Fight Aging!

Messenger RNA (mRNA) can be delivered into tissues and cells by encapsulating it into lipid nanoparticles (LNPs), and then injecting the nanoparticles. A target cell engulfs a LNP, and the cargo of mRNA is released into the cytoplasm where it is translated into protein. Typically a protein is manufactured in cells exposed to a LNP-mRNA therapy for a few days only before the last of the delivered mRNA is broken down and recycled, so the end result might be considered a half-way point between the characteristics of a gene therapy and the characteristics of a small molecule drug: a treatment that produces a protein of interest to cause specific desired outcomes in cell behavior, but that only lasts a little while.

The lipid nanoparticle industry looks today much like the viral vector industry did a decade ago. A great deal of research and early stage development of therapeutics is taking place, a great deal of invention, but much of the intellectual property remains locked down and either impossible or very expensive to use in a commercial product. To date only a small number of specific lipid nanoparticle formulations with a small number of different delivery characteristics have made it into clinical trials or become approved drugs. Many very interesting technology demonstrations in animal studies are taking place, however.

Today's open access paper is an example of one of the areas in which LNP-mRNA therapies may really shine, which is to take the concept of chimeric antigen receptor (CAR) cell therapies, and make them affordable. Delivery of a CAR T cell therapy involves taking a patient's cells, engineering them to express the desired CAR, growing their numbers in culture, and then returning the cells to the patient. The artificial receptor steers the T cells towards desired targets, such as cancer cells, and has proven quite effective in treating a number of different forms of cancer. Sadly it is enormously expensive as a mode of therapy, due to the time and complexity required to manufacture each patient-specific batch. LNP-mRNA that can turn native cells into CAR T cells (or in this case CAR natural killer cells) for a short while will be both much less costly and more controllable.

Reprogrammed NK immune cells target cancer and autoimmune disorders

Over the past decade, the U.S. Food and Drug Administration has approved seven new cancer treatments based on engineered T cells called chimeric antigen receptor (CAR) T cells. Chimeric antigen receptors are proteins that can be embedded into T cells, allowing them to detect a target antigen, such as a cancer protein. When the target is detected, the T cell becomes activated and destroys the target cell. In recent years, scientists have begun using a similar strategy to create CAR natural killer (NK) cells. One potential advantage of CAR NK cells over CAR T cells is that they could be used to kill diseased T cells. Using CAR T cells to treat T cell diseases often doesn't work well because T cells that are engineered to target T cell proteins may end up killing each other, in addition to the diseased T cells. That issue doesn't arise when using NK cells to target T cells.

However, manufacturing large quantities of CAR NK cells poses many of the same difficulties as generating CAR T cells. To simplify the process, researchers wanted to come up with a way to generate CAR NK cells in the patient's own body, without having to remove any cells. To generate these cells, the team designed lipid nanoparticles (LNPs) that can deliver an mRNA payload. These strands of mRNA encode a CAR that can be targeted to specific cell types. For example, they could deliver a CAR that targets CD19, a protein found on B cells, or CD3, a protein found on autoreactive T cells. The particles are coated with antibody fragments that bind to receptors found on the surface of NK cells, to ensure they reach the correct targets.

After these particles were infused into mice, the researchers found that they could successfully reprogram about 80% of the targeted NK cells. The researchers then tested the particles' potential to treat cancer and autoimmune hepatitis, which is caused by autoreactive T cells. In a mouse model of an aggressive form of melanoma, three of the five mice that received LNPs that reprogrammed their NK cells to target the cancer cells went into complete remission. The researchers also saw significant tumor destruction when they used the LNPs to treat T cell lymphoma in a humanized mouse model. In these mice, tumors were eradicated after five injections of the reprogramming LNPs. This result was similar to what the researchers saw when they treated mice with CAR NK cells that were generated using the conventional approach.

Lastly, the researchers demonstrated that their LNPs could generate CAR NK cells that target autoreactive T cells. For this application, they studied mice with autoimmune hepatitis, in which T cells attack hepatocytes in the liver. They found that in the treated mice, the autoreactive T cells were destroyed, and liver damage healed. These effects were seen after just one injection of the LNPs.

In vivo engineering of CAR natural killer cells for immunotherapy using ligand-directed lipid nanoparticles

Targeted lipid nanoparticles (LNPs) offer a nonviral approach for in vivo cell engineering but efficient programming of natural killer (NK) cells remains underexplored. Here we develop NK cell-targeted LNPs (NtLNPs) using engineered biparatopic NK cell ligands to drive receptor-specific uptake and mRNA delivery. Lead NtLNPs achieve up to ~80% NK cell transfection with minimal off-target effects in mice. Systemic delivery of chimeric antigen receptor (CAR) mRNA using NtLNPs generates CAR NK cells in vivo.

CD19-targeted CAR NKs completely deplete circulating B cells in healthy mice and CD3-targeted CAR NKs eliminate nearly all autoreactive T cells in an autoimmune hepatitis model, highlighting a potential advantage over CAR T therapies for T cell-driven disease. In solid tumors, NtLNPs targeting the inhibitory checkpoint NKG2A enhance antitumor efficacy by relieving Qa-1b-mediated immunosuppression. Lastly, we optimized NtLNPs for in vivo engineering of human CAR NK cells, enabling regression of two humanized hematologic malignancy models and establishing NtLNPs as a modular immunotherapy system.

Peroxisomes in cells are responsible for helping to maintain oxidative metabolism via making and removing hydrogen peroxide, but are also involved in numerous aspects of lipid metabolism, breaking down or converting various lipids necessary to cell function. They have other, less well mapped functions relating to defense against pathogens. There is some evidence for peroxisome loss to occur with age, for this to be a meaningful cause of further cellular dysfunction. As researchers note here, however, the evidence for forms of peroxisome dysfunction to contribute meaningfully to Alzheimer's disease is suggestive but far from conclusive. As is often the case, the fastest path to clarity would be an approach to restore a more youthful peroxisome function to cells in the brain and elsewhere, and see what happens as a result.

Peroxisomes are dynamic, single-membrane-bound organelles ubiquitously distributed throughout eukaryotic cells, containing abundant oxidases, catalase, and lipid-metabolizing enzymes. Their functions encompass the β-oxidation of very-long-chain fatty acids (VLCFAs), the degradation of branched-chain fatty acids, bile acid synthesis, and the biosynthesis of ether phospholipids - notably plasmalogens. Moreover, via catalase (CAT) and related enzymes, peroxisomes are instrumental in sustaining local reactive oxygen species (ROS) homeostasis.

These functions are of particular relevance to the nervous system, where membrane lipid composition, myelin integrity, synaptic plasticity, and redox homeostasis are intimately interconnected. Consequently, peroxisomal dysfunction may simultaneously impair multiple facets of neural cell physiology. Within the central nervous system, peroxisomes establish an integrated metabolic network with the endoplasmic reticulum, mitochondria, lipid droplets, and lysosomes. Thus, peroxisomal abnormalities can concurrently disrupt membrane architecture, energy metabolism, reactive oxygen species (ROS) signaling, and inflammatory responses.

Reduced plasmalogen levels, diminished peroxisomal enzyme activities, enhanced lipid peroxidation, and elevated oxidative stress have been consistently documented in both Alzheimer's disease (AD) brain tissue and animal models. Furthermore, peroxisome-regulated nuclear receptors - particularly the peroxisome proliferator-activated receptors (PPARs) - are closely intertwined with lipid metabolism, insulin sensitivity, inflammatory suppression, and mitochondrial function, rendering them promising targets for drug repurposing and novel therapeutic discovery.

Current evidence does not establish peroxisomal dysfunction as a necessary, sufficient, or universal cause of AD; it is more defensibly viewed as a context-dependent vulnerability, amplifier, or response within reciprocal metabolic-proteinopathy networks. PPAR agonism, lipid modulation, pexophagy regulation, and restoration of peroxisome-mitochondria communication remain investigational. Translation requires longitudinal human evidence, validated target-engagement biomarkers, and adequately powered trials in biologically defined populations. Peroxisomal biology therefore provides a testable framework for studying lipid-redox-organelle interactions in AD, while substantial uncertainty remains regarding temporal precedence, causal magnitude, and therapeutic tractability.

Link: https://doi.org/10.3389/fnagi.2026.1960320

Senescent cells accumulate with age, perhaps primarily because the aged immune system becomes less able to efficiently destroy senescent cells as it does in youth. When a cell becomes senescent it ceases to replicate, grows in size, and secretes a potent mix of pro-inflammatory, pro-growth signals that contribute to the chronic inflammation of aging and are disruptive to tissue structure and function. Here, researchers investigate some of the specific outcomes of an increased burden of cellular senescence in the aged liver.

The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages.

We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation.

Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

Link: https://doi.org/10.64898/2026.08.08.743614

Partial epigenetic reprogramming involves exposing cells to some or all of the Yamanaka factors for a long enough period of time to reset epigenetic decorations on nuclear DNA and its supporting structures to a youthful state, but not so long as to risk dedifferentiation, and thus loss of cell state and formation of induced pluripotent stem cells that can give rise to teratomas. It is a fine balance, and different cell types need different exposure times. Thus the first practical applications of reprogramming therapy under development are limited to one cell type, or small regions of tissue where greater control over delivery can be exerted. The limited options for delivery of gene therapies further restrict the options on which tissues can be targeted.

Life Biosciences sponsors the first clinical trial of a partial epigenetic reprogramming therapy, targeting degeneration of the retina and optic nerve in glaucoma patients. In animal models, reprogramming has shown itself capable of restoring function to a damaged optic nerve. Life Biosciences is using adeno-associated virus (AAV) as a vector, well proven in delivery to the retina and optic nerve via direct injection into the eye, to introduce an inducible package of Yamanaka factors into cells. Expression only occurs in the presence of doxycycline, which allows dosing of the Yamanaka factors to be tightly controlled and repeated over time as needed. AAV is effectively a permanent therapy in these tissues.

Life Biosciences Announces First-in-Human Data from Ongoing Phase 1 Trial Evaluating ER-100 in Optic Neuropathies

This first-in-human, Phase 1, open-label clinical trial (NCT07290244) is evaluating the safety and tolerability of ER-100 in adults with optic neuropathies. ER-100 uses controlled expression of three transcription factors, OSK (OCT4, SOX2, KLF4), delivered via a single intravitreal injection, with OSK expression induced by systemic doxycycline administered for 8 weeks (56 days). An oral prednisolone taper is administered to minimize risk of inflammation due to AAV-2 immune response. Multiple study visits assessing tolerability and visual endpoints were included in this first 56 day evaluation.

Optic neuropathies are a group of disorders characterized by damage to retinal ganglion cells (RGCs), the primary neurons connecting the eye to the brain. Because RGCs do not naturally regenerate, damage results in permanent vision impairment. One such optic neuropathy, open-angle glaucoma (OAG) is a chronic neurodegenerative disease and a leading cause of blindness in older adults. While often associated with elevated intraocular pressure, disease progression frequently continues despite treatment, and some patients suffer from OAG despite normal intraocular pressure. Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in adults over fifty. It involves sudden, painless vision loss due to insufficient blood flow, for which there are currently no approved treatments.

Interim data demonstrated that a single intravitreal administration along with daily oral doxycycline was well-tolerated through Day 56 in all three participants and showed preliminary signals of improvement in visual field testing in two participants. There were no reported dose-limiting toxicities, adverse events of special interest or serious adverse events. Improvements in Humphrey Visual Fields measurements, a standard eye exam that measures a participant's ability to detect light across many points in their field of vision, scored in decibels (dB), were observed in 2 of 3 OAG participants at Day 56. In each of these 2 participants, ≥ 28% of points in the visual fields showed a > 4 dB improvement.

The gut microbiome changes with age, and evidence suggests that this provides a meaningful contribution to degeneration and disease. Microbial populations that provoke chronic inflammation grow in size at the expense of populations that produce beneficial metabolites. Researchers here show that gut microbiome composition is a better predictor of the burden of inflammation and risk of disease than chronological age, much as one might expect given what is known of age-related changes in gut microbiome composition, and also given that researchers have built aging clocks from gut microbiome data. It is one more argument for a greater focus on the development and availability of therapeutic approaches capable of lasting rejuvenation of the gut microbiome, such as fecal microbiota transplantation and flagellin immunization.

Low-grade systemic inflammation increases with age and accompanies many age-associated lifestyle-related diseases, yet substantial inter-individual variability exists beyond chronological age. Given the gut microbiota's role in immune regulation, we analyzed paired fecal microbiota profiles, 30 plasma cytokines, and 19 biochemical and physiological measures in 1,199 adults (aged 20-72) from the population-based DanFunD cohort to assess the relative associations of microbiota composition and age with systemic inflammation and subsequent disease risk.

Here we show that despite an association between age and 40% of inflammatory cytokines and most physiological variables, gut microbiota composition explained more variance than age for 97% of cytokines and 84% of physiological variables. Individuals with the Bacteroides 2 enterotype exhibited elevated pro-inflammatory cytokines and adverse metabolic profiles already in early adulthood, displaying an inflammaging-like phenotype up to 37 years earlier than other enterotypes. This enterotype was associated with increased risk of future incident disease across multiple organ systems (hazard ratio 1.21), with mediation analyses suggesting that inflammatory cytokines accounted for part of this association. Conversely, a high-diversity enterotype was linked to lower inflammation and reduced disease risk.

These findings position gut microbiota composition as a stronger correlate of systemic inflammatory tone than chronological age and a potentially modifiable determinant of inflammation-related disease trajectories across adulthood.

Link: https://doi.org/10.1038/s41467-026-77499-9

The oldest land animal with an established age is an Aldabra giant tortoise, at 194 years. Researchers have sequenced the genomes of an old and young Aldabra giant tortoise to compare with other long-lived species and with less long-lived giant tortoises, part of a continuing effort to better understand aging via comparative biology. There is that hope that the comparative biology of aging can identify which mechanisms of aging are most important, as well as identify specific biochemical differences in long-lived species that may one day form the basis for therapies to slow aging in humans. We stand some way removed from that goal; only very recently have the first experiments taken place that move specific genes from long-lived species into short-lived species, and it will be years yet before those first studies could give rise to new medicine.

Recent studies on longevity have used comparative genomic analysis, focusing on long-lived animals like the naked mole rat, bowhead whale, Brandt's bat, immortal jellyfish, and long-lived variants of the African turquoise killifish. These investigations have deepened our understanding of gene markers that potentially slow aging and inhibit cancer in these species. To further explore longevity pathways, we evaluated the genome of Jonathan, an Aldabra giant tortoise (Aldabrachelys gigantea) with an estimated age of 194 years, considered the world's oldest known land animal. Giant tortoises are known for their long life spans, and some species harbor longevity-associated genetic features. Prior genomic analyses of two Aldabra giant tortoises and a Galapagos giant tortoise, Lonesome George (Chelonoidis abingdonii), identified longevity-associated nonsynonymous single-nucleotide variations (nsSNVs) in genes like IGF1R, DCLRE1B, and XRCC6. However, no existing study has assessed whether giant tortoises delay or avoid the epigenetic changes that typically accrue with aging in other vertebrate lineages or whether exceptionally long-lived individuals like Jonathan have unique epigenetic features.

Relative to other giant tortoises (A. gigantea and Chelonoidis abingdonii), Jonathan has unique gene variants in most aging pathways. Moreover, Jonathan has substantial DNA methylation and methylation entropy changes compared to four other Aldabras ranging in age from a 5-year-old juvenile to older adults. Notably, we found that lower-entropy regions in Jonathan's methylome were enriched for the promoters of genes involved in the mitochondrial electron transport chain, and RNA metabolism. This suggests that high-fidelity transcription of the genes in these pathways may be crucial for long-lived species. Our findings support a model for aging wherein the maintenance of low methylation entropy in gene promoters is coupled to efficient mitochondrial energy production, efficient RNA processing, and efficient genomic repair.

Link: https://doi.org/10.1126/sciadv.adw8887

Mediation analysis is a statistical technique can be used in an attempt to shed some light on why a correlation between two variables might exist, by involving a third variable that might be causative. In today's open access paper, the correlation of interest is between socioeconomic status and life expectancy, or socioeconomic status and the state of late life health. Socioeconomic status is one of a number of linked traits well established to correlate with longevity, such as wealth, education, and intelligence. How exactly these traits interact with one another and where the various arrows of causation are located, are the subjects of many hypotheses. Unfortunately concrete proof of any sort of causation is challenging to conjure forth from epidemiological databases.

Today's open access paper reports on an effort to seek insight into the degree that the greater life expectancy and lesser burden of age-related disease exhibited by high socioeconomic status study populations is a matter of these individuals tending to make better lifestyle choices, such as in the matter of smoking, diet, weight, exercise, and so forth. The result is interesting in that it suggests only a modest fraction of the differences between socioeconomic groups are caused by lifestyle choice. Other prominent potential causative factors that might differ between socioeconomic groups include exposure to air pollution, exposure to persistent infectious agents, and access to medical resources, all well studied in addition. Again, however, firm conclusions do not tend to emerge from studies of this nature.

How a healthy lifestyle mediates socioeconomic inequities in healthy ageing and life expectancies: A 20-year cohort of older adults

Lower socioeconomic status (SES) is associated with various adverse health outcomes, but its association with healthy ageing is less known, and whether adherence to a healthy lifestyle at late-life years can reduce socioeconomic disparities in health requires further investigation. In a 20-year cohort of 33,541 older adults aged ≥65 years across 23 provinces in China, we investigated socioeconomic disparities in mortality and unhealthy ageing considering physical, cognitive, mental, visual, and hearing functions, and evaluated whether adherence to a healthy lifestyle at late-life years can reduce these health disparities.

We categorized SES into low, medium, or high using latent class analysis based on education level, financial status, and occupation, and established the healthy lifestyle score by never smoking, no heavy alcohol consumption, regular physical and leisure activity, and a healthy diet. Compared with older adults of high SES, those of low SES had increased risks of all-cause mortality and unhealthy ageing, with adjusted hazard ratios (HR) of 1.25 and 1.46, respectively. Overall, a healthy lifestyle mediated 20.5% and 16.4% of socioeconomic inequity in all-cause mortality and unhealthy ageing, respectively. In low, medium, and high SES subpopulations, the healthiest lifestyle group had 3.18, 3.76, and 5.65 more years of total life expectancy, and 1.40, 2.73, and 3.90 more years of healthy life expectancy at age 65, respectively, compared to the least healthy group.

The aging of the immune system arises from the underlying causes of aging, but in and of itself causes significant further pathology. Here, for example, researchers discuss immune aging as a shared underlying cause of degenerative conditions of bone and joint tissues, and how this relates to the more traditional view of the cause of these conditions. In general, aging is not a neat straight line of cause and consequence, but rather a network of interacting processes of damage and dysfunction. In many cases the consequence can accelerate the cause. Consider senescent cells, for example, implicated in degenerative bone and joint conditions: the accumulation of senescent cells contributes to immune aging, which is a matter of both cellular senescence in immune cell populations and inflammatory signaling generated by senescent cells of all types, but immune aging is also one of the factors that allows senescent cells to accumulate, as the immune system is responsible for clearing senescent cells.

Traditional views often attribute osteoporosis to an imbalance in bone remodeling, estrogen deficiency, and increased bone resorption, while osteoarthritis is considered the result of abnormal mechanical loading, cartilage degeneration, and abnormal subchondral bone remodelin. However, osteoporosis (OP) and osteoarthritis (OA) are not simple manifestations within the same disease spectrum but are disease entities with different pathological scales and tissue characteristics: OP reflects systemic bone metabolic abnormalities and decreased bone strength, whereas OA primarily manifests as local joint structural degeneration and dysfunction.

Despite their significant differences, traditional mechanisms are still insufficient to fully explain their frequent co-occurrence and mutual influence in the elderly population. In recent years, an increasing number of studies have suggested that inflammaging, immune imbalance, oxidative stress, mitochondrial dysfunction, and metabolic abnormalities may constitute an important pathological background for their common progression. Among these, inflammaging, as a key biological feature of aging, can provide a new perspective for understanding the pathological link between the two by affecting bone remodeling, cartilage homeostasis, and the local immune microenvironment.

The osteochondral unit, composed of articular cartilage, calcified cartilage, and subchondral bone, is an important structural basis for maintaining joint mechanical transmission and tissue homeostasis. Recent studies have found that bone and joint tissues are not independent pathological units but form a dynamic interaction network through cell communication, immune regulation, and changes in metabolic status. Therefore, bone loss and joint degeneration may not occur completely independently but influence each other against the background of common microenvironmental changes and cellular functional imbalances.

Immune metabolic reprogramming provides a new theoretical framework for understanding OP-OA comorbidity. The metabolic status of immune cells and osteochondral-related cells can affect their functional phenotypes and participate in bone remodeling, inflammatory regulation, and tissue repair processes. In recent years, alterations in glycolysis, oxidative phosphorylation, lipid metabolism, and NAD+-related metabolic regulation have been implicated in bone metabolic imbalance in OP and in cartilage and synovial pathology in OA, respectively. However, current evidence mainly comes from studies focusing on OP or OA in isolation, and there is still insufficient evidence to establish that these form a common causal regulatory network in human OP-OA comorbidity. Therefore, immune metabolic reprogramming is more suitable as a candidate integrative framework for explaining the links among inflammaging, bone metabolic abnormalities, and osteochondral unit imbalance, rather than an established comorbidity-driving mechanism.

Link: https://doi.org/10.3389/fimmu.2026.1941310

Smaller dog breeds live for longer than larger dog breeds, which perhaps allows some insight into mechanisms of aging. Researchers here find that age-related change in the epigenetic regulation of nuclear DNA structure and gene expression proceeds more rapidly in larger dogs, particularly in regions containing transposable elements. Transposable elements are the remnants of ancient viral infections, capable of copying themselves across the genome when active, a form of damage that can break gene sequences. The virus-like particles created by expression of transposable elements provoke inflammatory responses, and thus loss of transposable element suppression contributes the disruptive chronic inflammation of aging. This study adds to the existing body of evidence suggesting that transposable element activation resulting from epigenetic change provides a meaningful contribution to mammalian aging.

Comparative studies across species have identified mechanisms associated with exceptional longevity, but they are less well suited to identifying the molecular drivers of aging variation among individuals within a species. Domestic dogs provide a model for addressing this challenge because body size strongly predicts lifespan, with larger breeds living substantially shorter lives than smaller breeds despite sharing many physiological and environmental conditions.

We generated 1640 methylomes from 894 companion dogs enrolled in the Dog Aging Project and paired these data with detailed demographic and genetic information. Using these data, we developed highly accurate DNA methylation (DNAm) age predictors with a median average error of 0.82 years. We found that dogs with epigenetic ages older than expected exhibited elevated mortality risk, demonstrating that DNAm captures biologically meaningful variation in aging. Larger dogs, males, and younger individuals showed molecular profiles consistent with accelerated epigenetic aging.

Age-associated differential methylation was highly structured by genomic context. Promoters generally gained methylation with age, whereas introns and transposable elements (TEs) predominantly lost methylation with age. Sex differences in age effects were most pronounced on the X chromosome, whereas size-associated differences were greatest in TEs: larger dogs had 31% stronger age-associated TE demethylation than smaller dogs. This amplification was widespread across TE classes and evolutionary lineages, including long interspersed nuclear elements (LINEs), short interspersed nuclear elements, LINE2s, and DNA transposons, but was most pronounced in evolutionarily young LINE1s.

Link: https://doi.org/10.1126/science.aeb2986

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