Fight Aging!

Today's open access paper links a number of different areas of research and development of interest. Firstly, that senescent cells accumulate with age to disrupt tissue structure and function with their inflammatory secretions. Secondly, that the innate immune cells known as microglia become overly active and inflammatory in the aging brain, and a growing body of evidence supports a significant role for these inflammatory microglia in the development of neurodegenerative conditions. Some of these inflammatory microglia are senescent. Thirdly, the stem cell therapies pioneered over the last thirty years, and the more modern use of extracellular vesicles such as exosomes derived from stem cell cultures, appear to largely produce benefits via a sustained reduction in chronic inflammation in older individuals. The transplanted cells do not tend to survive in large numbers, and it is a short burst of signaling following transplantation that produces months-long changes in immune behavior via its effect on native cells.

Because stem cell transplants work via a brief period of signaling, they also tend to work when human cells are transplanted into animals. Here, researchers show that one source of human stem cells for transplantation has positive effects on cognitive function in old mice. Using cell culture experiments, the researchers demonstrate that the signaling generated by stem cells has a senomorphic effect on harmful senescent microglia, meaning that it dampens the worst aspects of the senescent state and thereby improves cognitive function by reducing the ongoing harm done to the function of the brain. We might expect that extracellular vesicles derived from the same source as the stem cells used in this study to produce similar outcomes. The results reported here are in line with other studies in which senescent cells are removed, or their signaling is reduced via other means; senescent cells clearly actively maintain dysfunction in tissues, and matters improve when their are restrained or removed.

Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Cognitive Decline by Restoring Senescent Microglial Function via NF-κB-SREBP1 Pathway Inhibition

Microglia, the resident immune cells of the central nervous system (CNS), play a critical role in maintaining neural homeostasis by monitoring the CNS microenvironment, remodeling and pruning synapses, and clearing cellular debris through phagocytosis. Recent studies have identified a distinct subpopulation of microglia termed lipid droplet-accumulating microglia (LDAM), which exhibit a unique phenotype characterized by metabolic reprogramming, elevated oxidative stress, and heightened pro-inflammatory responses. These alterations disrupt microglial homeostasis, impair their ability to clear amyloid-beta plaques and tau protein aggregates, and contribute to the progression of neurodegenerative diseases such as Alzheimer's disease (AD).

Lipid droplets (LDs) are lipid-rich organelles enveloped by a phospholipid monolayer, primarily composed of triglycerides and cholesterol esters. Under physiological conditions, the homeostasis of intracellular LDs is tightly regulated. However, under pathological conditions, this balance is disrupted, leading to lipid droplet accumulation and subsequent cellular dysfunction. Accumulating evidence shows that LD content in microglia and neurons increases with age. In microglia, LD enrichment is linked with a pro-inflammatory phenotype and exhibits reduced phagocytic capacity toward cellular debris and protein aggregates.

Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments showed that senescent microglia exacerbate neuronal senescence and neuroinflammation, while also suppressing the apoptosis of senescent neurons. These findings suggested that senescent microglia contribute to age-related cognitive decline by exacerbating neuronal damage and impairing senescent neurons' clearance. We showed that hUC-MSCs reduce senescence-associated markers, decrease lipid droplet accumulation, and restore phagocytic function in senescent microglia through the inhibition of the NF-κB-SREBP1 pathway. This pathway modulation attenuates neuronal damage and promotes the apoptosis of senescent neurons, facilitating the clearance of damaged neurons.

Immunoglobulin proteins are also known as antibodies, and can circulate freely or be bound to cell surfaces. They serve to tag specific structures for recognition and attack by the immune system, so a very broad range of variants on the basic structure are manufactured by plasma cells derived from B cells in response to the presence of immune-provoking antigens. These immunoglobulins then go on to shape the behavior of the immune system as a whole. Here, researchers take a tour of what is known of age-related changes in immunoglobulins, an area of study in which all too little is completely mapped or understood. To understand what is observed, one would have to also understand a great deal about what exactly the immune system is doing, and how those activities are affected with age. While the big picture is well understood, at the detail level the exploration of the intricate complexities of the aging immune system remains an ongoing process.

Aging is a complex biological phenomenon, which involved in a large number of diseases such as cancer, neurodegeneration, and cardiovascular diseases. Understanding the mechanism of aging may facilitate the development of preventive strategies of age-related diseases. Immunoglobulin (Ig) includes proteins with antibody (Ab) activity or membrane-bound proteins that share a chemically analogous structure to Ab. Ig can recognize and neutralize numerous antigens, which constitutes the main characteristic of adaptive immunity.

The quantity, glycosylation, and function of Ig change with advancing age. Some Ig is found to be accumulated in aged tissues and appear to be regarded as a potential marker for aging, which indicates the critical role of Ig in aging. B cells are main producers of antibodies and undergo aging-related changes, leading to increased autoimmune responses and reduced vaccine responses. The immune dysregulation of B cells is also intensively involved in the alteration of Ig.

In this review, we focus on the current research findings on Ig, discuss the relation between Ig and aging, highlight the complex interplay among B cell, gut microbiota, Ig, and aging, and explore potential therapeutic strategy. We hope this review may provide an insight for investigating the regulatory mechanism of Ig in aging, as well as for evaluating the therapeutic potential in treating age-related diseases.

Link: https://doi.org/10.3389/fimmu.2025.1690018

The hundreds of mitochondria present in every cell work to produce the chemical energy store molecule adenosine triphosphate (ATP), necessary for cell function. With age, some combination of damage to mitochondrial DNA and changes in the epigenetic control of gene expression act to degrade mitochondrial ATP production and otherwise ensure that mitochondria function progressively less effectively. This stresses cells and negatively affects tissue function. Here, researchers review what is known of mitochondrial loss of function in muscle tissue, leading to the characteristic loss of muscle mass and strength that occurs with aging and leads to sarcopenia.

Sarcopenia is a progressive age-related decline in skeletal muscle mass, strength, and function, representing a significant health burden in older adults. Diagnostic criteria have been established that integrate measures of muscle mass, strength, and physical performance. Mechanistically, sarcopenia is driven by hormonal changes, chronic inflammation, cellular senescence, and, importantly, mitochondrial dysfunction. Age-related declines in sex hormones and activation of myostatin impair muscle regeneration and metabolism, while chronic low-grade inflammation disrupts protein synthesis and accelerates proteolysis via the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP). The accumulation of senescent cells and their secretory phenotype further exacerbates muscle degeneration and functional decline.

Mitochondrial dysfunction plays a central role, characterized by impaired biogenesis, excessive reactive oxygen species (ROS) production, compromised autophagy/mitophagy, and accumulation of mitochondrial DNA (mtDNA) mutations. These defects collectively disrupt muscle energy homeostasis, promoting atrophy. The AMPK/SIRT1/PGC-1α and mTORC1 signaling pathways, along with PINK1/Parkin-mediated and receptor-dependent mitophagy, are essential for regulating mitochondrial biogenesis, protein synthesis, and mitochondrial quality control.

Current and emerging therapeutic approaches include resistance and endurance exercise, nutritional and pharmacological agents targeting mitochondrial health, and hormonal modulation. Innovative treatments such as senolytics, exerkines, and gene therapies show promise but require further validation. Future advances in mechanistic understanding, diagnostics, and therapeutic strategies offer hope for mitigating sarcopenia and improving the quality of life in aging populations.

Link: https://doi.org/10.3389/fcell.2025.1590524

While the biochemistry of the brain is segregated from the biochemistry of the rest of the body by the blood-brain barrier, a lining of specialized cells wrapping blood vessels that pass through the brain, large amounts of cerebrospinal fluid flow through the brain and exit into the body, carrying away metabolic waste. The major known pathways include (a) channels in the bone of the cribriform plate that drain the olfactory bulb region of the brain, and (b) the glymphatic system that is made up of fluid filled channels that parallel blood vessels where they enter and exit the brain. Both of these pathways decline in efficiency with age: the cribriform plate channels ossify and close, while the glymphatic system loses its ability to drive fluid flow by pulsation. Researchers hypothesize that impaired drainage of cerebrospinal fluid contributes to neurodegeneration by causing a harmful buildup of metabolic waste in the brain.

The ability to measure flow of cerebrospinal fluid through the glymphatic system is a fairly recent innovation, indeed the structure and function of the glymphatic system itself is a relatively recent discovery. Now, however, researchers can use features of magnetic resonance imaging (MRI) in some portions of the glymphatic system to create a measure of the fluid flow exiting the brain. This works because MRI can measure the scatter of water molecules, and if that scatter is heavily biased in one direction, that can be taken as a flow - a technique given the unwieldy name of diffusion tensor image analysis along the perivascular space (DTI-ALPS). All that is needed is a good straight stretch of glymphatic vessel, and there is a location in human physiology that suffices for this purpose. Thus the research community can produce studies such as the one noted here, in which reduced cerebrospinal fluid drainage through the glymphatic system is correlated to dementia risk.

MRI markers of cerebrospinal fluid dynamics predict dementia and mediate the impact of cardiovascular risk

Impaired cerebrospinal fluid (CSF) dynamics may contribute to dementia, but human evidence is limited. Recently, a number of magnetic resonance imaging (MRI)-based proxies have been proposed allowing different aspects of CSF dynamics to be non-invasively studied in humans. These include perivascular space (PVS) volume, diffusion tensor image analysis along the PVS (DTI-ALPS), blood oxygen level-dependent CSF (BOLD-CSF) coupling, and choroid plexus volume. Using the UK Biobank, we measured CSF dynamics: PVS volume, DTI-ALPS), BOLD-CSF coupling, and choroid plexus volume. We assessed cardiovascular risk factors and their associations with CSF dynamics and dementia based on general practitioner, mortality, and hospital records. Mediation analysis evaluated CSF dysfunction in cardiovascular risk-dementia relationships.

Lower DTI-ALPS, lower BOLD-CSF coupling, and higher choroid plexus volume predicted dementia, but PVS volume did not. DTI-ALPS and choroid plexus volume mediated the effect of white matter hyperintensities and diabetes duration on dementia. In conclusion, we demonstrated three MRI proxies of CSF dynamics markers predict future dementia risk. Strategies to improve CSF dynamics may reduce dementia risk, although this needs testing in intervention studies.

Researchers here propose a novel form of damage and dysfunction contributing to the development of age-related hearing loss. Much of the focus of past years of research has been placed upon loss of connectivity between sensory hair cells of the inner ear and the brain, or outright loss of hair cells themselves. But there are other components of the overall problem of loss of function, as noted here, and the question of what to do about it doesn't always have as straightforward a path towards practical therapies as exists for loss of cells.

Age-related hearing loss is common among older adults and can result from several problems in the inner ear. The disorder is usually classified into three types: (a) Neural: due to damage to auditory nerve fibres, (b) Sensory: caused by the loss of the sensory cells that detect sound, and (b) Metabolic: involving degeneration of the cells in the cochlea's wall that help maintain the ear's internal environment.

In the metabolic type, often considered the most common one, the positive electrical potential normally found close to the sensory cells is much reduced - and without this positive potential, sensory cells cannot function normally. However, the possibility that degeneration in the cochlea's wall could affect the hearing organ in other ways has not been considered.

We used a physiologically based animal model to investigate what happens when cells in the cochlea's wall stop working. Using advanced imaging techniques, we discovered that calcium levels near the sensory cells dropped. This is an important observation because calcium is a key regulator of sensory cell function. We also found that the tectorial membrane - which helps transmit sound-evoked vibration to the sensory cells - often detached from the sensory cells. This detachment made it nearly impossible for sound to reach the sensory cells. To confirm that these findings are relevant for the human disorder, we examined samples from people with metabolic age-related hearing loss. We saw the same tectorial membrane detachment, and the extent of detachment predicted the severity of hearing loss.

Link: https://doi.org/10.1016/j.ebiom.2025.105976

Synucleinopathies such as Parkinson's disease are caused by the spread of misfolded α-synuclein through the brain. α-synuclein is one of a small number of proteins that, when misfolded, can encourage other molecules of the same protein to misfold in the same way, aggregating to form toxic solid deposits and a halo of disrupted biochemistry. Misfolded α-synuclein is particularly pernicious as it can pass from cell to cell, spreading pathology as it goes. Here, researchers explore one of the ways in which misfolded α-synuclein harms cells, by interfering in the supply of the energy store molecule adenosine triphosphate (ATP) that is produced by mitochondria and is essential to cell function.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and the most frequent movement disorder today, for which there is only symptomatic treatment. Amyloid fibers of the protein α-synuclein (αSyn) constitute the major content of pathological intraneuronal inclusions, Lewy bodies, found in dopaminergic neurons in PD patient brains. Amyloid toxicity has been attributed to the ability to seed new amyloids, to translocate between cells, to deteriorate membranes, to be a sink for functionally relevant proteins by binding, and to sterically block cellular functions. Amyloids were considered chemically inert until we showed that αSyn amyloids catalyzed hydrolysis of ester and phosphoester bonds in vitro.

Lewy pathology, i.e., amyloids, is also found in the nuclei of cells, and our earlier work showed αSyn monomers to interact with DNA. When we extended this to amyloids, we found that αSyn amyloid interactions with DNA promote strand breaks in the DNA. Thus, the chemical reactivity of αSyn amyloids may contribute to the noted widespread DNA damage observed in PD patients.

Neurons have disproportionately high energy demands compared to other organs but lack energy fuel storage (such as fatty acids and glucogen). In contrast to many other cells, neurons must continuously produce ATP from glucose to meet the cellular demands and maintain energy homeostasis. Decline in brain ATP levels has been connected to both Alzheimer's and PD. There is evidence that αSyn amyloids perturb mitochondria, resulting in lower ATP production.

Here, we combine biochemical, biophysical, computational, and structural methods to probe the interaction between αSyn amyloids and ATP. We report that αSyn amyloids display catalytic activity toward ATP hydrolysis in vitro. We propose that ATP depletion by αSyn amyloid hydrolysis may disturb the local energy balance in neuronal cells.

Link: https://doi.org/10.1002/advs.202508441

The Dog Aging Project has in recent years enrolled thousands of companion animals into multiple cohorts and studies, including a study of the effects of rapamyin as a treatment to slow aging in dogs. Much of the value of the Dog Aging Project taken as a whole lies in the generation of a large database of omics data that can then be mined for insights into aging in this species, some fraction of which will be applicable more generally to aging in other mammals - such as our own species.

In today's open access paper, researchers present their findings from an analysis of metabolomic data derived from the Dog Aging Project's smaller Precision Cohort, 784 dogs for whom more extensive biological data was gathered. Aging modifies circulating levels of a sizable fraction of the 133 metabolites measured in blood plasma from this cohort, which could be used as the basis for an aging clock, or inspected more closely for single measures that serve as biomarkers of aging.

The data points to increased levels of various acetylated amino acids as biomarkers of aging, the acetylated forms of phenylalanine, tryptophan, alanine, and glutamine that are produced when acetylated proteins are broken down. Changes in levels of these modified amino acids correlate with declining kidney function. It will be interesting to see whether human data exhibits a similar pattern; there is a fair amount of literature on the connection between protein acetylation and aging, similarly for protein acetylation and cellular senescence, and for other related topics.

Protein Catabolites as Blood-Based Biomarkers of Aging Physiology: Findings From the Dog Aging Project

Our understanding of aging has grown through the study of systems biology, including single-cell analysis, proteomics, and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) aims to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs.

Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP, 784 animals. By incorporating extensive metadata and whole genome sequencing, we overcome the limitations inherent in breed-based estimates of genetic effects, and probe the physiological basis of the age-related metabolome. We identified effects of age on approximately 36% of the 133 measured metabolites. We also discovered a novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which are generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. The only known source of free ptmAAs is the breakdown of protein, and we found additional evidence for protein catabolism within the metabolome. We found that clinical measures of kidney function at least partially mediate the age associations of the ptmAAs. These results suggest that ptmAAs accumulate with age among dogs and may serve as a biomarker of aging physiology.

This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

The practice of calorie restriction is well established to slow aging, albeit to a lesser degree in long-lived species than in short-lived species. Calorie restriction memetics are compounds that trigger some of the same beneficial mechanisms involved in the response to reduced calorie intake. They do not capture the full effect, but the best of them (such as rapamycin) are nonetheless still beneficial enough to command attention from the research community.

Like rapamycin, the calorie restriction mimetic spermadine has been shown to upregulate the operation of autophagy, an effect presently thought to be the most important aspect of the response to calorie restriction. Long-term treatment with spermadine modestly extends life in mice, to a lesser degree than rapamyin (~10% versus ~25%). Here, researchers focus on clinical trials that measured spermadine levels or treated with spermadine and observed the outcome on cognitive function; the data is mixed, but also not all that consistent, a common issue in the field.

Increasing evidence suggests that caloric restriction (CR) and intermittent fasting may elevate endogenous levels of spermidine (SPD), a polyamine compound now being investigated as a natural caloric restriction mimetic (CRM) candidate. Beyond its endogenous role in cellular metabolism, SPD can be obtained from dietary intake and synthesised by commensal gut microbiota. SPD is involved in several critical biological processes, including cell growth, differentiation, and autophagy, a fundamental mechanism for cellular maintenance and repair. Recognised as a natural inducer of autophagy, SPD is considered an antiageing compound with properties resembling those of CR, positioning it as a potential CRM.

This article provides a comprehensive synthesis of current evidence on the impact of SPD on cognitive ageing, drawing from both observational and interventional studies. A systematic search of major electronic databases identified 22 relevant studies, comprising 4 interventional trials and 18 observational studies. Observational evidence suggests a potential association between SPD levels and cognitive function, with indications of a protective effect against cognitive decline. However, the variability in results, driven by inconsistencies in SPD measurement methods (eg, brain tissue, blood serum/plasma, red blood cells, or dietary intake), poses challenges to drawing definitive conclusions.

Interventional studies offer preliminary evidence suggesting that SPD supplementation may serve as a potential strategy to mitigate age-related cognitive decline. Some studies have indicated positive cognitive effects of SPD supplementation on cognitive function, such as improvements in memory performance and cognitive assessments. However, inconsistencies remain. The observed differences may be potentially due to variations in SPD dosage, the sensitivity of cognitive assessment tools, and other methodological differences.

Link: https://doi.org/10.1136/gpsych-2024-101723

Any sufficiently large body of biological data taken from individuals at varying ages can be used to produce an aging clock via machine learning techniques. The clock provides a measure that should reflect biological age, the burden of cell and tissue damage and consequent risk of dysfunction, but that isn't a given and must be assessed for any new clock. Researchers have been creating new clocks from varied types of data at a fairly rapid pace for some years now. Here, researchers use data on blood flow obtained from consumer devices worn on the wrist. Photoplethysmography is the formal name for the use of devices that illuminate the skin and measure changes in light absorption in order to assess parameters of blood flow, and the growing popularity and low cost of these devices have given rise to large databases suitable for the development of aging clocks.

Aging biomarkers play a vital role in understanding longevity, with the potential to improve clinical decisions and interventions. Existing aging clocks typically use blood, vitals, or imaging collected in a clinical setting. Wearables, in contrast, can make frequent and inexpensive measurements throughout daily living. Here we develop PpgAge, an aging clock using photoplethysmography at the wrist from a consumer wearable.

Using the Apple Heart and Movement Study (n = 213,593 participants; >149 million participant-days), our observational analysis shows that this non-invasive and passively collected aging clock accurately predicts chronological age and captures signs of healthy aging. Participants with an elevated PpgAge gap (i.e., predicted age greater than chronological age) have significantly higher diagnosis rates of heart disease, heart failure, and diabetes. Elevated PpgAge gap is also a significant predictor of incident heart disease events (and new diagnoses) when controlling for relevant risk factors. PpgAge also associates with behavior, including smoking, exercise, and sleep. Longitudinally, PpgAge exhibits a sharp increase during pregnancy and concurrent with certain types of cardiac events.

Link: https://doi.org/10.1038/s41467-025-64275-4

The Yamanaka transcription factors can be used to recreate the transformation of cell type that occurs in early embryonic development, inducing a process of reprogramming that can transform any somatic cell into an induced pluripotent stem cell. Initially, this discovery was applied to the development of cell therapies and tissue engineering, a way to produce cells of a specific type matched to the recipient, or to generate cell banks able to reliably supply cells of specific types, or to chase the grail of universal cell lines that can be used in any patient. After nearly twenty years of development, some of the first therapies to transplant cells derived from induced pluripotent stem cells have reached clinical trials - progress in the highly regulated field of medicine is slow at best.

Separately, researchers have discovered that reprogramming doesn't just change cell type, it also rejuvenates a cell by restoring youthful epigenetic control over gene expression. That in turn restores youthful mitochondrial function and numerous other aspects of cell behavior and performance. It cannot repair DNA damage, and cannot enable cells to break down molecular waste that even youthful cells struggle to handle. Nonetheless, there is a great deal of interest in finding ways to use this phenomenon as a basis for therapy. What is known as partial reprogramming involves exposing cells to the Yamanaka factors for long enough to produce this desirable outcome of epigenetic rejuvenation, but not long enough to turn cells into induced pluripotent stem cells. Cells retain their state, with improved function.

Today's open access review provides a good introduction to the science behind the promise and the challenges of partial reprogramming as a basis for therapy. Positive results have been produced in animal studies, but sizable hurdles are involved in trying to reprogram large portions of the body rather than employing a very narrow, restricted use in isolated tissues such as the retina. Different cell types in different tissues have different requirements and restrictions for partial reprogramming. What is good for lung cells is bad for liver cells. What is good for one type of cell in the liver is bad for its neighbor. "Bad" in this context means cell death, tissue dysfunction, and cancer. There is no good solution at this time that would lead to a simple partial reprogramming therapy that affects the whole body without either (a) watering it down to produce negligible benefits, or (b) causing severe issues in some tissues.

Organ-Specific Dedifferentiation and Epigenetic Remodeling in In Vivo Reprogramming

The advent of in vivo reprogramming through transient expression of the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC, abbreviated OSKM) holds strong promise for regenerative medicine, despite ongoing concerns about safety and clinical applicability. This review synthesizes recent advances in in vivo reprogramming, focusing on its potential to restore regenerative competence and promote rejuvenation across diverse tissues, including the retina, skeletal muscle, heart, liver, brain, and intestine.

In physiologically aged mice, long-term cyclic induction of OSKM restores youthful multi-omics signatures - including DNA methylation, transcriptomic, and lipidomic profiles - across multiple organs such as the spleen, liver, skin, kidney, lung, and skeletal muscle. Importantly, this regimen also promotes functional regeneration: while short-term reprogramming enhances muscle repair through local niche control, sustained cyclic reprogramming improves wound healing and reduces fibrosis in both muscle and skin. Consistent with these findings, even a single 1-week cycle of OSKM in aged mice (55 weeks old) elicits systemic rejuvenation, evidenced by DNA methylation reprogramming across the pancreas, liver, spleen, and blood.

Nevertheless, significant challenges to its application remain, including tumor formation, intestinal and liver failure, and loss of cellular identity. Achieving precise spatiotemporal control over reprogramming will be essential to minimize these risks while preserving therapeutic benefits. Future efforts should prioritize refining delivery methods and exploring safer alternatives such as small molecules or modified gene sets.

Interest in this field is rapidly growing within the biotech sector, summarized in recent reviews which provide detailed accounts of company pipelines and translational strategies. In this review, we instead focus on mechanistic insights into injury-induced and OSKM-induced reprogramming, offering a framework for understanding how regenerative competence can be harnessed across tissues. With careful modulation, OSKM-based approaches hold strong potential to transform regenerative medicine and the treatment of age-related diseases.

Despite considerable effort, and the development of vast databases of genetic information, very few associations between specific genetic variants and longevity replicate across study populations, and the effect sizes are near all small. Based on the evidence to date, we should expect the genetic contribution to longevity to be small for most people, and across a population to be made up of tiny, conditional effects from thousands of gene variants. In this landscape, any new longevity-associated variant that occurs in multiple study populations is an unusual discovery worthy of note, even if the effect size is modest and it acts to reduce the odds of survival in later life.

Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Subsequently, significant associations were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank.

Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity. In Germans, HLA-DRB1*15:01:01 was less frequent among male cases (10%) than controls (15%), whilst female cases exhibited no substantial decrease (14%), suggesting that men carrying this allele have a lower chance of becoming long-lived. This finding was replicated in the UK Biobank and found to be consistent in the Danish cohort. Computational predictions further revealed that HLA-DRB1*15:01 is more likely to trigger an immune response against an apolipoprotein B-100 (APOB-100) epitope than other HLA-DRB1 alleles. Furthermore, the overall predicted APOB-100 immunogenicity of all HLA-DRB1 alleles was significantly associated with longevity.

In conclusion, the novel male-specific association between HLA-DRB1*15:01 and longevity has been observed in three independent cohorts. The anti-longevity effect of this association is perhaps a consequence of an increase in Alzheimer's disease (AD)-related mortality in men carrying this allele.

Link: https://doi.org/10.1186/s13073-025-01554-1

Why does intelligence correlate with life expectancy? This is one component of a web of correlations involving longevity, intelligence, socioeconomic status, and education, among others. While it seems likely that greater intelligence enables better access to and use of medical technology and maintenance of health, a range of evidence suggests that there is a biological component to this relationship, in that more intelligent individuals also tend to be more physically robust. Here, researchers compare data on correlations between genetic variations, measures of intelligence, and measures of mortality risk to estimate the degree to which genetic variation may explain correlations between intelligence and longevity. The result are supportive of some degree of shared genetic causation.

The goal of the research field of cognitive epidemiology is to describe and explain phenotypic associations between cognitive function tested in youth (which largely avoids reverse causation) and later-life health and death. Analyses of long-term follow-up data from large cohorts sourced from the UK, Denmark, Israel, and Sweden show that higher scores on cognitive function tests in youth (childhood, adolescence, or young adulthood) are associated with lower risk of mortality from all causes by mid to late adulthood.

What causes this association? The cognition-longevity relationship was not confounded by childhood socioeconomic position, was present across a range of cognitive ability, and was present in both men and women. Might part of the cognition-longevity association be caused by genetic differences? Large genome-wide association studies (GWASs) have been conducted to examine the molecular genetic etiology of people's differences in cognitive function test scores. There are also GWASs on longevity. These GWAS data enable a comparison between traits; that is, one may compare the loci that attain genome-wide statistical significance in cognition with those that are genome-wide significant in longevity.

To date, we are not aware of any genetic correlation having been reported between cognitive function tested in childhood and longevity. In order to address this lacuna in cognitive epidemiology, we use data from two GWASs to estimate the genetic correlation between cognitive function assessed in childhood and longevity (combined mothers' and fathers' attained age). Using study data on childhood cognitive function (n = 12,441) and on parental longevity (n = 389,166) we found a positive genetic correlation of r = 0.35 between childhood cognitive function and parental longevity. These results add to the weight of evidence that the phenotypic link between childhood cognitive function and longevity is partly accounted for by shared genetic etiology.

Link: https://doi.org/10.61373/gp025l.0098

The low (and still falling) cost of modern omics technologies ensure that databases of genetic information are expanding at a fast pace. Researchers who study aging have amassed a wealth of information on the biochemistry of people at various ages, but considerable focus has been placed on the genetics of extremely old individuals. The hope has always been to identify particular genes or protein interactions or other aspects of cellular biochemistry that are meaningfully protective, and thus could serve as a starting point for the development of therapies that will slow aging.

Unfortunately what has emerged from this research is (a) the likelihood that previous estimates of the contribution of genetic variants to life expectancy were too high, (b) that very few gene variants show even modest correlations with life span in multiple study populations, and (c) that the landscape of the genetics of longevity is likely one in which thousands of gene variants provide individually tiny, conditional effects that vary from individual to individual. This is not to say that surprises do not exist, see the sizable effect of the very rare PAI-1 loss of function mutation for example, but these surprises are not relevant to the overwhelming majority of people.

Today's open access paper fits squarely into this new view of the genetics of longevity, while focusing specifically on risk of Alzheimer's disease and its association with genetic variants other than the well-known APOE gene. Like all such studies, many associations are found when analyzing prevalence of gene variants in very old people. But few were found elsewhere, and few will be replicated in other studies. Further, correlations between the presence of variants and Alzheimer's disease risk appear modest at best. So: small effect sizes, nothing that could be the basis for therapies, and more reinforcement of the view of genetics noted above.

Increased genetic protection against Alzheimer's disease in centenarians

While the effect of the apolipoprotein E (APOE) gene on Alzheimer's disease (AD) is well-characterized, the search for additional reliable genetic factors for AD has been ongoing. A recent genome-wide association study (GWAS) analysis identified a total of 83 genetic variants associated with AD using 111,326 clinically diagnosed/"proxy" AD cases and 677,663 controls of White/European ancestry. In this list of genetic variants, 44 were novel loci at the time of publication. Given that individual single-nucleotide polymorphisms (SNPs) typically have a limited impact on disease risk, polygenic risk scores that aggregate the effect of multiple genetic loci have been developed for various human diseases and phenotypes.

We constructed a polygenic protective score specific to Alzheimer's disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the USA, Europe, and Asia. This AD PPS did not include variants on apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality.

Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.

The state of cellular senescence is normally irreversible; a senescent cell ceases replication and generates pro-inflammatory signaling to attract the attention of the immune system. That the immune system becomes less efficient in clearing senescent cells is one of the reasons why a growing burden of senescent cells exists in later life, their signaling producing chronic inflammation, damage, and dysfunction. Researchers have found a number of ways to reverse the normally irreversible senescent state by adjusting levels of regulatory molecules, but the question of whether this is a good basis for therapy remains. Some senescent cells are senescent for good reasons, such as potentially cancerous DNA damage. It remains to be seen as to whether the positive can outweigh the negative for reversal of senescence as a way to alleviate the harms done by the senescent cell population in old individuals.

Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we established lncRNA PURPL as a key regulator of cellular senescence, bridging the connection between epigenetic modifications and the transcriptional regulation of senescence-associated genes.

Our findings demonstrate that PURPL is significantly upregulated in both replicative senescence and doxorubicin-induced senescence models. Manipulation of PURPL profoundly impacts the senescence phenotype. These findings extend and are consistent with previous studies on ageing regulators such as EGR1, SERPINE1, and other lncRNAs, and provide novel mechanistic insights into how PURPL regulates ageing through epigenetic remodelling, highlighting its significant theoretical and clinical implications.

Although several studies have reported a strong correlation between increased PURPL expression and senescence at both the cellular and tissue levels, few have demonstrated causality. Recently, RNA interference was used to knock down PURPL expression in senescent cells, resulting in some morphological improvements. However, no changes in molecular markers such as p21 were observed. In this study, we employed a more persistent method of lentivirus-mediated CRISPR/Cas9 interference to knock down PURPL. Not only did we observe significant morphological changes, but we also detected decreased levels of CDKN1A/p21 (a tumour suppressor protein) at both the RNA and protein levels. Furthermore, we overexpressed PURPL in young cells to mimic the increased PURPL levels observed during cellular senescence. This overexpression accelerated cellular senescence, as evidenced by increased SA-β-gal activity, elevated p21 levels, and reduced LMNB1 levels. This study provides the first definitive evidence that PURPL acts as a driver of senescence.

Link: https://doi.org/10.1186/s12967-025-07208-5

The growth in the number of longevity clinics over the past few years might be viewed as analogous to the establishment of stem cell clinics twenty years ago. It is an attempt (in most cases a responsible attempt) to deliver interventions to patients without going through the very slow, very expensive processes of medical regulation. Absent these clinics, treatments would remain largely unavailable, as the cost of regulatory compliance serves to dramatically slow progress. On the one hand, this is a good thing if it leads to greater choice for patients, while on the other hand this seems likely to follow exactly the same track as the medical tourism industry for stem cell therapies - meaning that little to no robust data on patient outcomes will result, clinics will pad their offerings with useless, low value interventions, and the potentially useful therapies will prove to be highly varied in efficacy from clinic to clinic and patient to patient.

The idea of slowing, or even reversing, human aging has long occupied both science and imagination. While basic research over the past two decades has revealed hallmarks of aging and pointed toward possible interventions, the translation of these insights into accessible healthcare solutions remains in its infancy. Against this backdrop, longevity clinics, sometimes named age-management practices, personalized health centers, or wellness-longevity hybrids, have rapidly emerged across the globe. From USA to Switzerland, Singapore to Dubai, these clinics market comprehensive programs promising to monitor, manage, and mitigate biological aging

At their core, longevity clinics claim to combine cutting-edge diagnostics with personalized interventions aimed at extending healthspan. A typical client may undergo genomic sequencing, multi-omics profiling, advanced imaging, full body scans, immune system assessments, microbiome analyses, and epigenetic testing. The results are then used to design individualized regimens that can include exercise prescriptions, nutritional guidance, nutraceuticals, sleep optimization, stress-management strategies, hormone replacement, or more experimental therapies such as stem-cell infusions, injection of peptides, plasma exchange, and others. This approach gives a good example of what the medicine of the future should be: proactive, preventive, and fully personalized. However, some see it as a costly experiment bordering on pseudoscience.

The major issue is that longevity clinics not yet embedded within mainstream medical practice. They illustrate well both the enormous opportunities but also the very high risks inherent in translating geroscience into society. Understanding their potential, their limitations, and the conditions under which they might mature into credible engines of progress is crucial if we want the longevity movement to benefit populations.

Link: https://doi.org/10.18632/aging.206330

A number of lines of research indicate that fat tissue becomes actively harmful to other tissues with advancing age via forms of signaling. Much of this work is focused on the role of excess visceral fat tissue in long-term health. Visceral fat acts to increase the burden of senescent cells, which then promote inflammation throughout the body via inflammatory signaling, but fat cells can also act to directly generate pro-inflammatory signaling in other ways, such as via mimicking the signaling generated by infected cells. These are not the only mechanisms, and nor do fat cells act in isolation to cause issues in the aging body.

Researchers here produce evidence to show that fat cells mediate a problematic relationship between the gut microbiome and various the age-related cardiometabolic diseases with a strong inflammatory component, such as type 2 diabetes and atherosclerosis. With age, changes in the composition of the gut microbiome ensure that bacteria in the gut increasingly generate trimethylamine. Meanwhile other aspects of aging ensure that fat cells throughout the body increasingly express FMO3, converting that trimethylamine into trimethylamine-N-oxide (TMAO). TMAO is well established to promote inflammation, at this point a fairly well studied contribution to the inflammation of aging.

Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing

White adipose tissue (WAT) acts as an endocrine organ to maintain systemic energy and glucose homeostasis. Transcriptomic and proteomic analyses indicate that WAT is the first tissue showing functional decline in ageing. WAT is composed of diverse cell populations, including mature white adipocytes that produce bioactive adipokines to communicate and coordinate with the neighboring cells and distal metabolic tissues in control of systemic metabolism under varying nutritional and environmental conditions. Ageing alters composition and functionality as well as the interaction of the adipocytes and the WAT-resident cells.

Gut microbiota control host metabolism by generating an array of metabolites targeting to multiple metabolic tissues. Flavin-containing monooxygenase 3 (FMO3), a xenobiotic metabolizing enzyme primarily expressed in the liver, converts gut microbiota-produced trimethylamine (TMA) from its nutrient precursors (such as choline, L-carnitine, and betaine) into trimethylamine-N-oxide (TMAO) via hepatic FMO3. Early human and animal studies showed the important role of this microbiota-host axis in cardiometabolic health. In rodent models, knockdown of hepatic FMO3 using anti-sense oligonucleotides or global deletion of FMO3 improves hepatic insulin resistance, hyperlipidemia, obesity and atherosclerosis. Dietary treatment with TMAO promotes inflammation in visceral WAT (vWAT) by upregulating the expression of pro-inflammatory cytokines.

Although the liver is considered the main site for TMAO production via FMO3, we here demonstrate that adipocyte FMO3 is the contributor to the elevated TMAO level in ageing. We found that FMO3 and TMAO are abundantly expressed in mature adipocytes of WAT, and their levels are induced in humans and rodents with ageing via a p53-dependent pathway. Adipocyte-specific deletion of FMO3 protects against ageing- or obesity-induced functional decline of WAT, accompanied by improvement of glucose, lipid homeostasis and energy balance in mouse models. Adipocyte FMO3-derived TMAO acts as an autocrine and paracrine factor to trigger inflammasome activation and subsequent IL-1β production in mature adipocytes and adipose tissue-resident macrophages. Our proteomics analysis identifies numerous TMAO-binding proteins that participate in inflammatory pathways, particularly inflammasome activation. In summary, our study uncovers how aged adipocytes convert gut microbiota-derived metabolite to elicit adipose tissue dysfunction and systemic dysmetabolism in ageing.

The more visceral fat that is present in the body, the greater the burden of atherosclerotic plaque narrowing and weakening major blood vessels. This isn't just for those people who are very overweight, but the data shows that any degree of excess visceral fat correlates with a relative degree of acceleration of atherosclerosis: the more fat the worse the outcome. Visceral fat also contributes to other age-related conditions, with the most likely link being promotion of chronic inflammation via a number of different mechanisms. Visceral fat tissue promotes a greater burden of cellular senescence, fat cells produce signaling that mimics infected cells, and so forth.

Visceral fat (VAT), a type of fat stored in the abdomen, and buildup of fat within the liver are known to increase type 2 diabetes, high blood pressure, and heart disease risk. This study aims to see how these types of fat affect artery health. Participants in the Canadian Alliance of Healthy Hearts and Minds (CAHHM) cohort study (n = 6760; average age = 57.1; 54.9% female) underwent MRI for VAT volume, hepatic fat fraction (HFF), and carotid atherosclerosis assessed by carotid wall volume (CWV). Regression models were used to assess the associations of VAT and HF with carotid atherosclerosis, separately in males and females, controlling for other cardiovascular risk factors. Associations of VAT and proton-density hepatic fat fraction (PDFF) with ultrasound-measured carotid-intima media thickness (CIMT) were also assessed in the UK Biobank (UKB; n = 26,547; average age = 54.7; 51.9% female).

In CAHHM, we show that a 1 standard deviation higher VAT volume is associated with a 6.16 mm^3 higher CWV, but there is no association between HFF and CWV. In the UK Biobank cohort, a 1 standard deviation higher VAT volume is associated with a 0.016 ± 0.009 mm higher CIMT, and a 1 standard deviation higher PDFF is associated with a 0.012 ± 0.010 mm higher CIMT. After adjustment for CV risk factors, these associations are attenuated. A pooled analyses of CAHHM and UKB support a direct, positive association of VAT and HFF with subclinical atherosclerosis in both sexes, albeit slightly weaker for hepatic fat. Thus visceral fat, and to a lesser extent, hepatic fat, are associated with increased carotid atherosclerosis.

Link: https://doi.org/10.1038/s43856-025-01123-y

Researchers here report on potential targets to enhance the regenerative capacity of alveolar type 2 cells, a population necessary for regeneration in lung tissue, but which falters in this duty in the context of progressive and age-related lung disease. Compensating for poorly understood mechanisms of damage and disease that direct alveolar type 2 cells away from regenerative activity can in principle be achieved by overriding the regulatory system that controls this aspect of cell behavior, provided enough is understood of how that regulatory system works. This approach to therapy doesn't fix the underlying issues, but may well prove to be beneficial enough to pursue. There are numerous examples in the present practice of medicine of compensatory approaches that succeed in producing benefits for patients.

When a person's lungs are damaged, that organ's survival depends on a small but powerful set of cells that must choose whether to repair the tissue or fight infection. "We were surprised to find that these specialized cells cannot do both jobs at once. Some commit to rebuilding, while others focus on defense. That division of labor is essential - and by uncovering the switch that controls it, we can start thinking about how to restore balance when it breaks down in disease."

The new research centers on alveolar type 2 (AT2) cells, which play a dual role in the lung. These cube-shaped cells secrete surfactant proteins that keep air sacs open, but they also act as reserve stem cells capable of regenerating alveolar type 1 (AT1) cells - the paper-thin cells that form the surface for gas exchange. This regenerative capacity makes AT2 cells essential for lung repair after injury. For decades, scientists have known that these cells often fail to regenerate properly in lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and severe viral infections like COVID-19. What remained unclear was how AT2 cells lose their stem cell capacity.

Using single-cell sequencing, imaging and preclinical injury models, the team mapped the developmental "life history" of AT2 cells. They found that newly formed AT2 cells stay flexible for about one to two weeks after birth before "locking in" to their specialized identity. That timing is controlled by a molecular circuit involving three key regulators called PRC2, C/EBPα, and DLK1. The researchers showed that one of them, C/EBPα, acts like a clamp that suppresses stem cell activity. In adult lungs, AT2 cells must release this clamp after injury to regenerate. The discoveries could guide the development of therapies to fix AT2 cells that are broken in disease. Drugs that target C/EBPα, for example, may restore repair programs or reduce scarring in pulmonary fibrosis.

Link: https://newsnetwork.mayoclinic.org/discussion/new-discovery-may-unlock-regenerative-therapies-for-lung-disease/

A gene coding for a protein consists of multiple exon and intron sequences of DNA. During gene expression, the full DNA sequence of exons and introns is first transcribed into a RNA sequence, the primary transcript. That primary transcript undergoes a series of alterations that include RNA splicing. This splicing process removes the introns and stitches together the remaining exons to form a messenger RNA molecule. That messenger RNA is then used as a template by a ribosome manufacture many copies of the protein that it encodes.

Interestingly, many genes can undergo alternative splicing to produce several different messenger RNAs and proteins. A specific intron is not always excluded, a specific exon is not always retained. In some cases this is normal and expected, in other cases it has the look of an error that produces toxic proteins. The landscape of alternative splicing across all of the proteins encoded in the genome shifts with age, altering the balance of proteins produced via gene expression. Some research groups consider this to be a component of degenerative aging and a potential target for therapies to slow aging.

Species life span and the aging of individuals are related but may be driven by distinct mechanisms. Learning more about the determinants of species life span may or may not yield insights that are relevant to making individuals of any given species life longer. Differences in the regulation of alternative splicing may be important in determining species life span, but the research community is still at the early stages of gathering data to shed more light on this question. Today's open access paper is an example of this sort of exploration.

The Implications of Alternative Splicing Regulation for Maximum Lifespan

Alternative splicing (AS) is a post-transcriptional or co-transcriptional regulatory mechanism by which a single gene generates multiple distinct mature transcript isoforms, leading to protein diversity in higher eukaryotes. Up to 95% of multi-exon human genes undergo AS, often exhibiting tissue- or cell-type dependent regulation and dynamically controlled in distinct cellular processes. The association between AS and the intertwined realms of aging and longevity remains unclear. Age-associated splicing changes have been reported in different experimental systems, albeit in a piecemeal fashion, and alterations in certain splicing factor expressions in the spleen have been linked to differences in lifespan. These initial findings hint that splicing regulation might impact lifespan, but a comprehensive comparative analysis of maximum lifespan (MLS) as a species trait across species with widely varying maximum lifespans has not yet been conducted.

In this study, we systematically investigated MLS-associated AS events across multiple mammalian species spanning a broad range of maximum lifespans to uncover potential links between splicing and lifespan regulation. Our results suggest alternative splicing as an important factor correlated with both the evolved differences in mammalian lifespan and the human aging, and show potential molecular mechanisms (e.g., RNA processing, neural regulation, intrinsically disordered proteins, RNA-binding protein regulators) underlying these effects. Remarkably, nearly half of the highly conserved alternative splicing events show a significant association with maximum lifespan in at least one tissue. While many of these splicing associations are consistent across different tissues, the effects in the brain stand out as particularly distinct. Although the precise functions of many of these brain-specific events are unclear, previous studies have suggested a critical role for AS in regulating neuronal longevity and animal survival.

These findings suggest alternative splicing as a distinct, transcription-independent axis of lifespan regulation, offering new insights into the molecular basis of longevity.

A range of research suggests that an increase in the circulating levels of BDNF is beneficial to the function of the brain (and likely muscle tissue as well). This is one of the ways in which alterations to the diet and gut microbiome composition can affect the brain, as microbial production of butyrate via fermentation of dietary fiber acts to increase BDNF expression. The research community has an interest in finding other ways to increase BDNF levels more directly, and that is a work in progress. Meanwhile, researchers continue to produce evidence to support that goal, such as the data noted here.

Brain Derived Neurotrophic Factor (BDNF) plays a crucial role in supporting neuronal survival, promoting neurogenesis, and enhancing synaptic plasticity, all of which are vital for cognitive health. The aim of this study was to investigate the relationship between BDNF levels and cognitive impairment in the elderly population. This was a cross-sectional study involving older adults at a social service care. Cognitive function was assessed using the Montreal Cognitive Assessment-Indonesian Version (MoCA-INA). BDNF levels were measured in peripheral blood samples using the Enzyme-Linked Immunosorbent Assay.

Of the 88 participants with a median age of 69.5 years, 71 (80.7%) had cognitive impairment. The median MoCA-INA score was 15.0. The most affected cognitive domain was abstraction, absolute number of patients 87 patients (98.9%). The mean BDNF level was 1.55 (±0.62) ng/mL with 50 (56.8%) patients having normal level. A weak positive correlation was found between BDNF level and performance in the visuospatial-executive (r = 0.232) and abstraction domains (r = 0.249). BDNF levels were significantly lower in those with cognitive impairment compared to those with normal cognitive function.

In conclusion, we observed a correlation between BDNF levels and cognitive function, particularly in the visuospatial-executive and abstraction domains, highlighting the potential role of BDNF in cognitive decline in aging.

Link: https://doi.org/10.17392/1929-22-02

The medical tourism industry has adopted the therapeutic use of exosomes derived from stem cells in much the same way as it adopted the use of stem cell therapies. Transplanted stem cells produce benefits via signaling, and most signaling is carried via extracellular vesicles such as exosomes. From a logistics point of view, exosomes are more easily stored, transported, and used, while all of the tools needed to harvest exosomes from stem cell cultures already existed. Meanwhile, the regulated medical industry lags years behind, given the large costs and lengthy development programs required to satisfy regulatory requirements for manufacturing consistency and data on outcomes. Lack of consistency is certainly a long-standing issue in stem cell therapies, and will likely continue to be an issue for exosome therapies. This may simply be an inherent characteristic of material sourced from donors, and will continue to exist until such time as standardized universal cell lines are a going concern.

Stem cell-derived exosomes have broad application prospects in different medical fields, and are increasingly being considered a replacement for mesenchymal stromal cells (MSCs) therapy. Adipose-derived stem cells (ADSCs) are an efficient and high-quality source of stem cell exosomes because ADSCs can be easily obtained from autologous adipose tissue and there are only minor ethical concerns, also ADSCs shown multipotent differentiation potential, self-renewal potential, low immunogenicity, and high proliferation rate.

Exosomes derived from ADSCs have the function of promoting tissue regeneration through activation or inhibition of multiple signaling pathways (such as Wnt/β-catenin, PI3K/Akt), and immunomodulation, angiogenesis, cell migration, proliferation and differentiation, and tissue remodeling. This review presents the current state of knowledge on ADSCs exosomes and summarizes the use of ADSCs exosomes in stem cell-free therapies for the treatment of diabetes mellitus, cardiovascular, wound healing, neurodegenerative, skeletal, respiratory diseases, and skin aging and other conditions, thus providing novel insights into the clinical applications of MSC-derived exosomes in disease management.

Link: https://doi.org/10.3389/fphar.2025.1637342

Every tissue is supported by countless capillaries, the smallest vessels in the branching vascular network. Take a square cross-section of tissue a millimeter in each dimension and one finds hundreds of capillaries passing through it. This intricate branching network of vessels must be constantly maintained, but unfortunately the processes of maintenance decline with age, as is the case for all complex systems in the body. The resulting progressive loss of capillary density reduces the supply of oxygen and nutrients, and this is thought to provide a meaningful contribution to loss of tissue function and the onset of age-related disease.

What can be done about this? Manipulating some of the regulators and participants at various stages of angiogenesis seems promising. Angiogenesis is a multi-step process wherein a new branch from an existing blood vessel is constructed. It is an example of one of the better understood mechanisms involved in the maintenance of our biology, as it is extensively studied and the research community has a good understanding of how it works, but there is still room for exploration at the detail level. Studies have shown that upregulation of VEGF, an important signal in angiogenesis, can lead to greater angiogenesis. VEGF is involved in the creation of pathological, leaky blood vessels in macular degeneration, but no such issue is seen in the animal studies in which circulating VEGF is increased. Alternatively, strategies to mobilize hematopoietic progenitor cells from the bone marrow into circulation, such as CXCL12 upregulation, used when harvesting hematopoietic cells from a donor for transplantation, also promote angiogenesis.

Today's open access paper focuses on the more prosaic intervention of exercise. There is evidence for late life exercise to partially reverse loss of capillary density in muscle tissue. Exercise is in general beneficial for systems throughout the body, so this is perhaps not surprising. Relatively few of the manifestations of aging are completely immune to treatment via lifestyle choice, even though the degree of reversal that can be achieved is much smaller than desired.

The role of exercise induced capillarization adaptations in skeletal muscle aging: a systematic review

Skeletal muscle aging is often accompanied by capillary rarefaction, which limits the effective delivery and distribution of hormones, nutrients, and growth factors within skeletal muscle. Furthermore, exercise is widely regarded as having the potential to improve microcirculation and delay skeletal muscle aging. This review aims to explore exercise-induced improvements in capillarization and related adaptations to mitigate the adverse changes that occur during the aging process of skeletal muscle.

Studies have shown that older adults still possess the capacity to improve skeletal muscle capillarization through exercise. Moderate-intensity aerobic exercise not only significantly enhances the level of capillarization but also induces effects that can be maintained even after cessation of training. Capillarization adaptations induced by resistance training exhibit marked inter-individual variability, which is primarily determined by each individual's baseline level of capillarization, thereby resulting in distinct patterns of adaptation. The studies also revealed that the regulation of capillarization depends on the synergistic action of VEGF and eNOS, and that different types of exercise may elicit adaptations through distinct molecular pathways.

In conclusion: during the aging process, exercise-induced improvements in capillarization can enhance nutrient delivery, metabolic efficiency, and regenerative capacity in skeletal muscle. To some extent, these adaptations help suppress degenerative changes in muscle function and provide a targeted foundation for anti-aging intervention strategies.

Senescent cells accumulate with age in tissues throughout the body, generating sustained pro-inflammatory signaling that is increasingly disruptive to tissue structure and function. This is an important contribution to degenerative aging, as illustrated by the many animal studies in which senolytic therapies that selectively destroy senescent cells produce significant reversal of aspects of aging and age-related disease. Here, researchers review the evidence for senolytic therapies to effectively treat neurodegenerative conditions by removing the harms done by senescent cells in the brain.

The cellular phenomenon of aging is irreversible and is characterized by the arrest of cell division and induction of growth. It is believed that this mechanism contributes to age-related illnesses, such as neurodegenerative diseases, as well as the ageing process itself. The ability of aging cells in the brain to release pro-inflammatory chemicals like cytokines and chemokines is a factor that contributes to the deterioration of neurons and the advancement of neurodegenerative disorders. The accumulation of β-amyloid and tau proteins seen in Alzheimer's disease (AD), coupled with the clustering of senescent microglia and astrocytes in the brain, worsens neuroinflammation. Similarly, the accumulation of senescent dopaminergic neurons and microglia has been accompanied by the pathogenesis of Lewy bodies and the neuroinflammatory response in individuals with Parkinson's disease (PD).

Current research has looked at the possibility of alleviating the symptoms of neurodegenerative diseases by using senolytics, which are pharmaceuticals or chemical compounds that selectively remove aged cells. In animal models of AD and PD, senolytic therapy has been demonstrated to enhance cognitive function and decrease neuroinflammation in both diseases. Despite the promising potential of targeting cellular senescence, several challenges remain. Further research is needed to better understand the complex interplay between senescent cells and the surrounding microenvironment in the brain. Additionally, the long-term safety and efficacy of senolytic therapies need to be carefully evaluated in clinical trials.

Link: https://doi.org/10.3389/fnagi.2025.1627921

Cells can take up mitochondria from the surrounding environment, and researchers have demonstrated in mice that intravenous delivery of mitochondria allows some degree of replacement of the native populations in cells. This improves function when native mitochondria are dysfunctional, as occurs with age. At present, delivery of mitochondria as a therapy to restore mitochondrial function in older people is a work in progress. A few companies are working on the challenge, which largely involves developing the techniques needed to reliably manufacture mitochondria at scale. In this paper, researchers look beyond that effort to the next step in the road, which is to engineer the delivered mitochondria to be more efficient and more resilient, or to act as factories for therapeutic molecules, or to have some other desired capability.

Conventional mitochondrial transplantation (MT), a therapeutic process involving the isolation and delivery of healthy exogenous mitochondria to damaged cells or organs to restore bioenergetics and promote repair, typically relies on the direct injection or infusion of isolated, unmodified mitochondria. Inspired by cell surface engineering, we propose nanoengineered mitochondria, which are biohybrid systems formed by integrating synthetic nanomaterials or biomolecules with isolated mitochondria to confer new functionalities.

This emerging strategy operates at the interface of bioengineering and mitochondrial biology and aims to overcome the limitations of conventional MT. These tailored nanobiohybrid systems have the potential to improve mitochondrial quality, boost metabolic activity, and reduce oxidative stress. Moreover, these systems can enhance the targeting efficiency and motility of mitochondria, which is achieved through mitochondrial ligand-receptor recognition (e.g., triphenylphosphonium cation (TPP+)-modified nanoparticles and mitochondrial membrane potentials), stimulus-responsive navigation (e.g., pH/ROS-sensitive polymers guiding mitochondria to inflammatory sites), and external field-driven propulsion (e.g., magnetically steered nanocapsules). This mini-review therefore focuses specifically on the emerging of nanoengineered mitochondria, moving beyond the scope of earlier reviews that centered primarily on conventional transplantation. We envision nanoengineered mitochondria as a next-generation platform for precise anti-aging interventions.

Link: https://doi.org/10.3389/fragi.2025.1688482

Cells become senescent constantly, ceasing to replicate and generating inflammatory signaling. This occurs when cells reach the Hayflick limit on replication, and in response to damage, injury, and toxicity. Senescence helps to draw the attention of the immune system to where it is needed, and in youth senescent cells are efficiently destroyed by immune cells once that task is accomplished. With age, however, the immune system becomes progressively less efficient while the environment becomes more damaged. As a consequence a burden of lingering senescent cells grows over time, and their contribution to the chronic inflammation of aging disrupts tissue structure and function.

Usefully measuring the burden of senescence in older people in a low-cost, non-invasive way remains a work in progress. In principle different tissues may be burdened to different degrees, and only looking at immune cells in a blood sample can be misleading with regarding to the situation in other organs and systems. Nonetheless, blood samples are largely what the research community aims to work with when building assays; it is what the medical community is geared to focus on, and data from blood samples is largely what one finds in epidemiological databases.

In today's open access paper, researchers report on the results of applying a number of approaches to deriving a score for the burden of cellular senescence based on gene expression data to the data from a large epidemiological study. While some of these assessments can be conducted in multiple tissues, the study gene expression data is from blood samples only, so the usual caveats apply as to whether this is representative of the whole body. Nonetheless, the researchers do find correlations with other metrics of health and aging, suggesting that there is value in these efforts to produce practical measures of the burden of cellular senescence.

Gene expression composite scores of cellular senescence predict aging health outcomes in the Health and Retirement Study

Cellular senescence is one of the molecular/cellular-level hallmarks of aging that accumulates with advancing age and plays an important pathogenic role in a number of adverse health outcomes. In response to damage, senescent cells stop proliferating and enter into a generally irreversible state of growth arrest. However, senescent cells are still metabolically active; they release a wide range of pro-inflammatory cytokines, chemokines, proteases, growth factors, and other bioactive molecules to the local microenvironment. Such proinflammatory secretion is termed Senescence-Associated Secretory Phenotype (SASP), and is thought to mediate downstream aging outcomes.

Recent work has suggested a more comprehensive approach to capturing the entire effect of cellular senescence rather than solely relying on SASP. In addition to SASP, other key aspects of cellular senescence include cell cycle arrest (CCA) and macromolecular damage (MD). To profile these distinct aspects of cellular senescence, researchers developed three lists of genes that are involved in the canonical senescence pathway (CSP), senescence initiating pathway (SIP), and senescence response pathway (SRP) to respectively represent CCA, MD, and SASP. These gene lists were tested and validated in two independent RNA sequencing datasets, and were associated with senescence in previous studies based on various cell and tissue types in human and mouse brains. Another gene list reflecting intracellular changes specific to senescent immune cells, termed SenMayo, was also recently developed. SenMayo includes genes involved in CCA, MD, and SASP, and thus has the potential to measure cellular senescence comprehensively.

Using RNA sequencing data from the U.S. representative Health and Retirement Study (HRS) sample (N = 3,580), we examine how CSP, SIP, SRP, and SenMayo relate to sociobehavioral factors and aging-related outcomes. Results show that senescence scores generally increase with age except for CSP. Higher scores are observed in women and individuals with class II obesity. All scores, except for CSP, are associated with accelerated epigenetic aging, physiological dysregulation, multimorbidity, cognitive decline, and 6-year mortality. These associations largely persist after adjustment for the pace of aging clock DunedinPACE. Our findings suggest that cellular senescence gene expression composite scores capture meaningful variation in aging-related health and complement existing epigenetic aging biomarkers.

The composition of the gut microbiome is influential on health, perhaps to a similar degree as diet and exercise choices. This composition changes with age in ways that are detrimental to long-term health, reducing the supply of metabolites necessary for tissue function while increasing the number of microbes capable of provoking chronic inflammatory signaling. Altering the composition of the gut microbiome in lasting ways, such as via flagellin immunization or fecal microbiota transplantation, has been shown to produce benefits to health and longevity in animal studies. Bringing these or related techniques to wider human use remains to be achieved, however, and the presently available approaches of diet and probiotics to adjust the balance of populations in the gut microbiome are not as effective as desired.

The gut microbiome is a salient contributor to human health, with considerable evidence also supporting it as a marker and mediator of healthy aging. The gut microbiome undergoes compositional and functional changes throughout the human lifespan. Studies in model organisms have demonstrated that the gut microbiome affects aging and longevity through metabolic activities that modulate host immunity. This modulation is also present in the centenarian gut microbiomes, with unique characteristics that plausibly contribute to longevity, including increased microbial and metabolic diversity, enriched beneficial taxa like Akkermansia and Christensenellaceae, and enhanced gut homeostasis.

Mechanistically, the gut microbiome orchestrates the aging process through various pathways. These pathways change with age, with age-related gut dysbiosis reciprocally promoting inflammaging through the decreased production of anti-inflammatory short-chain fatty acids and declined gut barrier integrity. The worsened inflammation amplifies neuroinflammatory responses, triggering cognitive decline through the gut-brain axis. Furthermore, gut dysbiosis also negatively affect muscle mass and function, which in turn exacerbate frailty in the elderly.

Some intriguing questions remain open for investigation. First, the human aging process is composed of nonlinear waves in molecular changes, with approximately 44 and 60 years of age being the two critical periods characterized by the highest number of dysregulated molecules and microbes. These two chronological ages are therefore of research interest, warranting further investigation into strategies based on gut microbiome modulation that could mitigate dysregulation to slow down or, at the very least, alleviate the aging process and reduce disease risk in later life. Second, some microbially derived metabolites, such as phenylacetylglutamine, accelerate host cellular senescence. Identifying gut microbes driving these metabolic processes and targeting them through dietary interventions to reduce the substrates fueling these pathways could provide internal benefits to the aging process.

Link: https://doi.org/10.1186/s12929-025-01179-x

The CALERIE study of human calorie restriction was conducted some years ago. Participants aimed at 25% calorie restriction and achieved a ~12% reduction in calorie intake over a span of two years. A number of papers have been published on the positive results for participant heath, and researchers continue to produce new analyzes of the data. Here, researchers show that participants who conducted more physical activity while calorie restricted exhibit modestly better outcomes in a number of measures of health known to change favorably with the practice of calorie restriction.

It is unclear how physical activity energy expenditure (PAEE) influences calorie restriction (CR)-induced benefits in individuals without obesity. We examined associations between PAEE and healthspan markers and physical activity (PA) time during prolonged CR. In Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) 2, participants without obesity were randomized to 25% CR or ad libitum control. This post-hoc analysis included baseline and 24-month data from participants in both groups who demonstrated CR. PAEE was calculated from total and resting energy expenditure. Outcomes included grip strength, aerobic capacity, glucose, insulin, blood lipids, and self-reported PA time.

Overall, 136 participants (97 females; average age 38.6 years; average BMI 25.3) who showed CR were analyzed. A smaller decrease in PAEE was associated with improved grip strength, homeostatic model assessment of insulin resistance, and high-density lipoprotein-cholesterol. PAEE change was not associated with aerobic capacity, low-density lipoprotein-cholesterol, triglycerides, glucose, or insulin. A smaller PAEE decline was associated with greater PA time. For some blood lipids, change in PAEE interacted with baseline BMI class: in participants who were overweight, higher PAEE was associated with lower triglyceride and triglyceride to high-density lipoprotein-cholesterol ratio, whereas in participants who were normal weight, it was related to increased total-cholesterol.

In conclusion, a smaller reduction in PAEE during CR was associated with small improvements in several healthspan markers and greater PA time. Maintaining PAEE during CR may enhance healthspan in individuals without obesity.

Link: https://doi.org/10.1186/s12966-025-01825-5

We are all well aware of the differences in life expectancy between women and men. The underlying reasons for the female advantage in longevity are much debated, but since similar sex differences exist across many species, it is likely to have deep roots in evolutionary biology and the complex interactions between reproductive fitness, mating strategies, and biochemistry. More prosaic explanations invoking the consequences of cultural and lifestyle choices that differ characteristically between sexes seem unlikely to be correct.

The situation is more complex than just a matter of life span, however. While living longer, women in late life exhibit a greater burden of disease and dysfunction than equivalently aged men. This seems a paradox, as reliability theory suggests that failing complex machine will have a shorter life span. Yet the data is the data. The research community spends a fair amount of time and effort attempting to find an explanation for sex based disparities in late life health that can explain all of the observed outcomes. Today's open access paper is an example of the process of gathering yet more data that might help researchers to better understand what is going on under the hood.

Inflammaging and the sex-frailty paradox

During aging, the immune cell functionality gradually decreases, resulting in a phenomenon known as "immunosenescence", which undermines both the innate and adaptive immune systems, leading to an increased incidence of disease and infection. Immunosenescence is the basis of inflammaging, a phenomenon that occurs during aging and consists of a chronic and persistent state of low-grade inflammation characterized mainly by the production of components of the innate immune response. The theory posits that excessive stimulation of pro-inflammatory pathways and an ineffective anti-inflammatory response are a driving force behind the development of frailty and age-related diseases.

Specifically, frailty reflects a state of increased vulnerability to stressors, a consequence of the gradual decline in the individual's homeostasis and functional reserves. A sex-associated divergence in frailty and mortality, termed the "sex-frailty paradox", is widely known. This consists of the observation that women, while generally living longer than men, often show higher rates of frailty reflecting a worse health status. This could be due to the fact that men tend to suffer from more malignant conditions (e.g. stroke and ischaemic heart disease), while women mainly from "life-threatening" chronic conditions associated with greater morbidity (e.g. fractures, constipation, depression, and headaches).

Research on sex-specific differences in frailty and its contributing factors suggests that these disparities are probably the result of the complex interplay between biological, psychosocial, and behavioural factors which differ between women and men. Interestingly, some studies have shown a different association between certain inflammatory markers and frailty in women and men. We studied 452 subjects (315 women and 137 men) stratifying them by age (≤ 80, 81-99 and ≥ 100 years) and sex. A 47-item frailty index was calculated. Plasma concentrations of inflammatory markers were analysed by next-generation ELISA.

Women aged ≤ 80 years were less frail while those aged ≥ 100 years were more frail than their male counterparts. Interestingly, the 81-99-year-old group showed similar frailty degree between females and males. The observed differences in frailty index values between women and men in the three age groups paralleled the peculiar associations of biomarker concentrations. This finding was in agreement with the concentrations of IL-10 and TNF-α, which were higher in men aged ≤ 80 years, and with the concentrations of IL-6 and soluble TREM1, which were higher in men aged ≤ 80 as well as in men aged 81-99 years than in women peers. This data may support the fact that immune-senescence is accelerated in men compared to women, resulting in a greater decrease in B lymphocytes and naïve T lymphocytes and a greater increase of memory T lymphocytes and natural killer cells. This alteration of immune cell function results in elevated levels of pro-inflammatory as well as anti-inflammatory cytokines, the so-called inflammaging, and in immune system dysfunction, which may underlie reduced longevity in men.

A sizable body of epidemiological evidence links physical fitness to improved health, greater longevity, and slowed aging in later life. Use it or lose it, as they say. Here researchers quantify the degree to which physical fitness can slow the onset of the chronic diseases of aging. Obviously one can't escape degenerative aging via exercise, but given that maintaining fitness has one of the larger presently available effects on the long-term trajectory of health, why not make the effort?

Cardiorespiratory fitness (CRF) has been linked to lower risk of individual chronic diseases, but little is known about the CRF in relation to multimorbidity. Thus the authors here investigated the association between CRF and multimorbidity risk and explored differences in the trajectories of chronic disease accumulation at varying levels of CRF. The study included 38,348 adults from the UK Biobank (mean age 55.21 ± 8.15 years) who were followed for up to 15 years to detect the incidence of 59 common chronic diseases. CRF was estimated using a 6-minute submaximal exercise test and tertiled as low, moderate, and high (after standardization by age and sex). Multimorbidity was defined as the presence of 2 or more chronic diseases.

During the follow-up (median 11.57 years), 15,368 (40.08%) participants developed multimorbidity. The risk of multimorbidity was 21% lower in participants with high compared to low CRF (hazard ratio, HR: 0.79). The median time to multimorbidity onset was 1.27 years later for those with high compared to low CRF. Moreover, participants with high CRF experienced a significantly slower annual rate of chronic disease accumulation (β = -0.043). Thus high CRF is associated with lower multimorbidity risk, delayed onset of multimorbidity, and significantly slower accumulation of chronic diseases. The findings highlight the importance of CRF for healthy longevity.

Link: https://doi.org/10.1016/j.jacadv.2025.102198

Researchers have found that a number of antidiabetic drugs act to modestly slow aging in mice, albeit often differently by sex, while some effects are more reliable than others. Insulin metabolism was one of the first aspects of cell biochemistry to be well studied in the context of effects on aging, and drugs that affect insulin metabolism in the environment of the dysfunction of type 2 diabetes were thus thought likely to have at least some small effect on aging. The effect is indeed small and unreliable in some of the more studied drugs, such as metformin. Here, researchers assess the outcome of treatment with the antidiabetic drug canagliflozin in a mouse model of Alzheimer's disease, focusing on measures of brain aging and pathology, finding it to produce useful benefits in male mice only.

Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice.

In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose control improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.

Link: https://doi.org/10.1111/acel.70255

A tumor is a battleground of cell behavior and cell signaling. All cells can influence the behavior of surrounding cells via the signals they produce, and the evolution of cancerous cells that exhibit unfettered replication and continual mutation might be thought of as a blind search for whatever will trigger surrounding cells into assisting with more rapid growth. One of the most effective outcomes for tumor cells is to produce signals that can suppress the anti-cancer activities of the immune system. This capability is near universal for solid tumors, as without the ability to co-opt immune cells the tumor would likely never have come into being in the first place.

The innate immune cells known as macrophages are important in normal tissue maintenance and regeneration, and are particularly important in both suppression and growth of cancers. So are cells that have become senescent, that cease to replicate and secrete signals to rouse the immune system to action. Macrophage presence and cellular senescence are initially protective against cancer: senescence of damaged cells draws the attention of macrophages and other immune cells to destroy those cells before they can become cancerous. Macrophages and senescent cells are later co-opted into supporting tumor growth, however, in much the same way in which they interact to promote regenerative growth following injury. In today's open access paper, researchers discuss the overlap between these two considerations, the presence of senescent macrophages in tumor tissue. As they report, a great deal is known, but these are complex biochemistries, and much remains to be established.

Senescent macrophages in tumor: phenotypes, roles, and interventions

The tumor microenvironment (TME) refers to the local region in which tumor cells reside, incorporating a diverse array of non-tumor cell types, extracellular matrix (ECM) components, vascular networks, and soluble factors. This intricate milieu is critical in modulating tumor behavior and influencing therapeutic responses. TME-associated senescent cells manifest a dualistic role: on the one hand, senescence TME statue can inhibit tumor progression by slowing their proliferation; conversely, the dynamic interplay of immune cell functions and cytokines produced by senescent cells allows these senescence-associated factors to modify the immune escape mechanisms within the TME, thereby significantly promoting tumor growth and the spread of cancer to distant sites.

Macrophages are essential components of innate and adaptive immunity and are one of the major infiltrating immune cells in TME. These macrophages are known as tumor-associated macrophages (TAMs) and play a dual role in tumor initiation and progression, acting as promoters and tumorigenesis suppressors. Macrophages can be classified into two distinct subtypes, also known as the polarization states of macrophages: M1 type and M2 type. M1 macrophages are classically triggered, pro-inflammatory cells that exert direct tumor-suppressive effects by secreting pro-inflammatory cytokines, such as interleukin-6 (IL-6), and generating reactive oxygen species and reactive nitrogen species, all of which contribute to the amplification of anti-tumor immune responses. In contrast, M2 macrophages release immunosuppressive mediators, including IL-4, IL-10, and transforming growth factor-beta (TGF-β), which inhibit T cell and natural killer (NK) cell functionality, promote angiogenesis, and facilitate tumor cell invasion, thereby contributing to tumor progression.

Contrary to the disordered proliferation of tumor cells, immune cells such as macrophages present a state of exhaustion or senescence-related reprogramming in TME. As aging progresses, macrophages exhibit a progressive decline in phagocytic capacity, respiratory burst activity, levels of toll-like receptors (TLRs) and MHC class II (MHC-II), responsiveness to antigenic triggers, and the release of pro-inflammatory chemokines and cytokines, suggesting that the senescence of macrophages occurs with aging, and the molecular changes of senescent macrophages (sMACs) disrupt the regular immune cell dialog. In addition, in vivo animal experiments showed that elimination of sMACs could inhibit tumor growth, suggesting the clinical significance of combination therapy targeting sMACs. Nonetheless, there is still a lack of consensus regarding the characteristic phenotypes of sMACs within the TME and their mechanistic roles. This review aims to provide an overview of the current understanding of the tumor infiltration-sMACs, summarize the molecular characteristics and functional abnormalities of sMACs, and discuss the potential roles and interventions of sMACs.

Researchers here explain that one of the challenges involved in the development of cancer vaccines lies in finding ways to provoke a sufficiently robust response from the immune system. The larger the number of distinct sensing mechanisms that can be triggered by a vaccine, the more roused the immune system becomes. But cancer vaccines tend to be based on a single antigen that identifies a distinctive cancer cell surface feature and single immune-provoking molecule that works via only one of the many possible immune activation pathways. Thus researchers here build and test a nanoparticle platform that allows for the assembly and delivery of a mix of molecules that interact with multiple immune-provoking pathways, intended to induce the immune system into a greater, more sustained response to a cancer-targeted antigen.

While vaccination has emerged in recent years as a powerful frontier in the development of effective cancer therapies by training adaptive immune cells to recognize and eliminate tumor cells, effective adjuvanticity has remained a hurdle. Vaccines have two essential components: an antigen, which is uniquely expressed on the pathogen (or cancer cell), and an adjuvant, which activates the innate costimulatory signaling critical for priming an adaptive immune response. Historically, infectious disease vaccine design has transitioned from whole-pathogen vaccines to modern-day subunit vaccines to mitigate the risk of infection upon inoculation, but this shift has introduced notable trade-offs in efficacy. Chief among these limitations is that subunit vaccines largely include only single-adjuvant formulations, unlike their whole-pathogen counterparts, which include multiple innate immune agonists (or adjuvants) that together provide robust adjuvanticity.

Here, we use a versatile nanomaterials engineering approach to address this critical gap and report on the development and testing of a dual-adjuvant lipid-based nanoparticle system, termed "super-adjuvant" nanoparticles, that promotes powerful vaccine-specific immune responses when co-delivered with tumor antigen or lysate and directed to lymph nodes as a prophylactic approach. We focus here on the specific attributes of lipid-based nanomaterials, which enable co-encapsulation of hydrophilic and hydrophobic agonists on the same nanoparticle, synthesis within a small ∼30-60-nm-size window for rapid draining to lymph nodes and ready uptake by target dendritic cells, and "stealth" poly ethylene glycol (PEG) surface functionalization for physiological solubility.

We use a neutral lipid matrix to co-encapsulate hydrophilic cyclic-di guanosine monophosphate (cdGMP), an agonist of the STING pathway, and hydrophobic monophosphoryl lipid A (MPLA), an agonist of the Toll-like receptor 4 (TLR4) pathway together on the same nanoparticle for co-delivery to the same target dendritic cell. Previously delivered as a systemic formulation and directed to tumors, we demonstrated that dual-adjuvant nanoparticles promoted interferon (IFN)-β-mediated expansion of tumor antigen-presenting cells, such as dendritic cells, macrophages, and natural killer cells, and harnessed CD8+ T cell-mediated anti-tumor control for clearance.

Link: https://doi.org/10.1016/j.xcrm.2025.102415

Physical fitness confers a great many benefits. Based on the broad evidence for reduced mortality and improved health, it is worth the effort required to maintain an above average level of fitness into later life. The research noted here is one of many studies to look at specific immunological differences between relatively fit and relatively unfit older individuals. It is well understood that greater fitness produces improved immune function, but the immune system is very complex and there is a great deal of room for further exploration of the fine details.

Aging is associated with immune dysfunction, but long-term endurance training may confer protective effects on immune cell function. This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained older adults. Ex vivo expanded NK cells from endurance-trained (63.6 ± 2.1 years) and untrained (64.3 ± 3.3 years) males were exposed to adrenergic blockade (propranolol; 0-200 ng/mL) or mTOR inhibition (rapamycin; 10-100 ng/mL), both with or without inflammatory stimulation induced by phorbol 12-myristate 13-acetate (PMA). Flow cytometry assessed NK subsets, activation (CD38, CD57, CD107a, NKG2D), senescence (KLRG1), and inhibitory markers (PD-1, LAG-3, TIM-3, NKG2A). Seahorse analysis measured mitochondrial metabolic parameters.

Trained participants displayed healthier immune profiles (lower neutrophil-to-lymphocyte ratio and Systemic Immune-Inflammation Index) and higher effector NK cells with lower cytotoxic subsets. Propranolol at 100 ng/mL blunted PMA-driven increases in CD57, CD107a, and NKG2D, while potentiating regulatory markers KLRG1, LAG-3, and PD-1 in the trained group, indicating stronger immunoregulation. With rapamycin, trained NK cells preserved NKG2D and CD107a at 10 ng/mL, maintaining cytotoxicity and degranulation. In contrast, at 100 ng/mL rapamycin plus PMA, trained NK cells shifted toward an effector phenotype with higher CD57 and CD107a, yet a blunted PMA-increased LAG-3 and TIM-3, suggesting resistance to exhaustion. PD-1 and KLRG1 remained elevated, reflecting balanced immune control.

Mitochondrial analysis revealed that trained NK cells exhibited higher basal and maximal oxygen consumption rate, greater spare respiratory capacity, and oxygen consumption rate to extracellular acidification rate ratio, reflecting superior metabolic fitness. These findings indicate that endurance-trained older adults have NK cells with greater functional adaptability, reduced senescence, and enhanced metabolism under inflammatory and pharmacological stress.

Link: https://doi.org/10.1038/s41598-025-06057-y

Naked mole-rats live as much as nine times longer than similarly sized rodent species, suffer little age-related decline of function until very late life, and there are next to no examples of individuals in captivity suffering from cancer. Researchers have spent more than twenty years investigating the biochemistry of this species, in search of the reasons for their longevity and resistance to cancer. As for other areas of the study of the comparative biology of aging, the hope is that some of these findings could form the basis for therapies to treat cancer and slow aging in humans. Whether this is the case remains to be seen; researchers have only comparatively recently reached the point of identifying specific differences that might be relevant, and then introducing those differences into mice and other laboratory species to observe the results.

One of the noteworthy differences in naked mole rat cellular biology is that the species exhibits far more efficient DNA repair than is the case in most other mammals. This may contribute to both slowed aging and resistance to cancer, and so has attracted the attention of researchers. Today's paper is an example of progress on this front, in which the authors report that cGAS in naked mole rats has different sequence that encourages more efficient DNA repair. cGAS is more commonly discussed in the context of inflammation, as it is a sensor for mislocalized DNA in the cell cytosol, a part of the innate immune system intended to detect infectious pathogens and raise the alarm. Evolution tends to produce proteins with multiple distinct functions, however, and so in the cell nucleus cGAS has a different role, participating in the regulation of DNA repair. The researchers show that naked mole rat cGAS alterations can extend life in flies when introduced into that species, and reduce aspects of aging when delivered to mice via gene therapy, an interesting result.

A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging

DNA repair constitutes a crucial mechanism for stabilizing the genome. Earlier studies have demonstrated that the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) participates in regulating DNA double-strand break repair by suppressing the homologous recombination (HR) pathway, thereby promoting genomic instability. Although enhanced function of DNA repair proteins contributes to the evolution of longevity, it remains unexplored whether evolution has selected for the attenuation of negative regulators such as cGAS.

In a panel of assays, we found that naked mole-rat cGAS, in contrast to human and mouse cGAS, enhanced HR repair efficiency. This functional reversal is mediated by the substitution of four specific amino acid residues within the C-terminal domain of the cGAS protein. Mechanistically, this amino acid alteration enabled naked mole-rat cGAS to prolong its retention on chromatin in the wake of DNA damage by modulating its ubiquitination status, thereby altering its interaction with the segregase P97. The prolonged presence of naked mole-rat cGAS on chromatin facilitated the formation of a complex between the canonical HR factor RAD50 and FANCI, a factor primarily associated with the Fanconi anemia pathway. We further demonstrated that FANCI promoted the chromatin recruitment of RAD50, thereby potentiating HR repair.

Consequently, naked mole-rat cGAS attenuated stress-induced cellular senescence, mitigated organ degeneration, and extended life span in fruit flies. Critically, reverting these four amino acid residues abolished these protective effects. Furthermore, adeno-associated virus-mediated delivery of naked mole-rat cGAS to aged mice reduced frailty, attenuated hair graying, lowered circulating levels of immunoglobulin G and interleukin-6, and decreased cellular senescence markers in multiple tissues. Once again, these beneficial effects were dependent on the four specific amino acids.

It remains to be seen as to whether xenotransplantation of organs from genetically engineered pigs will be competitive in comparison to the tissue engineering of new organs. Even given the challenges faced to date, it seems likely that xenotransplanation will be a going concern before the manufacture of viable tissue engineered organs. Initial trials in patients volunteers have taken place for the heart and kidney. As the report here illustrates, the last mile of discovery in which pig organs are transplanted into the first volunteers is likely to require as much work and reveal as many unforeseen issues as was the case for the earlier stages of development, in which the need for genetic engineering of the donor pigs was discovered.

The advent of genetically edited porcine-to-human xenotransplantation has predominantly focused on cardiac and renal applications, with no reported cases of porcine-to-human liver xenotransplantation. This study presents the world's first successful genetically modified pig auxiliary liver xenotransplantation in a living human, achieving an unprecedented survival of 171 days, and provides valuable insights into the critical factors influencing the procedure's success.

A genetically modified pig liver, incorporating 10 targeted gene edits, was transplanted as an auxiliary organ into a 71-year-old patient with large hepatocellular carcinoma in the right hepatic lobe, which was initially deemed ineligible for curative resection. Liver function, metabolic, and coagulation markers were closely monitored throughout the perioperative period.

For the first 31 days post-transplant, no hyperacute or acute rejection, infections, or significant complications were observed, and the patient's hepatic and renal functions remained stable. Early postoperative coagulopathy, as indicated by elevated D-dimer and fibrin degradation products, was successfully managed through anticoagulant therapy. However, on postoperative day 38, the auxiliary liver was removed due to xenotransplantation-associated thrombotic microangiopathy (xTMA). Subsequent management with eculizumab and plasma exchange successfully resolved the xTMA. Unfortunately, repeated upper gastrointestinal hemorrhage ultimately led to the patient's death on day 171.

Link: https://doi.org/10.1016/j.jhep.2025.08.044

A number of studies have suggested that people who survive to extreme old age exhibit better immune function throughout later life in comparison to peers who died at earlier ages. This analysis is an example of the type, and the data shows a natural killer cell population that exhibits signs of greater efficiency and more youthful activity. How and why long-lived individuals exhibit better immune function is a separate question. Studies of genetic variation in very large human data sets suggest that genetics plays a much smaller role in late life survival than the consequences of lifestyle choices (such as physical fitness) and environmental exposures (such the burden of infectious disease).

Centenarians are an established model of successful and healthy ageing. Previous research on centenarians' immune systems has been limited to small-scale studies using a single methodology, such as flow cytometry or targeted gene expression analyses. However, these studies lacked comprehensive multi-omics integration and validation across diverse cohorts.

This study integrated single cell RNA sequencing (scRNA-seq), mass cytometry, and flow cytometry to analyse peripheral blood mononuclear cells (PBMCs) from 31 centenarians, 17 centenarian offspring, and 26 offsprings' spouses or neighbours as controls across three cohorts to generate a multi-omics atlas of centenarian immune status. Through comprehensive analysis, we showed that centenarians possess natural killer (NK) cells with "young" signatures and enhanced cytotoxicity linked to RUNX3 upregulation. Reinforced NK cell-T cell interactions via the MHC-I and MIF pathways promoted T cell function in centenarians. The study overcomes the limitations of prior studies by combining high-resolution single-cell data with functional assays, offering a unified model of immune health in extreme ageing.

Our findings, combined with existing evidence, redefine healthy immune ageing by demonstrating that centenarians maintain cytotoxic and regulatory balance through unique NK and T cell adaptations. For researchers, our study establishes a framework for exploring immune resilience, emphasising multi-omics approaches. For clinicians, targeting the identified pathways (RUNX3, MHC-I, or MIF) could help delay age-related immune decline, potentially reducing susceptibility to infections, cancer, and chronic inflammation.

Link: https://doi.org/10.1016/j.ebiom.2025.105922

Amyloid-β is an anti-microbial peptide, a component of the innate immune system. In the brain it is best known for increasing with age, misfolding, and then aggregating into toxic deposits. The presence of these aggregrates is thought to be the initial cause of Alzheimer's disease, eventually inducing the late stage mechanisms of neuroinflammation and tau aggregation that kill neurons and ultimately kill the patient. On its own, it seems likely that amyloid-β aggregation is capable of producing only mild cognitive impairment. Nonetheless, amyloid-β remains the primary target of research and development for the treatment of Alzheimer's disease.

Amyloid-β doesn't only exist in the brain. The body and the brain are separated by the blood-brain barrier that polices which molecules can pass, and in what amounts. Amyloid-β can move between body and brain via the blood-brain barrier, and the amounts of amyloid-β on the two sides exist in a state of dynamic equilibrium. Researchers have demonstrated that clearing amyloid-β from the vasculature can encourage its exit from the brain, and that approach has reached fairly late stages of clinical development. Separately, amyloid-β should be cleared from the brain via the various pathways that drain cerebrospinal fluid - the glymphatic system and the cribriform plate, both of which become dysfunctional with age. A few research and development programs are focused on restoring flow via one path or another; Leucadia Therapeutics is nearing clinical trials for their approach.

Today's open access paper reports a novel approach to draining amyloid-β from the brain via the blood-brain barrier, by upregulating the mechanisms involved in the normal export process. The fine details are somewhat complex, but involve adjusting the balance of materials presented for uptake to blood-brain barrier cells in order to prevent the cell from downregulating the expression and recycling of the LRP1 receptor used to take up amyloid-β. Cells tend to constantly shift levels of receptors used for uptake in response to circumstances, and downregulation of frequently used receptors is a common outcome that acts to prevent runaway uptake of any specific molecule. It is possible to confuse the underlying regulatory processes inside the cell by delivering carefully crafted materials that are taken up via other pathways, however.

Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques.

We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal.

In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 hours, as measured by ELISA. Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment.

This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level. Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.

It seems clear that it is a good idea to remove the excess senescent cells generated by a cancer therapy after the cancer is defeated, or at the very least permanently suppress the inflammatory signaling generated by those senescent cells. The added burden of cellular senescence carried by cancer survivors is likely a major contribution to a shorter life expectancy and raised risk of age-related disease. Whether it is a good idea to remove or alter the behavior of senescent cells during cancer therapy, while a cancer is still active, remains a debated topic. The answer may be different on a cancer by cancer basis. The presence of senescent cells can both harm and help the growth of cancerous cells, but which effects dominate in any given context may be hard to determine in advance, depending on the biochemistry of the cancer, tissue type, number of senescent cells, and other factors.

The aging microenvironment, as a key driver of tumorigenesis and progression, plays a critical role in tumor immune regulation through one of its core features - the senescence-associated secretory phenotype (SASP). SASP consists of a variety of interleukins, chemokines, proteases, and growth factors. It initially induces surrounding cells to enter a state of senescence through paracrine mechanisms, thereby creating a sustained inflammatory stimulus and signal amplification effect within the tissue microenvironment. Furthermore, these secreted factors activate key signaling pathways such as NF-κB, cGAS-STING, and mTOR, which regulate the expression of immune-related molecules (such as PD-L1) and promote the recruitment of immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells. This process ultimately contributes to the formation of an immunosuppressive tumor microenvironment.

Furthermore, the article explores potential anti-tumor immunotherapy strategies targeting SASP and its associated molecular mechanisms, including approaches to inhibit SASP secretion or eliminate senescent cells. Although these strategies have shown promise in certain tumor models, the high heterogeneity among tumor types may result in varied responses to SASP-targeted therapies. This highlights the need for further research into adaptive stratification and personalized treatment approaches. Targeting immune regulatory mechanisms in the aging microenvironment - particularly SASP - holds great potential for advancing future anti-tumor therapies.

Link: https://doi.org/10.1016/j.apsb.2025.07.022

Cells evolved to detect foreign DNA and respond with inflammatory signaling. Unfortunately aging brings with it the mislocalization of fragments of the cell's own DNA that is then misidentified as foreign, triggering these same inflammatory pathways. This response, and a number of other responses to forms of damage inside the cell, converge on the regulatory protein STING. The activity of STING that leads to inflammation is thus an interesting target for the treatment of age-related conditions involving excessive chronic inflammation. As for near all of the present potential approaches to the chronic inflammation of aging, sabotaging STING will harm the normal innate immune response to infection, cancer, and so forth. This may be worth it in some scenarios. The use of biologics for patients with rheumatoid arthritis shows how this will likely play out: long term and more subtle harms to immune function and health are accepted when short term, evident benefits can be realized.

The stimulator of interferon genes (STING) plays a crucial role as an adaptor in innate immune defense, orchestrating key inflammatory processes through the modulation of type I interferon signaling and activation of cytokine networks. Recent studies have identified STING-induced neuroinflammatory responses as a major factor in the progression of neurological diseases, particularly in neurodegenerative disorders.

This review methodically explores the structural basis of STING activation and its role in driving pathological inflammation. The classic and non-classic pathways of STING as well as their roles in neurodegenerative diseases were discussed. Additionally, it critically assesses new pharmacological approaches that target the STING pathway, emphasizing anti-inflammatory treatments ranging from synthetic small-molecule inhibitors to bioactive natural compounds, which aim to mitigate neurotoxic inflammation.

By combining mechanistic insights with therapeutic advancements, this paper presents an innovative transformation framework aimed at developing anti-inflammatory therapies targeting the STING pathway to treat neurodegenerative diseases. The core contribution of this framework lies in systematically bridging the innate immune regulation and neuroinflammation control mechanisms, providing a new strategy for disease intervention.

Link: https://doi.org/10.3389/fnagi.2025.1659216

When a cell becomes senescent it ceases replication, expands in size, and secretes a mix of pro-growth, pro-inflammatory molecules known as the senescence-associated secretory phenotype (SASP). Cells become senescent throughout life, mostly upon reaching the Hayflick limit on replication. Forms of damage, particularly DNA damage that might lead to cancer, the signaling of other senescent cells, and a toxic environment can also provoke cellular senescence. Senescence is also involved in coordinating regeneration from injury. When an individual is young, senescent cells are cleared efficiently by the immune system, but with age this clearance falters. The result is an accumulating burden of senescent cells that disrupt tissue structure and function with their signals.

In today's open access paper, researchers review what is known of the role of cellular senescence in the aging of the heart and vasculature, causing dysfunction that contributes to the various forms of cardiovascular disease. Cardiovascular disease is the greatest cause of human mortality, those deaths largely split between heart failure, heart attack, and stroke. Controlling the burden of senescent cells, such as by preventing the onset of senescence, selectively destroying senescent cells, or at the very least inhibiting the SASP, is hoped to reduce this aspect of aging. There are some caveats, such as whether senescent cells are holding together tissues (or unstable atherosclerotic plaques!) in very late aging, and thus destroying them could be problematic. There should be no such issues for inhibiting the buildup of senescent cells prior to that late stage, however.

The role of cellular senescence in cardiovascular disease

Cardiovascular disease poses a profound global concern for public health, with age standing as a crucial risk factor that contributes significantly to the progressive deterioration of cardiac structure and functionality. In mammals, the aging process is linked to the build-up of senescent cells. During aging, cells undergo mitochondrial dysfunction, DNA damage, and increased activation of the p53/p21 and p16 signaling pathways in response to cellular stress, ultimately contributing to the development and advancement of cardiovascular diseases.

In recent years, cellular senescence has garnered considerable interest as a potential target for alleviating age-related diseases and extending lifespan. Cellular senescence is a hallmark of aging, characterized by a stable cell cycle block accompanied by typical morphological changes in cells and a distinguishable secretory phenotype.

The aim of this review is to provide a comprehensive summary of the role of cellular senescence in cardiovascular disease and related mechanisms. To begin, an overview of the fundamental concepts, characteristics, and biological effects of cellular senescence will be provided. Additionally, we will delve into the regulatory mechanisms of cellular senescence, encompassing the key molecules and signaling pathways involved. Subsequently, our focus will shift to exploring the interconnections between cellular senescence and conditions such as hypertension, atherosclerosis, myocardial infarction, heart failure, arrhythmias, and cardiomyopathy. This exploration aims to illuminate the role of cellular senescence in the development and progression of these diseases.

Finally, we will also explore the impact of targeted cellular senescence-related therapies on the aforementioned cardiovascular diseases. For example, pharmacologically removing or knocking out senescent cells in mice mitigates cardiac hypertrophy and fibrosis induced by cardiac senescence while also facilitating cardiomyocyte regeneration.

It remains an open question as to whether studying the biochemistry of extremely old people can provide a basis for interventions that will help everyone live meaningfully longer. If genetics has little influence on longevity for the vast majority of people, as seems to be the case, then differences observed in extremely old people emerge from (a) lifestyle choices that we can control and (b) exposures that we presently have less control over, such as infectious disease burden and composition of the gut microbiome. However, any of the biochemical differences observed in extremely old individuals could be the outcome of mechanisms that provide only small improvements in the odds of survival. Is it worth pursuing a mechanism that results in, say, a 2% chance of reaching age 100 in the environment of the past 100 years of medical technology, versus an average 1% chance? That doesn't seem all that great. Better approaches are needed.

The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (more than 1,400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies.

Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile characterized by higher levels of primary and secondary bile acids - most notably chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) - higher levels of biliverdin and bilirubin, and stable levels of selected steroids. Notably, elevated levels of both bile acids and steroids were associated with lower mortality. Several metabolites associated with age and survival were inversely associated with metabolite ratios related to NAD+ production and/or levels (tryptophan/kynurenine, cortisone/cortisol), gut bacterial metabolism (ergothioneine/trimethylamine N-oxide, aspartate/quinolinate), and oxidative stress (methionine/methionine sulfoxide), implicating these pathways in aging and/or longevity.

We further developed a metabolomic clock predictive of biological age, with age deviations significantly associated with mortality risk. Key metabolites predictive of biological aging, such as taurine and citrate, were not captured by traditional age analyses, pointing to their potential role as biomarkers for healthy aging. These results highlight metabolic pathways that may be targeted to promote metabolic resilience and healthy aging.

Link: https://doi.org/10.1101/2025.09.10.675341

Researchers here provide a tour of better known pharmacological targets for the development of drugs to slow or potentially reverse loss of muscle mass and strength with age. The high bar to beat is the effects of resistance exercise, but there is likely merit in drugs that will enhance the improvements provided by resistance exercise, provided that they have a reasonable cost. A few common themes emerge in the targets. Many approaches produce a reduction in inflammation, as chronic inflammation is strongly implicated in loss of muscle tissue maintenance and tissue function, for example. Loss of stem cell activity and issues with neuromuscular junctions are also well studied in the context of muscle aging, and the research community has sought ways to address these issues. So far only limited progress has been made in bringing potential therapies to the clinic, but we might expect this to change over the next decade given the present strong interest in finding solutions to frailty, sarcopenia, and muscle loss produced by GLP-1 receptor agonists.

A progressive decline in muscle mass and strength presents a significant challenge for aging populations, underscoring the urgent need for innovative and diverse treatment strategies. While this review focuses on pharmacological options, structured physical exercise, particularly resistance and power training combined with sufficient protein intake, remains the most effective primary intervention for age-related muscle decline. Pharmacological methods should be viewed as supplementary or alternative options only when exercise is not possible or proves inadequate. Despite notable progress in understanding skeletal muscle degradation mechanisms, applying these findings to effective treatments requires further research and rigorous clinical testing. New therapies, including novel peptides, natural compounds, and multi-targeted pharmacological approaches, hold great promise to preserve muscle function and improve patient outcomes.

Looking ahead, priority biological targets include (i) modulation of the MSTN/activin A/GDF11 axis with careful cardiometabolic safety monitoring; (ii) stabilization of neuromuscular junctions (e.g., HDAC4-Gadd45a stress pathways; agrin/MuSK); (iii) restoration of mitochondrial quality control and bioenergetics (AMPK-SIRT1-PGC-1α signaling, mitophagy), with attention to preserving type II fibers; (iv) reduction of chronic low-grade inflammation (IL-6/TNF) and enhancement of insulin/IGF-1/Akt/mTOR signaling in sarcopenic phenotypes with metabolic comorbidities; and (v) strategies for extracellular matrix remodeling (balancing TGF-β/MMP activity) to improve the satellite cell niche.

Link: https://doi.org/10.3390/ph18091407

Urolithin A is a metabolite produced by gut bacteria, widely used as a dietary supplement, and has attracted attention from the aging research community for its positive effects on mitochondrial function. Of the various approaches to improving mitochondrial function with compounds classed as supplements, urolithin A is arguably the one that researchers know the least about when it comes to how exactly it functions, but equally there is stiff competition here. Knowledge of the exact mechanisms involved in translating the known immediate biochemical interactions of various compounds to better functioning mitochondria is sketchy at best for NAD+ upregulation, mitoQ, plastinquinones such as SkQ1, elamipretide, and so forth. Further, many of these do not appear to perform as well as exercise when it comes to measures of mitochondrial function.

The function of any one mitochondrion is complex and incompletely understood. Then there is the point that mitochondria exist in their hundreds in every cell, a dynamic population undergoing division, fusion, and transfer of component parts between one another. Further, mitochondria are policed by another incompletely understood set of mechanisms of quality control called mitophagy responsible for identifying and recycling damaged mitochondria. Strategies for improving mitochondrial function largely seem to improve mitophagy, but it isn't all that clear as to why this is the case, or whether it is the primary mechanism by which mitochondrial function is improved.

In today's open access paper, researchers focus on the anti-inflammatory properties of urolithin A. They provide evidence for this to occur in part by downregulating the inflammatory signaling generated by senescent cells. This connects to mitochondrial function because inflammatory signaling of this nature (and in non-senescent cells as well) can arise due to the mislocalization of mitochondrial DNA fragments. As mitochondrial function declines more such fragments of mitochondrial DNA are released into the cell, where they are mistaken for bacterial DNA, provoking the same inflammatory reactions as take place during infection. Less of this is a good thing.

Mitigating Pro-Inflammatory SASP and DAMP With Urolithin A: A Novel Senomorphic Strategy

Aging is associated with increased systemic sterile inflammation (inflammaging), which promotes several age-associated diseases. Key drivers of inflammaging include senescence-associated secretory phenotype (SASP) factors released by senescent cells. While the exact components of SASP vary between different senescent cells and tissues, core SASP factors include pro-inflammatory chemokines, matrix-degrading enzymes, and several damage-associated molecular pattern (DAMP) molecules. Pharmacological inhibition of SASP using small molecules known as senomorphics has been proposed as a potential intervention for age-associated diseases. However, such treatments include several flavonoid inhibitors of the p38 MAPK/NF-κB pathway, free radical scavengers, and Janus kinase (JAK) pathway inhibitors that are nonselective and broadly inhibit pathways also involved in homeostatic immune responses to various physiological challenges, thus limiting their systemic therapeutic application).

Here we present data indicating that the gut metabolite Urolithin A (UA) acts as a senomorphic compound. Senescent cells are known to contribute to aging and age-related diseases. One key way they influence aging is by secreting senescence-associated secretory phenotype (SASP) factors along with several damage-associated molecular pattern (DAMP) molecules. Consequently, inhibiting SASP and DAMP signaling (senomorphics) has emerged as a therapeutic strategy.

Digestive tract bacteria naturally produce UA through the metabolism of ellagitannins and ellagic acid, which are abundant in berries, nuts, and pomegranates. UA has been reported to be a potent anti-inflammatory agent, alleviating several age-related conditions in vivo. Preclinical studies have also shown its protective role against aging and age-related conditions affecting the muscles, brain, joints, and other organs. In a recent clinical trial, UA supplementation improved muscular endurance in older adults. Here we demonstrate that UA lowers the expression and release of pro-inflammatory SASP and DAMP factors, at least in part, by downregulating cytosolic DNA release and subsequent decrease in cGAS-STING signaling.

Treatments that cause issues when administered systemically (such as via oral ingestion or intravenous injection) at the doses required to place enough of the therapeutic in a specific location in the body can be made practical via methods targeting delivery to specific cells. Here, researchers use liposomes attached to a muscle-targeted peptide to deliver the polyphenol epigallocatechin gallate (EGCG) to muscle cells. EGCG is otherwise problematic, causing liver toxicity at high doses, and has low bioavailability when ingested. Nonetheless it does have interesting effects on inflammation, cholesterol metabolism, and mitochondrial function which is why researchers are making use of it here in the context of muscle aging.

Skeletal muscle aging frequently leads to a reduction in muscle mass and strength, significantly compromising the quality of life in elderly individuals. Skeletal muscle dysfunction during aging is widely recognized to be closely linked to chronic inflammation, oxidative stress, and mitochondrial dysfunction. In this study, we confirmed the successful synthesis of M12 (muscle homing peptide)-modified EGCG (Epigallocatechin gallate) liposomes (M12EGLP) and validated their specific targeting to skeletal muscle through immunofluorescence analysis and in vivo imaging in small animal models.

Both in vivo and in vitro experiments demonstrated that M12EGLP effectively suppressed the expression of inflammatory markers such as TNF-α and IL-6, thereby alleviating oxidative stress and restoring mitochondrial function in skeletal muscle. These effects ultimately contributed to the improvement of skeletal muscle dysfunction in aging mice, improving motor function and regenerative capacity. Therefore, as a novel and targeted drug delivery system, M12EGLP may provide a promising therapeutic strategy for the clinical management of age-related skeletal muscle dysfunction.

Link: https://doi.org/10.1016/j.mtbio.2025.102265

PhenoAge is an aging clock derived from patient data on age-related changes in nine clinical chemistry markers that are easily measured via a blood sample. A number of other blood biomarker clocks have been proposed that use more markers. The clock noted here claims a modest improvement over PhenoAge when it comes to predicting mortality risk, but that requires 25 markers. The trade-off is in the cost to the patient to obtain the necessary assays versus the degree of improved performance of the clock. This tends to be true across clocks more generally, regardless of the data used. The more popular clocks based on fewer measures continue to be popular because they do not greatly underperform the more expensive clocks that require many more measures. The work here reproduces that result by showing that combining a subset of markers with the full data set produces much the same result as the full set of markers, which is an interesting approach to controlling patient costs.

Biological age captures physiological deterioration better than chronological age and is amenable to interventions. Blood-based biomarkers have been identified as suitable candidates for biological age estimation. This study aims to improve biological age estimation using machine learning models and a feature-set of 60 circulating biomarkers available from the UK Biobank (n = 306,116). We implement an Elastic-Net derived Cox model with 25 selected biomarkers to predict mortality risk (C-Index = 0.778), which outperforms the well-known blood-biomarker based PhenoAge model (C-Index = 0.750), providing a C-Index lift of 0.028 representing an 11% relative increase in predictive value.

Importantly, we then show that using common clinical assay panels, with few biomarkers, alongside imputation and the model derived on the full set of biomarkers, does not substantially degrade predictive accuracy from the theoretical maximum achievable for the available biomarkers. Biological age is estimated as the equivalent age within the same-sex population which corresponds to an individual's mortality risk. Values ranged between 20-years younger and 20-years older than individuals' chronological age, exposing the magnitude of ageing signals contained in blood markers. Thus, we demonstrate a practical and cost-efficient method of estimating an improved measure of biological age, available to the general population.

Link: https://doi.org/10.1038/s42003-023-05456-z

There are many layers to aging research. There is the function of tissue, the behavior of cells, the pattern of expression of genes, the profile of circulating molecules of various classes. Typically one research program is focused on one layer (and often only in one organ, or a single function of a tissue), with only occasional excursions into another layer (or other organs, or other functions). There are the usual reasons for this, such as different skills and knowledge being required, different expensive equipment being required, the tendency for researchers to specialize into ever narrower niches, and the eternal pressure to do more with less that exists in academia. It does mean that much of the literature is siloed into layers that talk little to one another, and integration of these layers into a bigger picture of cause and effect lags behind.

Today's open access paper reports on altered behaviors in neurons involved in spatial memory in the aged mouse brain, and connects these changes to the age-related loss of spatial memory. Different forms of memory involve different neural networks and different regions of the brain, and so can be distinctly affected by aging even if the underlying damage and dysfunction contributing to aging is more or less evenly spread across tissues. This research attempts to link two layers of aging in some of the specific neurons involved in spatial memory, the layer of cell behavior and the layer of gene expression. The intent is to provide a foundation for later efforts to find ways to restore these cells to a more youthful pattern of behavior.

Spatial coding dysfunction and network instability in the aging medial entorhinal cortex

Across mammalian species, neural systems in the medial temporal lobe, including the medial entorhinal cortex (MEC) and hippocampus (HPC), are required for spatial memory. The MEC contains grid cells that fire periodically during environmental traversals and have firing fields that hexagonally tile physical space in rodents, non-human primates, and humans. This firing is proposed to provide a map of space that can support path integration. Head direction-, border-, speed-, and object vector-tuned cells have also been identified in MEC, providing information regarding an animal's movement through the environment and sensory features likely relevant to navigation. Additionally, MEC neurons can change their firing rates or shift where their firing fields are active, phenomena collectively referred to as 'remapping'. MEC remapping events often occur in response to changes in task demands and environmental features, potentially facilitating the differentiation of distinct contexts. Such remapping in MEC grid cells is likely complemented by place cells and goal-vector cells in the reciprocally connected HPC, which can also exhibit context-dependent remapping. Collectively, this network of functional cell types across MEC and HPC may provide the necessary neural substrates for an animal to navigate to goals in novel and familiar environments.

Several lines of evidence suggest that MEC-HPC circuit dysfunction contributes to aged spatial memory deficits. It is unclear how aging impacts the quality or stability of tuning to navigational variables across MEC functional cell types, however. The integrity and flexibility of population-level spatial maps in the aged MEC also remain unknown. Since the HPC and MEC are reciprocally connected, one possibility is that spatial coding dysfunction in these regions might interdependently contribute to spatial memory decline in aging. Eventually, rejuvenating aged spatial cognition dependent on MEC-HPC networks will also require a more precise understanding of the molecular mechanisms that drive cellular and circuit dysfunction.

Here, we combined in vivo silicon probe recordings with neuronal bulk sequencing in MEC in the same mice, complemented by single-nucleus RNA sequencing (snRNA-seq), to identify neural and molecular substrates of aged spatial memory function. Advanced electrophysiologic tools permitted the simultaneous recording of hundreds of neurons per day from each mouse. As a result, we could robustly analyze age effects on MEC spatial coding at the animal level. Moreover, we interrogated how aging altered single neuron firing patterns and population-level spatial coding phenomena. Using a virtual-reality (VR) task with two dynamically interleaved contexts and another with invariant cues, we demonstrated how aging impacts the flexibility and stability of MEC spatial coding at both these levels. Finally, by correlating key spatial coding metrics with the expression of neuronal genes differentially expressed across age groups, we identified potential molecular drivers of aging-mediated spatial cognitive decline in MEC.

Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that are primarily responsible for generating adenosine triphosphate (ATP), a chemical energy store molecule used to power the cell. Mitochondrial function declines with age, negatively impacting health, and thus researchers are interested in finding ways to either enhance function to compensate for this decline or find ways to prevent and reverse the loss of mitochondrial activity. Most currently available approaches fail to much improve on the effects of exercise on this front, and appear to largely work by improving quality control mechanisms that have evolved to remove damaged mitochondria. Here, researchers report on a novel target to improve mitochondrial function in older individuals, one that improves both quality control and generation of new mitochondria.

Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number.

Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the damage, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS.

PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.

Link: https://doi.org/10.1126/sciadv.adw7376

Elamipretide, originally known as SS-31, is a mitochondrially targeted small molecule originally thought to be an antioxidant akin to plastiquinones (such as visomitin / SkQ1 which is approved for use in Russia), but which may primarily function through other mechanisms to improve mitochondrial function. As we should all know by now, mitochondrial function declines with age, and compensatory therapies that improve function may be at least modestly useful in a range of age-related conditions. So far, however, the available options (such as mitoQ and vitamin B3 derivatives like nicotinamide riboside) largely compare unfavorably to the benefits of exercise on mitochondrial function.

The recent FDA approval of elamipretide is for the treatment of a rare disease, as is often the case for new therapies with broad potential, as it is faster and easier to obtain approvals in rare disease indications. An approved therapy can be prescribed off-label for other uses, but it remains to be seen as to whether the community of anti-aging physicians develops a favorable view of elamipretide based on results in their patients, and whether the company is willing to manufacture enough of the drug for off-label use at this stage.

Stealth BioTherapeutics Inc. (the "Company" or "Stealth"), a commercial-stage biotechnology company focused on the discovery, development and commercialization of novel therapies for diseases involving mitochondrial dysfunction, today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to FORZINITY™ (elamipretide HCl) to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kilograms (kg) (approximately 66 pounds). Barth syndrome is a life-limiting pediatric mitochondrial cardioskeletal disease that affects approximately 150 individuals in the United States.

"The approval of FORZINITY, the first treatment option for Barth syndrome and the first FDA-approved mitochondria-targeted therapeutic, is a pivotal victory for the Barth syndrome community and offers hope for expedited regulatory attention to other ultra-rare diseases. We appreciate the FDA's close engagement in recent months and are grateful to the trial participants, caregivers, advocates, researchers and healthcare providers who persevered in partnership with us over this decade-long journey. We plan to continue providing expanded access to children weighing less than 30 kilograms who are currently receiving treatment or require emergency access, while we work with the FDA to generate data needed to expand the indication to include these children. We are committed to the continued development of therapies to treat all patients with Barth syndrome and other devastating diseases of mitochondrial dysfunction."

The approval of FORZINITY is supported by the efficacy and safety data from the TAZPOWER clinical trial. During the open-label portion of the TAZPOWER trial, knee extensor muscle strength improved from study baseline. The most common adverse reactions were injection site reactions which can be treated with oral antihistamines or topical corticosteroids. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.

Link: https://stealthbt.com/stealth-biotherapeutics-announces-fda-accelerated-approval-of-forzinity-elamipretide-hcl-the-first-therapy-for-progressive-and-life-limiting-ultra-rare-genetic-disease-barth-syndrome/

A number of lines of research indicate that coordination of gene expression within and between cells deteriorates with age. If any two genes are tightly correlated in the expression levels in youth, that correlation tends to decline in strength with age. On the one hand there is increased noise in the distribution of behaviors from cell to cell in response to the same environmental circumstances. Further, where systems of regulation interact with one another, those interactions drift out of synchronization, such as the loss of coordination between central and peripheral circadian clocks. We can hypothesize on how these changes might arise from a stochastic distribution across cell populations of the well known forms of damage associated with aging, including mutations in nuclear DNA, mitochondrial dysfunction, and cellular senescence. But clear chains of cause and effect are at present challenging to establish in the complexity of the biochemistry of a single cell, never mind in tissues and organisms made up of countless such cells.

Nonetheless, measures of loss of coordination of gene expression might prove to be useful biomarkers of aging. This is the conclusion of today's open access paper on the topic. Many age-related changes are visible and interesting in large study populations, but are too varied in their behavior and relationships with the rest of biology to use effectively as biomarkers for individuals. Telomere length measured in immune cells from a blood sample is a good example. The researchers involved in the study noted here conclude that loss of coordination in gene expression is not like this, and does in fact correlate well with other measures of aging on an individual basis. They go on to speculate on whether this loss of coordination is pathological, a cause of age-related dysfunction. Are specific aspects of age-related changes in gene expression meaningfully harmful in and of themselves, or are they a reaction to other harms that do not in and of themselves cause much further damage? That is an ongoing debate, and it won't be settled here.

Personalized transcriptional network analysis links age-related loss of gene coordination to individual biological aging

Aging is characterized by widespread dysregulation across various biological levels, including a decline in gene-to-gene transcriptional coordination. This decline leads to reconfigured interrelations within gene transcriptional networks, which warrants study to better understand the biological system disorders in the aging process. However, the gene pair coordinated expression relationships (CERs) in past analyses were estimated using correlation coefficients across a bulk of samples, capturing only population-level trends. Changes in CERs within individuals during aging remain unclear. Especially since such an analysis cannot determine whether two genes are coordinated in a single individual, it is difficult to connect the gene coordination to personalized biological functioning and health status, thus limiting its potential as an indicator or biomarker of an individual's biological aging or even disease risk. Therefore, a study focusing on gene-to-gene transcriptional coordination at an individual-specific level is urgently needed to gain deeper insights into its biological significance in aging and even age-related outcomes.

To systematically explore the individual-level gene-gene expression coordination dynamics during aging, we constructed 15,933 personalized transcriptional networks in 26 tissues from 967 donors (ranged from 20 to 80 years old), sourced from the Genotype-Tissue Expression (GTEx) project. We revealed that the loss of gene coordination is positively correlated to an individual's senescence-related molecular traits (e.g., senescence-associated secretory phenotype (SASP) and immune cell infiltration) and biological functioning processes (e.g., reactive oxidative species (ROS) and oxidative phosphorylation). Notably, we provided evidence showing that age-related CER loss has the potential to serve as an indicator of an individual's biological aging and health status. Moreover, we found that gene-to-gene relationship loss during aging leads to disrupted gene expression coordination in key pathways, such as proteolysis, which are closely related to longevity and healthy aging. Further analysis indicated that the aging-related CER loss may be pathogenic in a gene dosage-dependent manner.

Here, researchers link increased expression of IL-33 to increased cellular senescence and dysfunction in cartilage tissue in joints and the consequent progression of osteoarthritis. Using small interfering RNA to reduce IL-33 expression, the researchers demonstrate a slowing of the progression of this destructive condition in an animal model. Regeneration of damaged cartilage remains a preferred goal, but progress on that front is slow, and research and development tends to focus more on available approaches than on approaches that require an uncertain amount of work to realize.

Osteoarthritis (OA) imposes a substantial health and economic burden globally. Currently, there is a lack of disease-modifying osteoarthritis drugs (DMOADs). This study aimed to elucidate the relationship between chondrocyte senescence and OA progression, as well as to develop an effective small interfering RNA (siRNA) nanodelivery platform for OA treatment. We engineered neutrophil membrane-coated, siIL33-loaded nanoparticles (NM-NP-siIL33) for OA management. The therapeutic efficacy of NM-NP-siIL33 was evaluated through both in vitro and in vivo experiments.

Our findings revealed that IL-33 expression was significantly upregulated in damaged articular cartilage in both young and aged mice following anterior cruciate ligament transection (ACLT) surgery. In vitro experiments demonstrated that IL-33 promotes chondrocyte senescence by inhibiting cellular autophagy via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Additional in vivo studies showed that NM-NP-siIL33 effectively delivered siIL33 to target cells within OA tissues, thereby mitigating the degradation of articular cartilage. Our results suggest that IL-33 plays a critical role in OA progression by accelerating chondrocyte senescence. Furthermore, NM-NP-siIL33 represents a promising therapeutic strategy for managing OA.

Link: https://doi.org/10.1186/s12951-025-03686-3

Researchers here outline a mechanism by which excess fat tissue may accelerate the onset and progression of Alzheimer's disease, by affecting the content of extracellular vesicles passing into the brain, that in turn increase the aggregation of misfolded amyloid-β that is characteristic of the early stages of the condition. Excess visceral fat also contributes to chronic inflammation via a range of different mechanisms, and Alzheimer's disease is clearly an inflammatory condition. As is usually the case, determining which mechanisms of disease are more or less important than the others is challenging. It is unclear how much weight to assign to this new discovery.

Obesity is a major modifiable risk factor for Alzheimer's disease (AD), but the mechanistic link between peripheral metabolic dysfunction and AD progression remains unclear. Adipose-derived extracellular vesicles (EVs) may penetrate the brain and alter lipid homeostasis, contributing to neurodegeneration. We isolated exosome-enriched EVs from subcutaneous and visceral fat of lean and obese individuals, followed by lipidomic profiling. An in vitro amyloid-β (Aβ) aggregation assay using purified Aβ40 and Aβ42 peptides was performed under lipid environments mimicking physiological and pathological states.

Our study shows that EVs from obese adipose tissue carry specific lipid species that modulate Aβ40 and Aβ42 aggregation in a lipid-type- and concentration-dependent manner. These findings provide compelling molecular evidence linking peripheral lipid imbalance to Aβ aggregation, suggesting that metabolic dysfunction associated with obesity may contribute to central amyloid pathology via adipose-derived EV lipids. Further in vivo validation is warranted to substantiate this proposed link. These findings support lipid-targeted strategies as potential therapeutics for neurodegenerative diseases.

Link: https://doi.org/10.1002/alz.70603

Amyotrophic lateral sclerosis (ALS) is a somewhat age-related disease in that it tends to show up in later life, with fewer than 10% of cases occurring under the age of 40. The relationship between age and risk of ALS is not a clear progression of increasing risk after age 40, however. Most patients with ALS start to exhibit the condition in their 40s or 50s, and the risk declines at older ages. The reasons for this remain obscure, as the research community has struggled to identify the cause of the condition, or even why it progresses very rapidly in some patients versus more slowly in others.

There has long been a strong suspicion than ALS is an autoimmune disease, based on the relationship with age and other aspects of its epidemiology, even lacking firm mechanistic proof of that suspicion. Today's research materials offer a first step towards that firm proof. Researchers provide a mechanism by which the immune system malfunctions to attack motor neurons, and aspects of this mechanism can explain the difference between patients whose disease proves fatal within a couple of years and those who live on for a decade or more.

As this and the relatively recent discovery of type 4 diabetes indicates, we might suspect that a great deal of poorly characterized, quite varied, and poorly understood autoimmunity occurs in later life as the immune system finds ways to malfunction in response to the damage and dysfunction of aging. Only when the onset of a form of autoimmunity occurs relatively early in later life and the outcome is quite characteristic across much of the patient population do we see a lot of attention given to the problem. And even there, as ALS demonstrates, it can take a long time to make progress. Meanwhile the suspected autoimmunities of later old age are obscured by other health issues, and receive comparatively little attention from the research community.

ALS appears to be an autoimmune disease

Around 5,000 Americans are diagnosed with amyotrophic lateral sclerosis (ALS) each year. About half of patients die within 14 to 18 months of being diagnosed, usually due to breathing failure. The exact cause of ALS has long been unknown. Now, scientists have uncovered evidence that ALS may be an autoimmune disease. The researchers discovered that inflammatory immune cells, called CD4+ T cells, mistakenly target a specific protein (called C9orf72), which is expressed in neurons. This kind of "self-attack" is the defining feature of autoimmune disease.

By examining T cell responses in ALS patients, the researchers were surprised to find two distinct patient groups. One group had shorter predicted survival times. Their inflammatory CD4+ T cells were quick to release inflammatory mediators when they recognized C9orf72 proteins. The second patient group also had harmful inflammatory CD4+ T cells, but they also had higher numbers of different T cells, anti-inflammatory CD4+ T cells. This second group also had significantly longer projected survival times. This suggests that the anti-inflammatory CD4+ T cells may reduce harmful autoimmune responses and slow the progression of ALS.

Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Neuroinflammation is apparent in affected tissues, including increased T cell infiltration and activation of microglia, particularly in the spinal cord. Autoimmune responses are thought to have a key role in ALS pathology, and it is hypothesized that T cells contribute to the rapid loss of neurons during disease progression. However, until now there has been no reported target for such an autoimmune response.

Here we show that ALS is associated with recognition of the C9orf72 antigen, and we map the specific epitopes that are recognized. We show that these responses are mediated by CD4+ T cells that preferentially release IL-5 and IL-10, and that IL-10-mediated T cell responses are significantly greater in donors who have a longer predicted survival time. Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T cell responses. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells, and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.

There is a sizable literature of animal studies in which researchers increase or decrease intake of one specific dietary amino acid and observe the outcomes. Despite this, there are a lot of gaps and contradictory results in the understanding of the long term effects of increased intake of specific single amino acids, even for the smaller number of essential amino acids. Here, researchers find that increased cysteine intake can improve intestinal stem cell function in mice, and thus promote tissue health in the small intestine. While the context of the research is injury, such as the consequences of radiotherapy, this may be able to somewhat compensate for the loss of intestinal stem cell function that occurs with age.

A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear.

Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment.

These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

Link: https://doi.org/10.1038/s41586-025-09589-5

The H. pylori bacterium is famously associated with stomach ulcers; a researcher gave himself stomach ulcers by drinking a mix containing H. pylori to prove the point, in one of the more widely publicized self-experiments of recent history. Here, researchers review the evidence for H. pylori infection to correlate with the risk of suffering an aneurysm of the abdominal aorta. An aneurysm is a weakened blood vessel wall that forms a bulge at risk of rupture. In a major vessel such a rupture is frequently fatal. Inflammatory signaling is thought to be involved in the formation of an aneurysm, so one can consider that the persistent presence of a pathogen such as H. pylori may contribute via their effects on the inflammatory environment. There may be other mechanisms involved, however.

Abdominal aortic aneurysm (AAA) is a condition of considerable clinical importance, characterized by the dilation and weakening of the abdominal aorta. While several risk factors have been identified, recent studies have suggested a potential link between Helicobacter pylori infection (HPI) and the development of AAA. Abdominal aortic aneurysms pose a significant public health challenge, particularly among the elderly population. The prevalence of AAA increases with age, affecting a total of 35.12 million individuals, and its rupture can lead to catastrophic outcomes, including massive internal hemorrhage and mortality. Identifying modifiable risk factors is crucial for prevention and early intervention. Traditionally associated with gastric ulcers and gastritis, H. pylori is a bacterium that colonizes the gastric mucosa. However, recent investigations have explored its potential involvement in other systemic conditions, including cardiovascular diseases. It is hypothesized that chronic inflammation induced by H. pylori infection may contribute to the pathogenesis of AAA.

This study aims to quantify the association between Helicobacter pylori (H. pylori) infection and AAA development through a systematic review and meta-analysis, emphasizing numerical results for clarity. Following PRISMA guidelines, PubMed, SCOPUS, Medline, and Embase searches were conducted. Data extraction and quality assessment were performed using standardized tool. Among the 8 selected studies, H. pylori infection exhibited a statistically significant overall risk ratio of 1.54 for AAA development. Subgroup and sensitivity analyses were conducted to address high heterogeneity, revealing consistent results. These findings underscore the importance of further research to elucidate underlying mechanisms and inform preventive strategies and interventions aimed at mitigating the risk of AAA in individuals with H. pylori infection.

Link: https://doi.org/10.1186/s12872-025-05148-y

Methods of both modestly impairing and modestly improving mitochondrial function have been shown to slow aging in short-lived species such as flies and nematodes, albeit for different reasons. Every cell contains hundreds of mitochondria that undertake the energetic process of producing adenosine triphosphate (ATP), a chemical energy store molecule used to power cell operations. The chemistry of ATP manufacture produces damaging oxidative molecules as a side-effect, but that flux of oxidative molecules is also a signal that a cell reacts to with increased maintenance, such as an increase in autophagy to clear out damaged proteins and structures. Better mitochondrial function is directly helpful to the cell, but modestly worse mitochondrial function can inspire a sufficient increase in cell maintenance to still come out ahead. Better cell function throughout the body tends to translate to improved health and slowed aging.

In today's open access paper, researchers report on their assessment of one of the many approaches to modestly impair mitochondrial function, by impeding the uptake of calcium ions through the mitochondrial membrane. As is the case for a number of such approaches, this adjustment increases the production of oxidative molecules in mitochondria, causing the cell to react with improved maintenance. Interestingly, this harms survival in early life, which explains why evolution has not provided species with mitochondria altered in this way to slow aging and improve overall life span.

Enhancing Late-Life Survival and Mobility via Mitohormesis by Reducing Mitochondrial Calcium Levels

Mitochondrial calcium (Ca2+) homeostasis plays a critical role in aging and cellular fitness. In the search for novel antiaging approaches, we explored how genetic and pharmacological inhibition of mitochondrial Ca2+ uptake influences the lifespan and health of Caenorhabditis elegans. Using live-cell imaging, we demonstrate that RNA interference-mediated knockdown of mcu-1, the nematode ortholog of the mitochondrial Ca2+ uniporter (MCU), reduces mitochondrial Ca2+ levels, thereby extending lifespan and preserving motility during aging, while compromising early-life survival.

This longevity benefit requires intervention before day 14 and coincides with a transient increase in reactive oxygen species (ROS), which activates pathways involving pmk-1, daf-16, and skn-1, orthologs of human p38 mitogen-activated protein kinase (p38 MAPK), forkhead box O (FOXO), and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. This pathway promotes antioxidant defense mechanisms and preserves mitochondrial structure and function during aging, maintaining larger, more interconnected mitochondria and restoring the oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio and oxygen consumption rates to youthful levels.

Pharmacological inhibition of mitochondrial Ca2+ uptake using the MCU inhibitor mitoxantrone mirrors the effects of mcu-1 knockdown, extending lifespan and improving fitness in aged nematodes. In human foreskin fibroblasts, short-term mitoxantrone treatment also transiently elevates ROS production and induces enhanced expression and activity of antioxidant defense enzymes, underscoring the translational relevance of findings from nematodes to human cells. Our findings suggest that modulation of mitochondrial Ca2+ uptake induces mitohormesis through ROS-mediated signaling, promoting improved longevity and healthspan in nematodes, with possible implications for healthy aging in humans.

The search for genetic determinants of longevity in humans has, on the whole, not gone well. Only a very small number of widespread gene variants (such as those in the APOE gene) manage to show effects on life span in multiple study populations, and their effect sizes are largely much smaller than those attributed to exercise. The modern existence of large genetic databases has, if anything, pushed down the estimate of the degree to which genetic variation contributes to longevity. The study of the genetics of extremely long-lived individuals has been underway a while and has not produced data to support a credible set of longevity genes. We are left with a picture of thousands of relevant genes, with every single variant exerting a situational, small contribution, and collectively their influence on longevity far outweighed by the effects of lifestyle choices. Nonetheless, researchers continue to produce studies such as the one noted here, and as for any such study, based on past outcomes we should expect there to be low odds of the results replicating in a different study population.

Aging, age-related diseases, and longevity are interconnected processes influenced by shared molecular and genetic mechanisms. In this study, we investigated the role of genetic variation in the Chromogranin A (CHGA) gene, which encodes a multifunctional precursor of regulatory peptides, in human longevity and age-related traits. Using a case-control design with two age cohorts (older adults: 65-85 years; long-lived: 86-107 years), we analysed nine selected CHGA single nucleotide polymorphisms (SNPs) for associations with survival to advanced age and relevant clinical parameters.

Five SNPs (rs9658628, rs9658631, rs9658634, rs7159323, and rs7610) were significantly associated with longevity. In the older adult cohort, the 5′-UTR rs9658628-A allele was associated to reduced odds of reaching advanced age and correlated with increased insulin resistance, type 2 diabetes, and lower cognitive performance, traits typically linked to higher mortality risk. Paradoxically, this allele was also associated with a lower risk of cardiovascular disease, suggesting pleiotropic effects potentially mediated by its regulatory effects on CHGA expression across different tissues. Functional annotation supported rs9658628 as an expression quantitative trait locus (eQTL) for CHGA and neighboring genes (ITPK1, FBLN5 genes in particular) in relevant tissues. Additionally, the 3′-UTR rs7610-T allele was associated with both increased diastolic blood pressure and enhanced survival, highlighting the complexity of blood pressure regulation in aging.

These findings suggest that genetic variations in CHGA exert a complex and multifactorial influence on pathways related to metabolism, cognition, and vascular health, with possible consequences for longevity. This intricate pattern could be due to the multiple, sometimes opposing, functions of CHGA and its active fragments. The biological rationale and potential clinical implications of these associations call for further investigation and independent confirmation.

Link: https://doi.org/10.3389/fragi.2025.1625070

Researchers can now accurately measure the composition of the gut microbiome, and how the distribution of different microbial species changes for the worse in association with age and disease. Studies have been conducted to map specific changes in the gut microbiome to specific diseases and outcomes. Another ongoing project is to link these relatively new findings with the established body of work covering the effects of diet on long-term health. Diet evidently has considerable influence over the composition of the gut microbiome, but there is a great deal of room to understand at the detail level how diet, disease, aging, and the gut microbiome interact with one another.

The interplay between diet, gut microbiota, and aging represents a dynamic and modifiable system with profound implications for human health. Aging is accompanied by notable shifts in gut microbial composition, including reduced diversity and the loss of beneficial taxa, which contribute to systemic inflammation, impaired immunity, and metabolic dysfunction. However, dietary patterns, especially those rich in fiber, polyphenols, and healthy fats, can reshape the microbiota, enhance production of beneficial metabolites, like short-chain fatty acids, and mitigate age-related decline. The Mediterranean, plant-based, and other nutrient-rich diets have shown promise in promoting microbial profiles associated with reduced frailty, preserved cognition, and improved metabolic health.

Importantly, the gut microbiota functions not just as a target but also as a mediator, translating dietary inputs into molecular signals that influence host aging processes. Emerging evidence supports the potential of microbiota-targeted dietary interventions such as prebiotics, probiotics, and precision nutrition to promote healthy aging. Nonetheless, translating these findings into real-world solutions requires deeper mechanistic insights and broader clinical validation. By recognizing the gut microbiota as a key interface between nutrition and aging, future strategies may more effectively support longevity and functional health across the lifespan.

Link: https://doi.org/10.3390/ijms26188785

Type 2 diabetes is near entirely a condition caused by the presence of excess visceral fat tissue, by being overweight or obese. Even in relatively late stages, type 2 diabetes can be reversed by low calorie diets and the consequent loss of that excess visceral fat. Visceral fat is metabolically active, and directly provokes chronic inflammation through a range of mechanisms, such as by mimicking the signaling of cells infected by pathogens. Excess visceral fat also disrupts insulin metabolism and control of blood glucose. The abnormal, sugar-rich diabetic metabolism also directly provokes inflammation, such as via the interaction between molecules altered by sugars known as advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE) on cell surfaces.

However it is caused, unresolved inflammatory signaling is disruptive to tissue function and structure, changing the behavior of cells for the worse. This chronic inflammation accelerates the onset and progression of all of the common fatal age-related conditions. That outcome is well established, both the mechanisms and the epidemiology demonstrating correlations between inflammation and age-related diseases.

Today's research materials add to the existing mountain of epidemiological data that aims to quantify the harms done by type 2 diabetes. As one might expect, patients with type 2 diabetes have significantly worse outcomes in long-term health. Sadly we live in an era in which obesity is prevalent, for reasons that have yet to be concretely determined. Many factors may contribute, from lesser degrees of exercise to refined dietary components that were not common a century ago to microplastics in the environment. Whatever the hierarchy of causes, the outcome is clearly harmful to health, medical costs, and life expectancy.

Type 2 diabetes may accelerate development of multiple chronic diseases, particularly in the early stages

Type 2 diabetes (T2D) is projected to become the biggest epidemic disease in the world, affecting an estimated 1.3 billion people by 2050. T2D frequently occurs with other chronic conditions, such as high blood pressure, heart failure, chronic kidney disease, and depression, contributing substantially to the global burden of multimorbidity. Researchers explored how T2D influenced the rate of chronic disease development in 502,368 UK Biobank participants. The average age of the participants at enrollment was 58 years, and around 46% were men. Researchers used health records to track health outcomes over 15 years on average.

To calculate the pace of chronic disease development, researchers used multistate models to compare transition rates between groups with equivalent total disease. For example, they compared how long it took someone with T2D and one additional chronic condition to acquire a third condition, versus how long it took someone with two non-T2D chronic conditions to develop another condition. This approach isolates the role of T2D by ensuring both groups start with the same total number of chronic conditions.

Individuals with T2D consistently experienced higher transition rates (more rapid progression) between multiple disease stages. For example, for individuals with two chronic conditions, those with T2D as one of them progressed to a third condition at a rate of 5.7% per year, compared to 3.5% per year for those with two non-T2D conditions. This corresponds to people with T2D continuously facing a 60% higher risk of a new disease being diagnosed compared to those without T2D.

The role of type 2 diabetes in shaping multimorbidity progression: evidence from the UK Biobank cohort

We analyzed data from the UK Biobank, a prospective population-based cohort study (n=502,368, median age 58 years [range 37-73], 46% male at baseline) with a median follow-up 15.3 year. 9.5% of participants were diagnosed with T2D over the period. We counted the current number of morbidities (among 80 long-term chronic conditions) identified through hospital admission records using ICD-10 diagnosis codes.

The total follow-up time was 7.5 million person-years (PY), of which 0.33 million PY was in T2D. Individuals with T2D consistently experienced higher transition rates between morbidity transition stages. For example, the transition rate from 2 to 3 morbidities was 3.48 per 100 PY without the presence of T2D, compared to 5.68 per 100 PY once T2D was present (rate ratio=1.6). The disproportion of transition rates was most pronounced in early disease stages. Further, the transition rates were consistently influenced by T2D status and age, with younger individuals with T2D showing the most accelerated progression.

Hundreds of mitochondria are present in every cell, responsible for generating chemical energy store molecules to power cell processes. Mitochondria are the descendants of ancient symbiotic bacteria, still replicate like bacteria, and retain a remnant genome. With age mitochondria become dysfunctional for reasons relating to damage to mitochondrial DNA and changes in the expression of mitochondrial genes in the cell nucleus. This dysfunction is known to contribute to the chronic inflammation of aging via its interaction with innate immune mechanisms, making rejuvenation of mitochondria an important goal in the treatment of aging. While this paper is focused on the aging of the ovaries, most of the discussion of mechanisms is relevant to the rest of the body as well, as mitochondrial dysfunction occurs in all tissues with age.

Ovarian ageing is a key factor in the decline of female fertility. It is primarily characterised by diminished oocyte quality, follicular depletion, and dysregulated hormone levels. In recent years, mitochondria-driven inflammation has emerged as a potential mechanism in ovarian ageing. Mitochondrial dysfunction results in the accumulation of reactive oxygen species (ROS) and the release of mitochondrial DNA (mtDNA), as well as the leakage of mitochondrial components and metabolites into the cytosol or extracellular space. These elements act as damage-associated molecular patterns (DAMPs), activating inflammasomes like NLRP3, thereby initiating and amplifying innate immune responses and contributing to sustained inflammation.

The differential regulation of these signals under physiological versus pathological ageing conditions is particularly poorly characterised. Moreover, existing therapeutic strategies often target isolated pathways. For instance, antioxidant treatments may reduce ROS accumulation but have limited effects on the broader signalling networks involved in ovarian ageing. From a clinical translation perspective, several challenges remain, including insufficient drug targeting, unclear optimal timing of intervention, and limited understanding of long-term safety. For example, during the activation of primordial follicles, augmented mitochondrial biogenesis contributes to the preservation of oocyte energy balance. Conversely, the follicular atresia phase is closely associated with excessive activation of inflammatory signalling, and moderate inhibition of the NLRP3 inflammasome has demonstrated efficacy in retarding granulosa cell apoptosis and decelerating the atresia process. However, current therapeutic strategies lack the precision to temporally regulate these dynamic changes.

Link: https://doi.org/10.1186/s12967-025-06966-6

The most important lines of cancer research are those that might lead to therapies that can be applied to many (or even all) types of cancer with little adjustment of delivery or payload. This requires a mechanism that is present in most or all cancers, and which is essential to the cancer, such that cancer cells cannot just evolve away from using it in response to treatment. At present only a few areas of focus offer this potential, such as interference in telomere lengthening. Here, researchers describe a novel approach that seems to have a broad potential to treat the majority of cancers. It involves the delivery of a molecule that encourages T cells to bind to specific surface molecules that are characteristic of cancer cells, but which normally bind poorly and have thus been ignored as a possible target in the past.

Bispecific antibodies and chimeric antigen receptor T cells (CAR T) potently reduce tumor burden in B cell-related malignancies. Both trigger T cell-mediated killing of cancer cells by targeting a cell-surface cancer antigen using modified antibodies. However, applying this therapeutic strategy to the majority of cancer types, particularly solid cancers, is limited by a lack of safe targetable protein antigens.

Many cell-surface cancer antigens are not proteins but rather complex carbohydrates and are termed "tumor-associated carbohydrate antigens" (TACAs). Two well-described TACAs are β1,6GlcNAc-branched N-glycans and the Tn antigen, the latter an abnormally truncated O-glycan. As both markers and drivers of diverse cancers, β1,6-branching and Tn antigen provide excellent targets for antigen-specific immunotherapies. However, anti-glycan antibodies typically have affinities 1,000-100,000-fold lower than antibodies to peptide antigens. This is due to higher flexibility of glycans than peptides, absence of T cell help to B cells from lack of major histocompatibility complex (MHC) presentation of pure glycans, and attachment of glycans to a vast array of different proteins/lipids resulting in a non-uniform antigen.

The inability to generate an antibody to β1,6-branching and effective antibodies to pure Tn antigen has prevented effective targeting of these well-established tumor-associated antigens. To address this issue, we envisioned a class of immunotherapeutics that utilize sugar-binding proteins (lectins) that have well-established specificity, rather than antibodies, to target glycan antigens. We have termed this "glycan-dependent T cell recruiter" (GlyTR, pronounced "glitter"). GlyTR bispecific proteins fuse a carbohydrate-recognition domain (CRD) from a lectin to a single-chain variable fragment (scFv) from an antibody targeting CD3. Lectins utilize high binding avidity (velcro-like binding) to achieve specificity for glycan targets. This is in distinction to antibodies, where high affinity (key-lock binding) achieves specificity.

We developed GlyTR1 and GlyTR2 to bind immunosuppressive β1,6GlcNAc-branched N-glycans or multiple TACAs, respectively. GlyTR1 and GlyTR2 overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Thus density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.

Link: https://doi.org/10.1016/j.cell.2025.09.001

There is at present a tremendous appetite for the development of novel pharmacological approaches to weight loss. This is in large part a response to the rising prevalence of obesity. No robustly proven answer exists as to the question of why exactly people are now becoming obese in such large numbers. There is no shortage of hypotheses, from excessive use of modern sugar substitutes to lack of exercise to specific widespread dietary additives to the presence of microplastics in the environment to changes in the average gut microbiome composition. The absence of a good answer and means of prevention means that efforts have turned to pharmacology for weight loss. This is not a new phenomenon, weight loss drugs have been greeted with enthusiasm since use of the mitochondrial uncoupler 2,4-dinitrophenol was pioneered in the early 20th century. The recent financial success of GLP-1 receptor agonists, that induce weight loss by suppressing appetite, has improved the prospects for any research efforts that can be in some way tied to producing weight loss.

So to the topic of today's open access paper, the effects of MT1-MMP in the aging brain. It appears that in parallel to effects on satiety and appetite, MT1-MMP also influences a range of mechanisms relevant to neurodegenerative conditions. Expression of MT1-MMP rises with age, perhaps driven by the chronic inflammation of aging, and this may be a useful target for the development of therapies. Interestingly, pharmacological inhibition of MT1-MMP activity restores some of the cognitive function lost to either aging or obesity when assessed in mice. Given that inhibition of MT1-MMP affects energy metabolism and produces weight loss, the balance of mechanisms involved in benefits produced in old mice versus obese mice may be quite different.

MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol.

Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity.

Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.

Cryonics is important. Low-temperature storage of the brain is presently the only near-term approach that can provide those who die from old age with some greater than zero chance at a renewed life in the future. The cryonics industry has remained small since its inception decades ago, and only a few hundred people have been cryopreserved. The best way to expand and advance the small cryonics industry is to develop reversible vitrification of organs, a capability that has been demonstrated at the small scale in laboratories, and which has tremendous value to the organ transplant industry if made reliable. The ability to store a donated organ indefinitely would change all of the presently challenging economics of transplantation, and bring significant new funding into efforts to make cryopreservation that much more robust. Further, acceptance of the ability to vitrify and thaw organs would make acceptance of cryopreservation as a life-saving medical intervention of last resort that much easier.

Cryonics startup Until Labs has closed a $58 million Series A financing round, bringing its total raised to over $100 million as it works to build technology for reversible cryopreservation. The new funding round will enable Until to expand its team and infrastructure while advancing its first medical product: organ cryopreservation for transplant patients and surgeons.

The company's immediate focus is on overcoming one of transplant medicine's most rigid bottlenecks: the narrow window of organ viability. Hearts, lungs and livers must reach recipients within 4 to 12 hours of procurement, while kidneys last no longer than 24 to 36. These limits dictate the logistics of transplantation, confining patients to hospitals, requiring surgeons to charter planes to retrieve organs, and resulting in thousands of donations being discarded each year due to timing mismatches.

To address these challenges, Until is developing perfusion hardware, cryoprotective agents, and rapid rewarming infrastructure designed to preserve organs indefinitely without damaging their structure or function, then safely restore them for transplantation. The company says it has already built a discovery engine for new cryoprotective molecules, created a custom electromagnet for rewarming, and scaled its work from neural tissue slices to large-animal organs. It is now focused on refining protocols that preserve post-thaw organ quality.

The company's longer-term vision, however, extends far beyond transplant logistics, ultimately aiming for the holy grail of whole-body reversible cryopreservation. Its early work demonstrated recovery of electrical activity in rewarmed slices of rodent neural tissue. The company's previously stated roadmap includes showing preserved synaptic function in neural samples, successful cryopreservation of large-animal organs, human organ preservation clinical trials, and eventually reversible whole-body cryopreservation in animal models.

Link: https://longevity.technology/news/cryopreservation-startup-lands-58m-to-pause-biological-time/

Considerations of the role of dysfunction of oligodendrocytes and their precursor cell population in aging usually focus on myelination. Oligodendrocytes are responsible for maintaining the insulating myelin structure that wraps the axons that connect neurons, and which is required for effective propagation of nerve impulses. Researchers have shown that this function declines with age, perhaps to a meaningful degree. Here, however, researchers instead focus on the effects of cellular senescence in oligodendrocyte precursor cells. Senescent cells accumulate with age in the body and brain, and are well known to cause harm to the degree to which they linger and their population grows. Different cell types likely produce different specific harms when they become senescent, however. The researchers show that specific components of the inflammatory signaling produced by senescent oligodendrocyte precursor cells interfere in the activity of other cells in the brain to accelerate cognitive decline.

Aging contributes to cognitive decline in the adult brain with unclear mechanisms. Cellular senescence is characterized by an irreversible cell cycle arrest and featured by the senescence-associated secretory phenotype (SASP). The latter contains pro-inflammatory cytokines, chemokines, growth factors, and proteases, through which senescent cells affect themselves and the neighboring cells via autocrine and paracrine mechanisms. Distinct types of neural cells such as neurons, astrocytes, microglia, and oligodendrocyte precursor cells (OPCs) have been shown to express senescent markers, and these senescent cells accumulate in the brains with aging and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The selective elimination of these senescent cells attenuates cognitive deficits in naturally aged mice and reduces the accumulation of hyperphosphorylation of tau and amyloid-β in AD transgenic mice. However, despite these beneficial effects, which types of cells are predominant players in driving brain aging and how these senescent cells contribute to aging-related cognitive decline remain unknown.

OPCs, evenly distributed throughout the adult brain, are the primary proliferative cells in the adult central nervous system (CNS). One of the pivotal roles of OPCs is their capability to generate oligodendrocytes (OLs), which produce myelin, ensuring the fast and reliable conduction of action potentials (APs) and providing metabolic support to axons. Apart from being the cellular source of myelin, recent studies point out a myelination-independent function of OPCs in maintaining adult brain networks. OPCs regulate cognitive behaviors via secreting soluble factors and phagocytotic remodeling of synapses and axons. It is worth noting that OPCs form bona fide synapses with glutamatergic and GABAergic neurons. However, it remains unknown how OPCs regulate neuronal plasticity and whether the myelination-independent functions of OPCs are involved in aging-associated cognitive decline.

In this study, we report a myelination-independent role of OPCs in exaggerating cognitive decline in the aging brain via suppressing neuronal plasticity. Our results demonstrate that macroautophagic flux declines in aged OPCs. Inactivation of autophagy promotes the senescence of OPCs, which activates CCL3/CCL5 signaling to activate the CCR5 receptor. Through this, autophagy-defective OPCs impair glutamatergic transmission, neuronal excitability, and long-term potentiation, exaggerating the cognitive decline in the aging brain. Inhibition of CCR5 rescues this impaired neuronal plasticity and cognitive deficits.

Link: https://doi.org/10.1126/sciadv.adq7665

Gene therapies for neurodegenerative diseases that involve direct injection into portions of the brain have become acceptable enough to regulators that there is now progress towards the clinic on this front. This is despite the invasive nature of the delivery, and despite the high bar for safety that that tends to be applied to treatments that produce permanent changes in a patient. One might look at a recent trial for Huntington's disease, for example. This willingness on the part of regulators to allow more adventurous approaches might reflect a growing frustration with the failure to generate curative (or even meaningfully preventative) therapies for prevalent neurodegenerative conditions, after decades of significant funding and effort.

Another example at an earlier stage of development is the reprogramming approach taken by YouthBio Therapeutics. The company intends to deploy a viral vector injected into the brain in order to insert reprogramming factors that are only activated in the presence of a small molecule such as doxycycline - so after the initial therapy, partial reprogramming of cells to restore a more youthful function can be induced as needed. This approach will be used to treat Alzheimer's disease. The company recently held its first formal interaction with the FDA, one step on a long path towards discovering and satisfying regulatory requirements prior to a clinical trial.

YouthBio Therapeutics Announces Positive FDA INTERACT Feedback for YB002, Establishing Clear Path to Clinic for First-in-Class Alzheimer's Gene Therapy

YouthBio Therapeutics, a biotechnology company pioneering partial cellular reprogramming to treat diseases of aging, today announced a successful INTERACT meeting with the FDA for its lead Alzheimer's candidate, YB002. In its formal response, the FDA agreed that existing preclinical data support the bioactivity of YB002 and YouthBio's proposed first-in-human trial. This feedback represents a major de-risking event for YouthBio, which will now focus on CMC activities and a pilot toxicology study to support a Pre-IND meeting and finalize designs for IND-enabling studies.

This milestone continues YouthBio's strong record of execution. It builds upon compelling scientific evidence, including a study in which YB002 ameliorated cognitive decline in mice. Additional Alzheimer's models have demonstrated that partial reprogramming can reverse disease pathologies, counteract epigenetic aging, and rescue memory and learning. YB002 is a first-in-class gene therapy designed to safely and transiently express Yamanaka factors in the brain - a process known as partial reprogramming. This approach aims to reverse epigenetic changes that accumulate with aging while preserving cell identity, thereby restoring youthful gene expression and improving cellular function.

YouthBio's Science

we are working on a gene therapy that involves delivering genes responsible for epigenetic rejuvenation into target tissues. These genes would be inactive by default but can be periodically activated by a small molecule, rolling back the epigenetics of target tissues to a younger level and rejuvenating them. Our long-term vision is to apply this therapy systemically, decreasing patients' biological age and improving their health. Numerous studies have provided strong evidence for the rejuvenating power of partial reprogramming, showcasing its potential in various contexts, such as improved muscle regeneration, heart regeneration, and intervertebral disc rejuvenation. The results of these studies serve as the foundation for our work at YouthBio.

When examining human epidemiological data, a web of correlations link health, life span, education, wealth, intelligence, and socioeconomic status. One can hypothesize about why these correlations exist, and to what degree different mechanisms contribute to the overall effect, but it remains challenging to draw firm conclusions from the data. For example, reasonably compelling evidence suggests that intelligence is related to physical resilience via biological mechanisms, and so relationships between intelligence and health outcomes may not be entirely a matter of behavior. How much is behavior versus physiology is up for debate. The paper noted here is focused on socioeconomic status and is illustrative of much of the research into such correlations, in that it suggests that a differing distribution of lifestyle choices across the socioeconomic spectrum is not the only mechanism at play in producing differences in health outcomes.

Lifestyle factors significantly influence the risk of developing non-communicable diseases like type 2 diabetes, cancer, and cardiovascular diseases and can modify health trajectories towards multimorbidity. Separately, socioeconomic position (SEP) is a key determinant of health outcomes and is recognised as a driver of inequalities in the risk of multimorbidity. Multimorbidity is socially patterned, with lower SEP linked to higher risk.

We examined whether a Healthy Lifestyle Index (HLI) mediates the SEP-multimorbidity association. We used data from 244,886 participants in the European Prospective Investigation into Cancer and Nutrition study. HLI was derived from smoking, alcohol consumption, physical activity, body mass index, and diet. SEP was categorised into low, medium and high-SEP based on education. Multimorbidity was defined as the coexistence of at least two diseases among cancer, type 2 diabetes, and cardiovascular diseases.

Participants from lower SEP categories were older with worse health outcomes. Women had a healthier lifestyle than men across all SEP levels. In men, the hazard ratio of developing multimorbidity was 1.40 for those with low SEP compared with high SEP, in women 1.74. The study suggests that lifestyle factors partially mediate the relationship between SEP and the development of multimorbidity. However, this also indicates that other factors beyond lifestyle, such as biological or social determinants, may be at play.

Link: https://doi.org/10.1136/jech-2025-224476

The liver is perhaps the most regenerative organ in the body, but like all other organs it is negatively affected by the accumulation of cell and tissue damage characteristic of aging. Liver function is reduced, while prevalent liver diseases such as metabolic dysfunction-associated steatoheptatitis occur more readily in older people than in younger people. With this in mind, researchers here present a tour of vulnerabilities to disease and dysfunction that are induced by mechanisms of aging in the liver.

While the liver can maintain some of its homeostatic functions throughout aging, it becomes highly susceptible to liver injury and chronic liver disease. This susceptibility is mainly due to decreased hepatic volume, reduced blood flow, altered microvasculature, defective metabolizing enzymes, impaired proteostasis, mitochondrial dysfunction, and reduced expression of hormone receptors. Furthermore, chronic exposure to external factors such as polypharmacy, excessive alcohol consumption, and nutritional imbalances may exacerbate harmful inflammatory signaling, cellular senescence, and elevated oxidative stress. These changes ultimately hinder the aged liver's ability to manage cell death and disease progression effectively. These age-related anatomical and molecular changes in the aged liver exacerbate ischemia-reperfusion injury (IRI), drug-induced liver injury (DILI), alcohol-associated liver disease (ALD), and metabolic dysfunction-associated steatotic liver disease (MASLD).

The proposed role of aging in liver diseases. (A) IRI: Aging livers experience reduced levels of ATG4B and PARKIN, leading to decreased autophagy/mitophagy and increased reactive oxygen species (ROS). Enhanced NF-κB activation in macrophages causes greater inflammation, worsening IRI. (B) DILI: Older adults have decreased liver drug metabolism due to reduced activity of CYP enzymes and lower clearance, along with diminished GSH and SOD levels. These factors, combined with polypharmacy, raise susceptibility to DILI. (C) ALD: Aging diminishes alcohol-metabolizing enzymes and proteostasis mechanisms like autophagy/proteasome. Decreased SIRT1 levels and increased inflammation further exacerbate ALD. (D) MASLD: The aging liver shows elevated necroptosis and ferroptosis proteins, increased lipogenesis, and inflammation, while fatty acid beta-oxidation and autophagy decrease, leading to more severe MASLD.

Link: https://doi.org/10.1097/HC9.0000000000000808

Tissues in the body are supported by distinct stem cell populations that reside within structures of supporting helper cells known as stem cell niches. The primary purpose of stem cells is to deliver a supply of daughter somatic cells to replace lost cells, though they also provide signaling that affects cell behavior. All tissues undergo a slow turnover of cells as there is a limit to the number of times a somatic cell can replicate. Telomeres are lengths of repeated DNA sequences at the end of chromosomes that shorten with each cell division. When telomeres become too short, a cell reaches what is known as the Hayflick limit and either becomes senescent and is destroyed by the immune system or undergoes programmed cell death. Stem cells can maintain long telomeres via telomerase expression, and thus the replacement somatic cells created by stem cells also have long telomeres, beginning the countdown again.

In today's open access paper, researchers look at the effects of fasting on a well-studied population of stem cells, those that support intestinal tissue. Intermittent fasting is well established to slow aging in animal studies, more so in short-lived species than in long-lived species. All of the reduced calorie intake strategies induce a beneficial response that improves metabolism and long-term health, provided sufficient nutrients are provided to stay well above the line of outright starvation. The function of stem cells is one of the many line items that are improved by these strategies. Normally, stem cell function declines with age for reasons that are complicated, incompletely mapped, and touch on many of the known underlying causes of aging. A lower calorie intake slows this process.

Aging Reduces Intestinal Stem Cell Activity in Killifish and Intermittent Fasting Reverses Intestinal Gene Expression Patterns

The process of aging is associated with a decline in cell, tissue, and organ function, leading to a range of health problems. Increasing evidence indicates that dietary restriction can counteract age-dependent effects and improve health and longevity in whole organisms, but less is known about the influence of aging and the impact of nutrition on individual organs of an organism.

In this study, we examined the intestine of the very short-lived aging model system, the African turquoise killifish (Nothobranchius furzeri), throughout its lifetime. We investigated the effects of age and nutrition on the preservation of gut tissue at stages corresponding to human neonatal, adolescent, adult, and old age, and integrated morphological measurements, histology, and transcriptomics.

The intestinal mucosa is characterized by folds and intervening interfold regions, where intestinal stem cells localize. The stem cells occur in clusters, and the cycle time of stem cells increases with age. We also observed a reduction in intestinal length and volume with age. Age-dependent transcriptomic profiling revealed significant changes in the expression of peripheral circadian clock genes and stem cell niche markers.

Notably, the majority of these genes maintained their adult gene expression levels in old age following intermittent fasting during adulthood. Therefore, our results demonstrate that the decline in structural intestinal tissue homeostasis is associated with a decline in stem cell activity that can be counteracted by intermittent fasting. Since the intestinal mucosa of killifish is similar to that of mammals, the results of this study can be translated to general gut biology.

Researchers here offer opinions reflective of the present research mainstream on which mechanisms are important in the aging of the heart and its consequent dysfunctions. This sort of article is an interesting measure of the degree to which the "aging is accumulated damage" viewpoint exemplified by the Strategies for Engineered Negligible Senescence (SENS) has won ground in the ongoing war of ideas regarding the matter of research strategy for the treatment of aging and age-related disease. For example: targeting senescent cells is now mainstream; mitochondrial dysfunction remains a topic in which everyone agrees there is a problem, but disagrees on the nature of that problem; and epigenetic change has been eagerly adopted as a point of intervention by a research community that was already spending much of its time on trying to adjust gene expression for therapeutic effect.

Cardiac aging is a fundamental driver of cardiovascular diseases (CVDs), the leading cause of global mortality. While age is a non-modifiable risk factor, understanding its underlying molecular basis offers new avenues for therapeutic intervention. This review synthesizes the key mechanisms driving cardiac aging and evaluates promising strategies to counteract them. Our aim is to provide a forward-looking perspective, arguing that a paradigm shift from single-target interventions to synergistic, systems-level approaches is necessary to promote healthy aging and longevity.

We delineate the hallmark structural and functional changes of the aging heart, including left ventricular hypertrophy, diastolic dysfunction, and increased fibrosis. We then explore the core molecular pathways, highlighting the critical roles of dysfunctional autophagy, mitochondrial oxidative stress, telomere shortening, and profound epigenetic shifts, particularly the dysregulation of non-coding RNAs such as miR-34a. Building on this mechanistic framework, we assess a range of interventions, from lifestyle modifications like caloric restriction to targeted pharmaceuticals including rapamycin and senolytics. Furthermore, we discuss the potential of next-generation therapies such as microbiome modulation, cell-based regeneration, and gene editing.

Link: https://doi.org/10.1016/j.phrs.2025.107954

Older epidemiological study data sometimes offers the potential for reanalysis with modern aging clock algorithms to assess biological age. If the study continued since the data was obtained, then there is the possibility to demonstrate that measures of biological age do correlate well with specific long-term outcomes. The downside is that researchers are limited by past choices regarding what was measured, and thus which clocks can be used, and often limited in the degree to which data obtained decades ago remains accessible. Nonetheless, sometimes it works out and we see results such as those reported here. A study has followed one birth cohort since the late 1940s, and proteomic data was obtained 15 years ago. That data has now been used to assess biological age at that time, then correlated with later medical outcomes over the following 15 year span of time.

The pace of organ ageing varies substantially between individuals, yet drivers of variability remain poorly understood. This gap is critical, given only 20-30% of longevity is genetically inherited and age-related diseases are leading causes of morbidity and mortality. Proteomic clocks allow organ ageing to be estimated from blood sampling, facilitating study of how life course exposures shape biological ageing heterogeneity. Here, we leverage the unique design of the MRC National Survey of Health and Development (NSHD), the world's oldest continuously followed birth cohort, to track 1,803 individuals across eight decades since birth in 1946.

At mean age 63.2 years, we estimated proteomic ageing in seven organs. Despite near identical chronological ages, participants' proteomes revealed biological ageing disparities spanning decades. Extreme ageing in multiple organs was a strong prognostic indicator for all-cause mortality over the following 15 years (hazard ratio 6.62 for ≥ 4 extremely aged organs).

Adversity and being overweight in adolescence associated with accelerated ageing decades later in life. Completing secondary school education and maintaining physical activity linked to relative biological youth. Mediation analyses indicated liver, kidney, and immune ageing linked life course exposures to mortality. Across 10,776 plasma protein targets, we identified 143 predictors of longevity, including MED9, strongly linked to diverse socio-behavioural exposures. These findings provide unique insights into which factors are likely to shape how we age, when in life they may be influential, and how biological effects emerge, informing healthy ageing promotion.

Link: https://doi.org/10.1101/2025.09.07.25335188