Fight Aging!

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 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