological data that changes with age can be used to construct an aging clock. Here, researchers report on a clock derived from images of the nuclei of hematopoietic stem cells. Nuclear DNA exhibits structural changes in response to circumstances, regulated by epigenetic decorations to DNA and its supporting proteins, as regions unfold or are compacted. The structure of DNA determines which gene sequences are exposed to translation machinery, and thus whether or not a given gene is expressed. Some of these structural changes are characteristic of aging, and thus machine learning approaches should be able to visualize age-related differences in imaging.

The functional decline of the hematopoietic system during aging affects organismal function and contributes to reduced healthspan. Quantifying hematopoietic aging holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of aging that encode rich and informative signatures of the aging process, yet they remain largely unexplored as quantitative markers.

Here, we present an interpretable deep learning approach based on convolutional neural networks, ChromAgeNet, that learns changes in the spatial features of chromatin architecture upon aging of hematopoietic stem cells (HSCs). We trained our algorithm on 3D microscope images of DAPI-stained HSC nuclei to discriminate between young and aged murine HSCs, achieving an area under the receiver operating characteristic curve (AUROC) of 0.77 ± 0.03. This approach outperforms classical machine learning models trained on handcrafted chromatin features from the same dataset. We then applied explainable artificial intelligence techniques, identifying chromatin entropy, peripheral heterochromatin, and chromatin condensates as predictive markers.

As a proof of concept, we evaluated the potential of our model as a phenotypic screening tool for aged HSCs treated with epigenetic drugs to detect rejuvenation. Altogether, we demonstrate that changes in chromatin organization can be modeled via machine learning to predict age-associated chromatin states in the hematopoietic compartment. Our developed framework, ChromAgeNet, serves as an interpretable algorithm to unravel the intricate relationship between chromatin changes and stem cell aging, and advance high-throughput drug screening for rejuvenation therapies.

Link: https://doi.org/10.1111/acel.70656

The antimicrobial drug K21 acts via disruption of bacterial membranes, but is also known to produce improved wound healing, which suggests the involvement of mechanisms other than antimicrobial activity. Here, K21 is shown to favorably modulate macrophage activity, in that exposure improves the operation of the mitochondrial quality control processes of mitophagy in macrophages, which in turn improves mitochondrial function. Delivery of K21 to nematode worms resulted in longer life spans, as one might expect from any intervention that improves mitochondrial function without meaningful side effects.

Here, we sought to use single-cell RNA-seq to explore the diversity of the innate immune response and to understand its potential to be reprogrammed by antimicrobial therapy. Antimicrobials primarily target specific aspects of the pathogen's lifecycle to inhibit its spread, yet few drugs can effectively control viruses, bacteria, and other pathogens, including fungi, while improving cellular health. The only possible way to achieve this is to alter the host immune repertoire to effectively inhibit pathogenic survival. We chose to study the antimicrobial compound K21, a quaternary ammonium silane compound that not only exhibits broad-spectrum effects against viruses, bacteria, and fungi but also demonstrates potent wound healing activity.

As macrophages and macrophage polarization orchestrate the phases of wound-healing, shifting from pro-inflammatory signaling that combats infection to pro-regenerative signaling that recruits fibroblasts and keratinocytes to repair the epithelial tissue, we reasoned that K21 might operate by modulating macrophage properties, classes, and/or dynamics. We chose to examine the effects of K21 on monocyte-derived macrophages from human peripheral blood monocytes (PBMCs) because of their technical accessibility, their ability to be isolated in a relatively naïve state and co-cultured with other cell types, and their controllable M1/M2 polarization.

We found that supplementing cytokine and cell-surface marker profiling with scRNA-seq transcriptomic analysis provides unparalleled resolution of macrophage diversity and plasticity, allowing us to demonstrate how treatment with K21 remodels the macrophage repertoire both inside and outside the cell. We show that a key aspect of K21 treatment is the induction of mitochondrial fission and autophagy (mitophagy). We turned to the distantly related model system C. elegans to examine whether the mechanism used by K21 is used systemically in vivo and evolutionarily conserved. K21 induced DRP-1-mediated mitochondrial fission and mitophagy in vivo without impairing viability, development, or fertility; indeed, it reprogrammed metabolic gene expression and extended lifespan in these nematodes, consistent with its effects observed in mammalian cells.

Link: https://doi.org/10.26508/lsa.202603852

Aging clocks have yet to fulfill their promise, which is to produce a robust measure of biological aging that can be used to rapidly assess the results of potential therapies to slow or reverse the progression of aging, such as via repair of underlying cell and tissue damage that causes aging. This is because these clocks are produced by machine learning approaches applied to data from a patient population, such as omics data, that changes with age. Exactly why any specific combinations of measures identified in this way, such as the state of DNA methylation at scores of specific CpG sites on the nuclear genome in the case of epigenetic clocks, can predict age or mortality risk is a mystery. There is no way at present to connect a given CpG site or protein expression level or feature in imaging data to what is known of mechanisms of aging. Thus a clock cannot be trusted to assess a new approach to treating aging without calibrating it against that approach in slow, expensive life span studies. Which defeats the point of the exercise.

One of the ways in which researchers approach this challenge is to gathering as much data as possible for as many clocks as possible, in a search for patterns and understanding that will allow clocks to be better trusted. Prospective memory is the ability to remember to follow through on a previously made plan. Like all forms of memory function, it declines with age as the mechanisms of aging produce progressively greater neurodegeneration in brain tissue. In today's open access paper, researchers report on correlations in existing data between epigenetic age acceleration measured in the 40s and prospective memory dysfunction a decade later. The study wasn't large enough and the approach used to assess memory dysfunction was not robust enough to detect correlations at a given age between epigenetic age acceleration and memory function at that time. This suggests that early midlife is an important foundation for later health.

Linking epigenetic age acceleration to self-reported daily memory lapses: evidence from the National Study of Daily Experiences

DNA methylation algorithms, such as DunedinPACE, are increasingly used to study the mechanisms of aging and to identify associations with risk factors in adult development and aging. Growing evidence suggests that an increased pace of epigenetic aging is associated with cognitive impairment and dementia, but the correlation between epigenetic aging and subjective cognitive complaints (eg, forgetting a name or forgetting to take your medication), an early marker of dementia risk, remains unexplored.

Using data from The National Study of Daily Experiences (NSDE) and Midlife in the United States (MIDUS; N = 232), we examined the relationship between epigenetic aging rate (ie, DunedinPACE) and self-reported daily memory lapses (ie, occurrence, irritation, interference) in midlife and older adults. We found no significant main effects of the rate of epigenetic aging on self-reported memory lapses; however, a significant chronological age interaction indicates that among the comparatively younger adults in the sample (age 40-49), faster than average rates of aging (ie, higher DunedinPACE) were associated with more prospective memory lapses approximately a decade later as well as greater reports of prospective memory lapse irritation and interference. Additionally, for respondents in their forties, a higher DunedinPACE was associated with both greater prospective memory lapse irritation and interference.

These results suggest that early midlife may be a sensitive period during which the rate of epigenetic aging is more influential on cognitive health outcomes.

First generation stem cell therapies have become widespread; they are readily accessed in medical tourism clinics, and are also available for a range of issues in more regulated parts of the world. Initially it was hoped that transplanted cells would engraft and survive to assist tissues in repair and regeneration, but it has become clear that this is not how the therapies produce benefits. Rather it is a matter of signals generated by the transplanted cells in the short time they survive that beneficially alter the behavior of native cells. Unfortunately, while effects such as months-long suppression of chronic inflammation are fairly reliable, other hoped for improvements such as the stimulation of greater regeneration or regression of disease remain highly unreliable outcomes. One might ask where the field goes from here, and the consensus seems to be (a) attempts to make the generation of stem cells for transplantation much more robust and the outcomes more reliable, and (b) moving away from cells to instead manufacturing secretome or extracellular vesicle therapies derived from stem cell cultures.

Mesenchymal stem/stromal cells (MSCs) continue to drive innovation in regenerative medicine, yet the field is undergoing a critical evolution from the early concept of cellular engraftment to complex paracrine-mediated tissue repair. While MSCs were initially thought to repair tissues via direct engraftment and differentiation, accumulating evidence demonstrates that functional recovery relies predominantly on paracrine effects rather than direct cellular replacement. Through paracrine signaling, MSCs secrete a rich array of bioactive molecules - including cytokines, chemokines, growth factors, and extracellular vesicles (EVs) - that stimulate tissue regeneration, promote angiogenesis, and modulate inflammation, apoptosis, and fibrosis.

Despite these biological advantages and their ability to be expanded ex vivo for therapeutic use, the clinical outcomes of MSC-based interventions remain highly variable across different disease models. While MSCs have demonstrated promising regenerative capacity, their efficacy in complex organ regeneration and chronic inflammatory diseases is often inconsistent. Differences in tissue source, donor characteristics, manufacturing protocols, and the host disease microenvironment collectively influence therapeutic efficacy

To bridge this translational gap, a systematic reassessment of MSC therapies is urgently needed. Beyond the biological characteristics and general applications of MSCs, this review provides a critical, translational perspective on overcoming current clinical bottlenecks. It is our perspective that overcoming present limitations demands a strategic pivot towards precise cell-free MSC-EV therapies and advanced bioengineering strategies.

Link: https://doi.org/10.1016/j.scib.2026.09.057

The commensal microbes of the gut microbiome generate a range of metabolites that are beneficial or necessary to cell function. Levels of a number of these metabolites have been shown to decline with age as the composition of the gut microbiome changes for the worse. Overall the gut microbiome clearly makes a meaningful contribution to health and longevity, as demonstrated by the sizeable benefits resulting from providing a young microbiome to an old animal, but it isn't clear as to how much of these effects derive from changes in the production of any specific metabolite.

Metabolites produced by gut bacteria are taken up by the host and have a direct impact on its health. However, to our knowledge, no studies have investigated the effects of gut bacterial metabolites on the lifespan of the host using gnotobiotic animals colonized with gut bacteria deficient in biosynthetic genes involved in the production of specific metabolites.

Polyamines, such as putrescine and spermidine, are among the most important metabolites of gut bacteria. Previous studies have shown that increasing polyamines in the colon of mice extends their lifespan and biological functions. In this study, we produced gnotobiotic flies colonized with Escherichia coli, in which polyamine biosynthetic genes were deleted or complemented. Gnotobiotic flies were fed a polyamine-free diet, and the effects of metabolites derived solely from gut bacteria on the lifespan of the host were analyzed.

The results showed that polyamines derived from gut bacteria significantly prolonged the lifespan of the flies. Furthermore, the expression of TotM and Halo was suppressed in flies monocolonized with polyamine-producing E. coli compared with those monocolonized with mutant bacteria incapable of producing polyamines.

Link: https://doi.org/10.1128/mbio.01484-26

The effects of calorie restriction and even larger effects of growth hormone receptor knockout on the lifespan of mice have proven to be hard to beat. In large part, this is because (a) aging is the result of a number of very different causes, (b) producing comprehensive rejuvenation will require a number of very different therapies applied in combination, and (c) next to no-one is assessing the results of combination therapies targeting the root causes of aging. One of the other consequences of aging having multiple distinct (but interacting) causes is that it is in principle possible to make good progress on treating a cause of aging without producing an appreciable gain in healthspan or lifespan, or without reversing a given class of age-related disease, because that particular cause is not the limiting cause. If dysfunction results from several different mechanisms, then removing one of them may or may not help, and may or may not help in a sizable way, because the other mechanisms are still sufficient on their own to cause dysfunction. Nonetheless, all of the mechanisms will have to be dealt with to remove that dysfunction.

We can see examples in the development of rejuvenation therapies from recent years that illustrate the range of possible outcomes. Firstly, senolytics to clear senescent cells are very good at reversing age-related conditions in mice, but don't extend life to the same degree as calorie restriction, indicating a strong contribution to age-related disease, but a complex relationship with other aspects of degenerative aging - and those other aspects are enough in and of themselves to produce mortality. Secondly, clearance of amyloid-β aggregates is in principle a good idea, as that protein aggregation can cause pathology in the aging brain, but that clearance does little for patients in later stages of Alzheimer's disease, because other mechanisms become dominant in driving disease progression. With this in mind, today's opinion piece argues for a greater weight to be placed on the assessment of the ability of individual therapies to achieve their stated goal in reduction of specific forms of age-related cell and tissue damage, rather than effects on healthspan or lifespan, and for a greater focus on funding the assessment of therapies in combination, rather than individually.

When Lifespan, Healthspan, and their Surrogates are the Wrong Metrics for the Aging/Longevity Field

Aging is multifactorial. It is several diverse and distinct molecular subproblems. Very effective treatment of aging will clearly require the intelligent combination of several elements (several separate therapeutic interventions). Lifespan and healthspan extension are the ultimate result of very effective comprehensive treatment of adult biological aging pathology. They are the obvious outcome metrics for any final or somewhat comprehensive solution to aging. However, that does not make them, or their surrogates, the right metrics for testing individual interventions or for tracking progress of the field.

To illustrate the essence of the claim about how to evaluate individual interventions, consider a simpler imaginary system in which their are only two subproblems that limit functional lifespan. Pretend that a boat must ferry cargo across a body of water but suffers from 2 main problems: (1) Its hull is old and develops small holes regularly due to direct exposure to the corrosive water, and if uncorrected these holes slowly expand. (2) It must travel over some kelp some of which extends from the bottom close enough to the surface to become tangled in the boats propeller or rudder.

Now consider three interventions: A. Repair/patch the holes in the hull periodically. B. Remove the kelp strands from the propeller periodically. C. Replace the containers that the cargo is carried in with lighter-weight containers such that the boat rides higher in the water, causing both less of the hull to be exposed directly to the water causing fewer holes to develop and causing the propeller and rudder to ride higher where it encounters fewer kelp strands causing fewer to become tangled. Imagine the following: Studies of the effect of intervention C alone show that it extends the useful life of the boat vs. no intervention. Studies of the effect of intervention A alone and separate studies of intervention B alone show that neither alone increases the useful life of the boat vs. no therapy at all. Should we conclude that interventions A and B have no value? No, of course not. The monotherapy studies of A or B alone each left the unaddressed subproblem to eventually worsen to the point of ending the boat's useful life.

Multiple things go wrong in aging. Multiple interventions will eventually be required to do the best job possible at mitigating all these problems to the best extent possible. All that matters is: what is the best overall combination of interventions (for each person at each time). How important each intervention is depends almost entirely on how well it helps the ultimate endpoint of interest within the overall suite of interventions and hardly at all on how well it works with respect to the ultimate endpoint when used by itself, a way in which no one will use it in the long run. Some people want lifespan extension from monotherapy use to demonstrate relevance. This is misguided.

Why is the APOEε2 variant of the APOE gene associated with a lower risk of Alzheimer's disease and slightly longer life expectancy? Past research has investigated the role of APOE in cholesterol metabolism and inflammation in microglia, the innate immune cells of the brain implicated in neurodegenerative conditions. Here, researchers focus instead on pericytes and their role in maintaining the blood-brain barrier. The barrier prevents unwanted molecules and cells from entering the brain, but becomes leaky with age. This leakage of the blood-brain barrier generates inflammation and damage in the brain, and is thought to be an early inciting event in the onset of neurodegenerative conditions.

Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity.

To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation.

Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated lipid droplet accumulation in APOE3 and APOE4 pericytes.

Link: https://doi.org/10.1093/brain/awag311

Given a wildly successful drug, the standard pharmaceutical industry playbook is to push as hard as possible to find new uses for that drug, an effort that will tend to increase publication on the topic in the academic literature. The drive to classify GLP-1 receptor agonists as an anti-aging drug rather than a weight loss drug is an example of this behavior. While, yes, there are a few interesting preclinical studies suggesting interesting biology going on in the brain at doses too low to cause weight loss, for the most part we are discussing an attempt to find additional anti-aging effects of a drug that makes patients engage in calorie restriction, the most robust anti-aging intervention known to date.

Calorie restriction produces sweeping, incompletely understood, beneficial changes to the operation of metabolism throughout the body, changes that, in preclinical studies in mice, outweigh every pharmacological approach demonstrated to date to slow aging - and most of that pharmacology merely mimics portions of the response to calorie restriction. It seems unlikely that one can analyze the human GLP-1 receptor agonist study data obtained to date and responsibly claim that GLP-1 receptor agonism is doing something meaningfully more for aging than only reducing calorie intake. Maybe it is, maybe it isn't - but this is trying to find a tree in the forest.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events, all-cause mortality, and systemic inflammation in randomized controlled trials, with effect sizes exceeding those predicted from glycemic and weight-related improvements alone. The convergence of these findings with a maturing body of evidence linking metabolic dysfunction to accelerated epigenetic aging has prompted renewed interest in GLP-1 RAs as candidate gerotherapeutic agents. The present review synthesizes contemporary preclinical, mechanistic, and clinical evidence relevant to this question.

The SELECT trial demonstrated a 19% reduction in all-cause mortality (hazard ratio [HR] 0.81) in patients with obesity without diabetes, the FLOW trial demonstrated a 24% reduction in the primary kidney composite endpoint (HR 0.76), and the first randomized evidence of GLP-1 RA modulation of validated DNA methylation clocks was reported in 2025, with significant deceleration of DunedinPACE, PCGrimAge, and PhenoAge over 32 weeks of semaglutide therapy. Mechanistic studies have identified convergent pathways involving the hypothalamic GLP-1 receptor, AMPK/SIRT1 signaling, and microbiome-derived short-chain fatty acid production. The aggregate evidence supports the framing of GLP-1 RAs as a candidate class of geroprotective therapeutics, although definitive trials with prespecified epigenetic aging endpoints, durability follow-up, body-composition assessment, prespecified sex-stratified analyses, and adequate representation of diverse populations remain to be conducted.

Link: https://doi.org/10.1016/j.exger.2026.113325