Fight Aging!

The immune system declines with age, and this causes more than just a progressive failure to adequately defend against infectious pathogens. The immune system is deeply involved in normal tissue function, maintenance, and regeneration. It is also responsible for destroying senescent and potentially cancerous cells throughout the body. Thus immune decline both degrades tissue function and increases the risk of cancer. Researchers tend to bucket aspects of immune aging into two broad categories, immunosenescence and inflammaging. Immunosenescence is the loss of capacity, while inflammation is a continual overactivation of the immune system, placing it in a state of chronic, unresolved inflammatory signaling.

There are obviously sex differences in the pace and structure of degenerative aging. In our species, women live longer but suffer greater disability. Given that the immune system touches on so much of heath and tissue function, we might expect to find a catalog of specific differences in immune system aging between the sexes. This is indeed the case. Today's open access paper provides a tour of what is known on this topic. It is possible that comparisons between the sexes might teach us useful things about aging, but equally the causes of aging are the same from individual to individual. The differences lie in the way in which damage spirals out into interacting webs of dysfunction and further damage. A therapy that targets an underlying cause of aging should be useful to all older individuals, though it is certainly possible that it will be more useful for some categories of individual than for others.

The problem with one-size-fits-all medicine: Biological sex and the aging immune system

The immune system can be divided into two categories: innate and adaptive. Innate immune cells (e.g., neutrophils, macrophages, and dendritic cells [DCs]) release cytokines and pro-inflammatory mediators that coordinate the immune response and protect the host. By contrast, the adaptive immune system provides a targeted and long-term defense against pathogens. While innate responses are rapid and general, adaptive immunity is slower and highly specific.

Like other biological systems, the immune system undergoes age-related functional decline. Indeed, the latest hallmarks of aging recognized by the field now include chronic inflammation as a distinct hallmark, recognizing its crucial role in aging phenotypes. Changes in the immune system can both promote or restrain aging across multiple organs. Two main characteristics of immune aging are 'immunosenescence' and 'inflammaging'. Together, these processes promote the development of age-associated diseases (e.g., atherosclerosis, dementia, osteoarthritis). Understanding hallmarks of immune aging is critical, as they influence both life span and healthspan.

In addition to shared age-related changes, sex differences further shape immune aging. Sex differences lead to divergent patterns of life span and healthspan between males and females. Overall, females tend to live longer than males, yet experience more age-related and immune-related diseases, whereas males are more likely to develop severe outcomes from infections. This discrepancy, in which females outlive males but spend more years in poor health, is referred to as the 'morbidity-mortality' paradox. One potential driver of sex differences in disease susceptibility and health outcomes is maternal-fetal microchimerism, which has been shown to modulate the immune system. However, sex differences in disease susceptibility and health outcomes are thought to be mainly driven by the effect of sex chromosomes (XX versus XY) and/or sex hormones on the immune system.

Indeed, the X chromosome contains many immune genes, some of which escape X inactivation with aging, contributing to stronger immune responses in females. By contrast, the Y chromosome encodes relatively few immune genes, which contributes to sex differences in immune system robustness. Reflecting this difference in copy number, females generally produce more cytokines than males regardless of age. Sex-steroid receptors are expressed broadly in immune cells, though absolute levels vary. Estrogens exert both pro-inflammatory and anti-inflammatory effects, depending on concentrations, whereas androgens suppress immune activity.

With aging, females maintain adaptive immune responses more effectively than males, suggesting that the female immune system has higher baseline activity, with stronger expression of adaptive versus innate immune pathways. Conversely, aging males rely more heavily on innate immunity, which may partly explain heightened innate responses but poorer outcomes following infections and vaccinations. This sex difference may be due to overall higher levels of testosterone in males, which has been shown to have important impacts the immune system over time. However, while stronger immune responses provide protection in females, they also increase autoimmunity risk with age. Sex differences in immune aging highlight how differences in both adaptive and innate immunity shape lifelong susceptibility to infections and age-related diseases, emphasizing the importance of sex as a biological variable in both immunological research and clinical care.

Far too little research into infectious disease and the development of vaccines and other approaches to therapy employs old animals. It is accepted that infectious disease becomes worse with age and treatments become less effective, and then left to the smaller aging research community to see if anything can be done about it. Here, for example, is an example of research in which scientists attempt to build an incrementally better picture as to what exactly is going wrong in the aging immune system, in the specific context of a single infectious disease, tuberculosis. Matters move slowly.

Aging profoundly impairs immune competence, a phenomenon termed immunosenescence, rendering older adults (≥60 years) highly vulnerable to infectious diseases such as tuberculosis (TB). Clinically, older adults exhibit reduced vaccine effectiveness alongside heightened susceptibility to TB, with epidemiological data indicating 2-3 times higher TB incidence and up to four times higher mortality than younger patients. Despite this growing burden, current TB research predominantly employs young adult mouse models (6-8 weeks old, equivalent to ~18-year-old humans), which do not adequately capture the immune landscape of older hosts. Evidence from studies suggests that old mice exhibit higher bacterial burden, delayed CD4+ T cell responses, and altered immune activation compared to younger counterparts. However, the impact of immunosenescence on bacterial clearance dynamics, immune cell phenotypes, and host responses during TB treatment remain largely unexplored.

Here, we monitored the immunopathology, frequency, and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with TB and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks post infection, mycobacterial load in tissues (lung, spleen, and liver) of old (17-19 months old) and aged (31 months old) C57BL/6 mice was similar to that of young (2-4 month old) mice. However, at two weeks post-treatment, older mice showed a slower rate of TB clearance in the lungs. TB-infected old mice had higher splenic T-follicular cytotoxic (TFC)-like cells, and proteomic analysis of flow-sorted CD4+CD44+ T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase, and prostaglandin E synthase), suggesting impaired mitochondrial function.

Collectively, these findings suggest that age-associated immune alterations may disrupt immunometabolic pathways, thereby contributing to the delayed TB clearance. Targeting immunometabolic dysfunction therefore represents a promising strategy to enhance TB treatment efficacy and reduce disease burden in older populations.

Link: https://doi.org/10.18632/aging.206374

Given access to a large body of biological data from people of various ages, creating an aging clock from that data is fairly straightforward and costs relatively little in time and funding. Thus clocks are proliferating, a new one published by an academic research group every few months. Most will vanish into obscurity. The problem is not the lack of a perfect clock for any given situation, but the lack of understanding as to how any given clock will react to a novel potential approach to slowing or reversing aging. The real potential value of clocks is not risk estimation for patients, but rather the rapid assessment of potential therapies to treat aging. But that latter use is challenging when one can't trust that a clock will in fact react appropriately and correctly judge the degree to which aging has been slowed or reversed.

Identifying individuals at risk of dementia is essential for prevention and targeted disease-modifying strategies. We investigated whether mid-life metabolomic ageing is associated with incident dementia and its age of onset and assessed joint associations and interactions with APOE genotype and dementia polygenic scores. In the UK Biobank, plasma metabolites were quantified at baseline. Metabolomic age (MileAge) delta reflects the difference between metabolite-predicted and chronological age. Dementia was identified via health records.

Amongst 223,496 participants, 3,976 developed dementia. A higher MileAge delta was associated with higher hazards of all-cause, unspecified and vascular dementia (hazard ratio, HR = 1.61) and earlier onset. Key metabolites were lipids, lipoproteins, and amino acids. MileAge delta and genetic risk were jointly associated with dementia. Individuals with a high MileAge delta and two APOE ε4 alleles had a 10.30-fold higher all-cause dementia risk. Thus metabolomic ageing and genetic risk likely represent independent biological pathways contributing to dementia risk.

Link: https://doi.org/10.1002/alz.71280

The integrated stress response in cells acts to reduce protein synthesis while enhancing maintenance activities. A number of sensors for different forms of cell stress all converge on activation of the integrated stress response. These stresses include lack of nutrients, the presence of viral material, and too many unfolded proteins cluttering up the endoplasmic reticulum, among others. The degree of activation of the integrated stress response is important: mild activation is generally beneficial, but too much activation will produce apoptosis, the cell destroying itself in programmed cell death.

Like other stress response systems in the cell, some studies show that manipulation of the integrated stress response can modestly slow aging and extend life in short-lived species. Thus there is considerable research interest in the manipulation of the integrated stress response as a basis for therapy. A number of drugs capable of promoting or suppressing the integrated stress response exist already, and others are in development. The challenge in targeting the integrated stress response lies in the threading the needle of settling on enough activation to be useful, but not too little activation or too much activation, either of which can be harmful. What constitutes the right level of integrated stress response activation may vary between cell types in a tissue, between different tissues, and between individuals. Thus integrated stress response targeting drugs tend to have unpleasant side effect profiles.

Today's open access research paper illustrates this challenge in the move between laboratory species. The authors report that flies react quite differently to manipulation of the integrated stress response than nematode worms. Given the present state of medical technology, I do not think that we should be confident in the emergence of a very safe therapeutic approach to the adjustment of integrated stress response activity intended to slow aging. That is not to say it is impossible, it is just more difficult than would be cost-effective to attempt in the environment of what is readily possible today.

Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly

Recent progress in geroscience suggests that targeting broad aspects that underlie the biology of aging could prevent many age-related diseases simultaneously. One such treatment is the activation of stress response pathways. Recently, activation of the integrated stress response (ISR) orchestrated by the transcription factor ATF4 has been studied. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in longevity in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNA interference) of dATF4 extends lifespan.

We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown may upregulate proteostasis and DNA repair pathways. Our work reveals that ATF4 may exhibit a dual, dose-, and context-dependent role in aging. Chronic dATF4 activation is detrimental in flies, while chronic suppression is prolongevity.

Despite the failure to produce any useful approach to therapy based on upregulation of sirtuin 1 expression, and an entirely unhelpful hype cycle that came and went associated with those efforts, research into sirtuin 1 continues apace. In the example here, researchers connect sirtuin 1 expression to the improved metabolism following exercise. As is usual in matters of cellular biochemistry, connecting specific benefits to specific mechanisms is challenging; a great deal changes with exercise, and it has hard to say which of those changes are more versus less important.

Sirtuin 1 (SIRT1) was initially identified as an enzyme that deacetylates histones and suppresses gene activity. Since then, its roles have expanded considerably, and it is now recognized as a multifunctional protein conserved across various organisms. Despite increasing interest, it remains essential to clarify how exercise-induced changes in SIRT1 counteract multiple hallmarks of aging, as well as the full scope of SIRT1's impact on different physiological systems. This review highlights recent findings on the short- and long-term effects of exercise on SIRT1 signaling in both rodents and humans during aging. We explore the molecular pathways activated in various tissues, providing insight into the specific biological functions of SIRT1 within aging cells.

Optimal levels of SIRT1 help maintain homeostasis and a biochemical environment conducive to healthspan, influencing biological processes such as mitochondrial dynamics, metabolic pathways, tissue remodeling, autophagy, inflammatory responses, and redox balance. This indicates that SIRT1, a pleiotropic molecule, orchestrates multiple responses throughout aging. SIRT1 may act as a dynamic sensor for exercise benefits and protect against aging by maintaining genomic integrity. Different exercise protocols (acute and chronic) and modalities (aerobic, resistance, and combined training) can increase messenger RNA levels, activity, or protein levels of SIRT1 in various vital organs (adipose tissue, hippocampus, heart, liver, bone, and skeletal muscle) of aged animals and older adults, promoting health. Taken together, these observations support the notion that SIRT1 functions as a potential exerkine, and understanding its role in exercise-induced adaptations offers new insights into non-pharmacological strategies to enhance longevity.

Link: https://doi.org/10.1007/s10522-026-10442-z

Nerves are made up of bundled axons, the long connections between neurons, and so regeneration following injury involves new axons finding their way across the area of damage as they regrow, a process hampered in mammalian species by the formation of scar tissues. The antibody NG101 has long been known to promote regrowth of nerve tissue following damage. It has been a long road from the initial discovery a few decades ago to a recent clinical trial in patients with spinal cord injury. That trial allowed more data to be gathered on the regeneration process via imaging approaches, and researchers made use of the opportunity to examine in more detail as to how NG101 enhances regeneration in humans. Unlike animal studies where histology and dissection of nerve tissue is possible, human studies must rely on imaging, and those imaging techniques must be developed as trials progress.

One promising therapeutic strategy to enhance axonal plasticity is the inhibition of Nogo-A, a potent neurite growth suppressive membrane protein in central nervous system (CNS) myelin and neuronal membranes. Preclinical studies show that NG101, a humanized monoclonal antibody targeting Nogo-A, promotes axonal sprouting and functional recovery. Recent exploratory findings from a phase 2b clinical trial suggest that NG101 may also improve upper extremity motor function in participants with motor incomplete cervical spinal cord injury (SCI), supporting the translational potential of Nogo-A inhibition.

To better understand how Nogo-A inhibition influences structural recovery in human SCI, and to sensitively track potential regenerative effects, objective in vivo biomarkers are needed. Cross-sectional cord area (CSA) is a robust macroscopic marker of spinal cord atrophy, reflecting structural loss from axonal degeneration and demyelination, secondary to traumatic SCI and correlating with clinical impairment. Microstructural imaging provides reproducible metrics such as magnetization transfer saturation (MTsat), which is sensitive to myelin content and enables detection of demyelination and remyelination of spinal fiber tracts.

No study has yet assessed how macro- and microstructural Magnetic Resonance Imaging (MRI) biomarkers respond to a targeted neuroregenerative treatment in acute cervical SCI, or how these measures can be combined to optimize trial design. In this study, we investigated whether CSA and MPM-derived indices can track NG101-induced structural effects. Compared to placebo, NG101-treated participants exhibited faster lesion volume reduction and a slower decline of CSA and MTsat in the corticospinal tracts and dorsal columns. Crucially, multimodal stratification incorporating MRI and electrophysiological measures substantially enhanced the detection of clinical treatment effects. These findings suggest NG101 slows trauma-induced progressive macro- and microstructural degeneration or promotes fiber sprouting.

Link: https://doi.org/10.1038/s41467-026-71412-0

The primarily alternative to epigenetic clocks and other omics clocks to assess biological age is the use of aging clocks constructed from clinical chemistry, physical, and other simple measures, such as result from the Klemera-Doubal Method or Phenotypic Age. Examples of suitable measures include specific metabolite levels in serum, blood count data, morphometry based on waist circumference, blood pressure, grip strength, and so forth. The construction of a clock proceeds in much the same way regardless; data is assembled from a large study population of different ages, and machine learning approaches are employed to discover algorithmic combinations of data that predict chronological age. Where the predicted clock age is higher than chronological age, it is said that this person exhibits accelerated aging. The advantage of simple measure clocks versus omics clocks is that the data used is easier to theorize on; if one sees that an individual has a higher predicted age because their blood pressure increased, for example, one can form a hypothesis quite quickly and easily. When the cause is a different prevalence of DNA methylation on seven CpG sites on the genome, well, that is largely inscrutable.

That said, given the way in the which a clock is produced, a great deal of work is required in order to understand how it actually behaves, and whether it actually reflects biological age in any useful way. This is the case regardless of the type of underlying clock data. For early clocks, the discovery process has been underway for quite some time now, and it remains an interesting open question as to the degree that we should trust or can make good use of clock data in assessing interventions thought to affect aging. The uncertainty runs the other way as well, in that perhaps some of the results produced by clocks might cause us to question how we define biological age or what we might think a priori is a useful intervention. Most clocks have quirks that are distinct from these points, such as the relative insensitivity to physical fitness exhibited by first generation epigenetic clocks. In today's open access paper, researchers note that a short change of diet can move the biological age predicted by the Klemera-Doubal Method clock by a couple of years. Is this meaningful? A limited quirk? Something that should cause us to question the clock more broadly? These sorts of questions remain hard to resolve.

Short-Term Dietary Intervention Alters Physiological Profiles Relevant to Ageing

Ageing is a complex process influenced by modifiable factors such as diet, which may accelerate or decelerate physiological decline. While chronological age increases uniformly, biological ageing varies between individuals, reflecting differences in health status and the resilience of biological systems. The Klemera-Doubal Method (KDM), a composite biomarker-based index often used as an estimate of biological age, has been associated with morbidity and mortality in large cohorts. This study examined whether dietary manipulation of protein source and macronutrient composition affects KDM estimates in older adults.

We analysed data from the Nutrition for Healthy Living study, a dietary intervention trial involving 104 participants aged 65-75 years. Participants were randomised to one of four diets: omnivorous/high-fat (OHF), omnivorous/high-carbohydrate (OHC), semi-vegetarian/high-fat (VHF) or semi-vegetarian/high-carbohydrate (VHC). KDM-derived δAge (the difference between KDM-age and chronological-age) was calculated before and after a 4-week intervention.

The OHF group, most like participants' baseline diets, showed no meaningful change in δAge. Compared to OHF, participants in the OHC group showed a significant reduction in δAge. The VHF and VHC groups showed similar reductions in δAge, relative to OHF, though not all reached statistical significance. KDM-derived δAge appears responsive to dietary change within 4 weeks and may offer a useful proxy for evaluating shifts in physiological status. Caution is warranted in interpreting such changes as evidence of biological age reversal as observed shifts may reflect acute physiological responsiveness to dietary inputs rather than altered ageing trajectories. Longer-term treatment would be needed to assess changes in age-related disease risks.

With advancing age the composition of the gut microbiome changes in detrimental ways and the immune system becomes progressively incapable. These two aspects of aging do not happen in isolation from one another. The relationship between the aging of the gut microbiome and aging of the immune system is likely bidirectional. The immune system is responsible for gardening the gut microbiome, suppressing the populations of undesirable microbes, and so loss of immune function enables the growth in number of pathogenic microbes. At the same time, however, the populations of undesirable microbes can dysregulate immune function, such as via secretion of metabolites that provoke chronic inflammation. Thus gains in health are possible by either improving immune function or restoring a more youthful gut microbiome composition.

Aging is associated with systemic immune remodeling and disease susceptibility, but its impact on intestinal mucosal immunity, particularly changes in M cells, remains largely unknown. This study aimed to investigate how aging alters intestinal mucosal immune phenotypes, specifically follicle-associated epithelial cells (FAE) and the gut microbiota, and to identify interconnected pathways that may be exploited to maintain intestinal immune function in the elderly. Using intestinal tissue from young and aged mice, this study assessed manifestations of intestinal epithelial aging, changes in immune cells in the lamina propria, and microbial composition.

Aging was associated with increased expression of senescence-associated secretory phenotype (SASP) markers (IL-1β, TNF-α, p16) and decreased levels of tight junction proteins (Occludin, Tricellulin), suggesting epithelial barrier dysfunction. Aged mice exhibited decreased Naïve Th cells, increased Effector Th and Th17 subsets, and decreased fecal Immuoglobulin A. Microbiome analysis revealed enrichment of inflammatory bacteria, such as Desulfovibrio and Candidatus_Saccharimonas, and elevated dysbiosis indices. RNA sequencing of FAEs revealed 578 differentially expressed genes, including downregulation of Gp2 and Ccl28, indicating impaired M cell function. Association analysis between microbiome changes and mucosal immune aging revealed that enrichment of key inflammatory bacteria may contribute to impaired M cell function and dysregulated intestinal mucosal immunity.

These findings reveal a multi-layered disruption of intestinal homeostasis during aging-comprising barrier function, immune imbalance, FAEs dysfunction, and shifts in specific microbial taxa -leading to increased susceptibility to pathogens. Targeting these age-related pathways may provide strategies for maintaining intestinal immunity in the elderly.

Link: https://doi.org/10.1111/acel.70533

Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Overly reactive and senescent microglia are implicated in the development of neurodegenerative conditions, producing sustained inflammatory signaling while failing in their normal portfolio of tasks related to tissue maintenance and support of neurons. Here, researchers extend this line of thought to the aging of the retina and the progressive blindness of macular degeneration. To what degree are microglia a contributing cause of pathology in retinal degeneration? It is hoped that future strategies developed to address microglial dysfunction in the context of conditions such as Alzheimer's disease may have broader application.

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in older adults. Advanced AMD comprises an atrophic ("dry") form characterized by retinal pigment epithelium (RPE) and photoreceptor degeneration and a neovascular ("wet") form driven by choroidal neovascularization (CNV). Beyond genetic predisposition and environmental stressors, chronic dysregulation of innate immunity is increasingly recognized as a convergent mechanism linking drusen/Bruch's membrane alterations to outer retinal cell death and pathological angiogenesis.

Retinal myeloid cells - including resident microglia and, in specific disease contexts, recruited monocyte-derived macrophages - can support homeostasis by clearing lipids and cellular debris, yet may also exacerbate inflammation, matrix remodeling, and neovascularization. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia and other myeloid cells that regulates phagocytosis, lipid handling, migration, survival, immunometabolism, and inflammatory tone. Recent retinal studies suggest that TREM2-associated programs can restrain lesion expansion in outer retinal degeneration models and modulate CNV severity in experimental neovascularization; however, interpretation remains limited by disease stage, anatomical niche, and the difficulty of cleanly separating microglia from infiltrating macrophages in vivo.

Here, we synthesize current evidence on retinal myeloid contributions to dry and neovascular AMD, provide an updated mechanistic framework for TREM2 signaling, and discuss therapeutic strategies and translational challenges for targeting TREM2 in AMD.

Link: https://doi.org/10.3389/fopht.2026.1804578

The accumulation of senescent cells with age is clearly an important aspect of degenerative aging. Senescent cells contribute to chronic inflammation and disrupt tissue structure and function. Of the early senolytic treatments shown to clear a fraction of senescent cells in the tissues of aging, only the dasatinib and quercertin combination has undergone initial clinical trials in human patients, and even there the trials are small and the doses relatively low. Data is promising but not conclusive. The field has moved past the initial interest in clearance without actually implementing that initial interest, albeit a number of companies are working towards clinical trials for their varied senolytic strategies. Meanwhile the research is more focused on understanding differences between senescent cells and has, perhaps, become overly cautious about deploying therapies in advance of building a much more comprehensive map of senescent cells and their activities.

It is true that scenarios could exist in which blunt clearance of senescent cells will cause harms alongside benefits. For example, where senescent cells are a part of the structure of an unstable atherosclerotic plaque. Clearing those cells may tip the plaque over the edge and into fragmentation under the next incidence of pressure stress. There are no doubt other age-related circumstances in which clearance of senescent cells fails the cost-benefit test. How common are these scenarios? It seems to me that no-one is much interested in finding out, and researchers are more focused on generating the groundwork for a next generation of therapies to emerge over the next few decades. Those therapies don't yet exist, but first generation senolytics do exist. A little more thought given to the evaluation of the cost-benefit of their use seems needed, and absent.

Cellular senescence: from pathogenic mechanisms to precision anti-aging interventions

Cellular senescence, characterized by a state of stable cell-cycle arrest, has evolved from an initial observation in in vitro experiments to a central theoretical pillar for understanding systemic aging and age-related pathological processes. The traditional research paradigm primarily relies on a suite of consensus biomarkers for the identification of senescent cells. Among the most representative are the cyclin-dependent kinase inhibitors p16INK4a and p21CIP1, the activity of senescence-associated beta-galactosidase (SA-β-gal), and DNA damage. By adopting a biomarker-based definitional model, we gain a critical instrument to map the landscape of senescent cell accumulation, offering preliminary insights into its mechanistic associations with dysfunction across multiple organ systems.

In fact, senescent cells are not a homogeneous group but exhibit profound functional heterogeneity. Senescent cells with similar molecular phenotypic characteristics, regulated by their cell origin, tissue microenvironment, and induction background, may have vastly different or even opposite effects on tissue homeostasis. For example, senescent glial cells in the brain have been proven to be key factors driving neuroinflammation and cognitive decline, but senescent pancreatic β cells display superior insulin secretory capacity relative to younger cells, representing a distinct functional shift during the aging process. This insight has catalyzed a pivotal paradigm shift: moving beyond rudimentary "senescence profiling" to a mechanistic dissection of the functional trajectories of discrete senescent subpopulations. Emerging evidence increasingly highlights that certain senescent cohorts are not merely deleterious bystanders but active rheostats of tissue homeostasis, characterized by profound context-specificity and functional pleiotropy.

Current molecular markers, while useful for identification, fail to discriminate between functionally distinct senescent subpopulations. Consequently, the focus of research is shifting from "identifying the senescent state" to "evaluating functional pathogenicity," prioritizing the targeting of cell clusters that actively disrupt tissue homeostasis or drive specific disease ontologies. This shift necessitates an evolution in senolytic strategies toward "non-toxic precision clearance," requiring intervention tools to act as molecular scalpels capable of distinguishing deleterious cells from neutral or even beneficial ones. The future of this field is pivoting toward a profound integration of precision clearance and prospective intervention.

Elucidating the inductive mechanisms of cellular senescence constitutes the cornerstone for implementing effective clinical interventions, centered on a "prevention-over-cure" paradigm. The primary objective is upstream intervention: maintaining genomic stability, mitigating oxidative damage, and modulating canonical pro-senescent signaling axes (e.g., p53/p16) to delay the onset of the senescence program and restrict the systemic accrual of senescent cells. Elucidating the molecular triggers of cellular senescence is not only fundamental to understanding the core biological laws of life but also provides the precision targets required for homeostatic maintenance. The paradigm of senescence intervention is undergoing a fundamental transformation from a crude "anti-state" approach to a sophisticated "systemic management" framework.

Platelets play a vital role in blood clotting. A population of hematopoietic cells known as megakaryocytes spawn platelets by pinching off parts of their membrane and cytosol, forming what are essentially mini-cells that lack some of the usual components, such as a nucleus, but retain many of the others, such as mitochondria. As such platelets are capable of many of the functions of a full cell, such as secreting factors that influence other cells. Unfortunately, platelets become problematic with age in ways that contribute to greater inflammatory behavior and increased risk of the inappropriate clotting of thrombosis. Researchers here identify a specific protein, HuR, that regulates inappropriately inflammatory behavior in platelets in aged tissues. Suppressing HuR in only the platelets of aged mice reduces inflammation, burden of cellular senescence, and loss of physical and cognitive function characteristic of aging.

Aging involves morphological and functional changes across different organs, but how these changes are linked among the different organs remains to be elucidated. Here, we uncover a central role of platelets in systemic aging. In response to physiological or pathological stimuli, platelets synthesize and release many different growth factors, cytokines, chemokine, vasoactive substances, and other bioactive factors. During aging, platelet reactivity generally increases, even though the number of platelets decreases. As components of the blood, platelets penetrate the entire body, permitting platelets to affect the entire body. However, the role of platelet activation and platelet-secreted pro-inflammatory factors (PSPF) in aging is unclear.

In aged mice, the levels of platelet-secreted pro-inflammatory factors (PSPF) increased greatly in the serum and platelets, leading to a diffuse increase of platelet infiltration in the brain, liver, lung, kidney, and aortic root. The RNA-binding protein HuR/ELAVL1, a major regulator of RNA metabolism, promoted the production of PSPF in platelets. Platelet-specific deletion of HuR reduced the expression of PSPF in platelets, alleviated platelet infiltration in the brain, liver, lung, kidney, and aortic root, and delayed systemic aging. By using single-nucleus sequencing, platelet-specific HuR ablation was found to alleviate p53 and pro-inflammatory signaling pathways in liver, lung, and brain tissues in aged mice. Our findings highlight a role of platelets in coordinating aging traits across organs.

Link: https://doi.org/10.1038/s41467-026-72481-x

Researchers here report an surprising, interesting, but not immediately useful discovery relating to the interaction of the immune system with wound healing in aged skin. Regeneration in aged skin is impaired, and non-healing wounds are one consequence of this impairment. The researchers found that priming aged skin with a dose of lipopolysaccharide, a toxic bacterial product that the immune system reacts to, improves skin regeneration after later injury. In the real world injuries are hard to predict ahead of time, so a better understanding how the observed changes in immune cell behavior provoked by this intervention are regulated is required in order to develop a form of therapy that usefully recreates the effects.

Tissue repair is often hampered during aging. Worldwide, chronic wounds in elderly present a major challenge to the medical and socioeconomic infrastructure of societies. A comprehensive understanding of how the aging innate immune system impacts wound homeostasis is lacking. Here we employed the approach of immune modulation to restore disrupted wound repair in aged mice skin. We found that a short pulse of bacterial lipopolysaccharide (LPS) before wounding markedly accelerate tissue repair in aged mice, which - if non-primed - exhibit a defective epidermal wound closure. LPS priming induces rapid sealing of wounds, immune cell activity, keratinocyte responsiveness and their differentiation towards a newly reconstituted wound epithelium.

Structural elements such as neutrophil extracellular traps (NETs) composed of DNA and membrane protrusions derived from LPS-activated neutrophils and macrophages, respectively, reinforce physical skin barrier in aged wounds. The physical barrier established by LPS-primed innate immune cells subsequently facilitates epithelial tongue migration and adhesion of extracellular matrix (ECM)-producing mesenchymal cells. Collectively, this not only prevents the invasion of pathogens into the restoring skin tissue after injury, but also averts the persistence of low-grade inflammation associated with aged wounds. These findings underscore the benefit of immune cell priming in promoting cellular interactions between innate immune cells and epithelial cells that consequently restores physical skin barrier and promote tissue repair.

Link: https://doi.org/10.1186/s12979-026-00570-y

Programs of scientific research are ever short of funding, and this profoundly steers both the operation of these individual programs, as well as the standards for various fields of research that emerge via consensus and collaboration. Consider that the primary driving force behind most choices in the use of animal models of disease is the matter of reducing cost and time. Artificial models that turn out to have too little a connection to the real condition, or that mislead research in ways that sabotage progress, emerge time and time again because of the imperative to run studies more rapidly and at a lower cost. Young animals with forms of damage or toxicity or genetic disability are used to replicate the phenotypes of diseases that develop slowly in genetic normal old individuals. Assumptions about mechanisms are baked into the animal models. Alzheimer's disease and many cancers are the most prominent examples of conditions in which the well-established models are highly artificial and often questionable in comparison to the real conditions they are mimicking, but these are by no means the only examples.

Today's research materials provide an example of the sort of gap in knowledge that can arise when only young mouse models are used in work on cancer, a predominantly age related condition. Melanoma is a very well studied form cancer, and at this point once of the least threatening given recent advances in immunotherapy. Nonetheless, while the way in which melanoma risk changes with age in humans is well characterized, little investigation has taken place in mice to attempt to understand why this pattern of incidence exists - as that research requires a greater cost in time and funding in order to use old mice. Thus when researchers do in fact find that funding, they tend to discover new information. Melanoma is a relatively well controlled cancer in the grand scheme of things, but consider the many other far worse forms of cancer in which this same story is playing out over the years with different details.

Older Mice May Offer New Insight Into Cancer and Aging

Cancer risk increases with age and is often more aggressive and difficult to treat in older adults. However, fewer than 10% of mouse studies use aged animals, with most relying on mice roughly equivalent to humans in their early 20s. This discrepancy is one potential reason so many cancer drugs that show promise in preclinical models go on to fail in human trials. New research suggests melanoma behaves differently with age. The data showed cancer spread was the lowest in young mice, peaked in middle-aged mice, and declined in very old mice.

Researchers suggest that a key factor involves a specific group of immune cells called gamma delta (γδ) T cells, which act like early warning guards that help prevent cancer from spreading. Young and very old mice had more of these protective immune cells, and their cancer was more likely to stay dormant or spread less. Middle-aged mice had fewer γδ T cells, and their melanoma was far more likely to spread to organs like the lungs and liver. The study also showed that melanoma cells themselves can actively weaken the immune system as animals age. In middle-aged mice, melanoma released certain molecules that shut down or exhaust γδ T cells, allowing previously quiet cancer cells to "wake up" and spread aggressively. Notably, when researchers removed γδ T cells from young and very old mice, melanoma spread increased, suggesting these immune cells normally help keep the cancer in check. By contrast, blocking immune-suppressing signals restored immune protection and reduced cancer spread, but only in middle-aged mice.

Abstract 2072: Role of the aging on the ᵧδ; T-cells in metastatic cutaneous melanoma progression.

Melanoma incidence, metastasis, and mortality are significantly associated with age. Interestingly within the clinic, melanoma incidence is low in young adults, peaks between ages 65-79, and decreases thereafter (79+). This phenomenon has never been studied as pre-clinical studies predominantly focus on young (8-week-old) mouse models. Here, syngeneic melanoma cells have been injected into C57Bl/6 young (8 weeks), aged (12 months) and geriatric (18-24 months) male mice. Spleen, lungs, and liver have been collected to analyze metastasis and immune infiltration by flow cytometry. Histological analysis has been performed to quantify the number of metastases and to determine different immune markers (e.g. CD45, CD8, CD4).

Our data highlighted that middle aged mice had significantly increased γδ T cell infiltration in the metastatic lung and liver relative to young and geriatric mice, which had less metastasis. Based on this, we used a γδ T cell mouse model of depletion coupled with depletion antibodies against gamma delta in young and geriatric mice respectively. Our preliminary data indicated that upon reactivation in middle-aged mice, melanoma cells secreted PROS1, which drives cancer proliferation. Its effects on the immune system within our model have not been studied. We overexpressed PROS1 in melanoma cells, injected them, and analyzed metastasis and γδ T cell infiltration. Our data shows that middle-aged mice have significantly increased lung and liver metastasis relative to young mice. Interestingly, geriatric mice have lower levels of metastasis, replicating what is seen in the clinic.

Age induced decrease of γδ T cell infiltration in middle-aged mice, induced largely by PROS1 secretion from melanoma cells, promotes aggressive metastases. Adoptive treatment with γδ T cells or use of a PROS1 inhibitor may be a viable therapeutic option for metastasis in elderly individuals.

Epigenetic clocks are typically created from bulk epigenetic data from immune cells in blood samples taken from a population of various ages. Machine learning techniques derive algorithmic combinations of DNA methylation status at hundreds or thousands of CpG sites on the genome that tightly correlate with chronological age or mortality risk. There are certainly other ways to go about the task, but this describes most of the earlier and more mainstream clocks. Interestingly, this approach produces clocks that do not appear to be all that sensitive to physical fitness, despite what we know about the correlations between physical fitness and life expectancy. This probably says something interesting about our biochemistry, but we do not know yet know what that interesting thing is.

Physical activity reduces the risk of mortality and age-related chronic diseases, yet its association with biological age measured by DNA methylation (DNAm) clocks remains unclear. This systematic review and meta-analysis aims to evaluate the association between physical activity and biological age measured by DNAm clocks.

We identified 44 studies that were included in a systematic review comprising 145,465 participants with mean ages ranging from 24.1 years to 78.5 years. Across studies, higher levels of physical activity were generally associated with lower DNAm age, although many individual associations did not reach statistical significance. Seven cross-sectional studies contributed to the meta-analysis. Each one standard deviation (SD) higher in metabolic equivalent of tasks (MET)-minutes per week was associated with 0.03 SD lower Horvath epigenetic age acceleration (EAA) and 0.09 SD lower GrimAge EAA. No statistically significant association was observed for Hannum EAA or PhenoAge EAA.

Higher physical activity is significantly associated with lower biological age as measured by Horvath EAA and GrimAge EAA. However, evidence is predominantly from cross-sectional studies, limiting causal inference. Future longitudinal studies and clinical trials using standardised, objectively measured physical activity are warranted to clarify dose-response relationships, and to determine whether physical activity can causally modify ageing trajectories, thereby informing precision strategies for healthy longevity.

Link: https://doi.org/10.1016/j.lanhl.2026.100835

The work noted here might be taken as a companion piece to a recent paper on eusociality as a driver of the evolution of exceptional longevity in a wide variety of clades, not just mammals. Here, researchers take a broad look across mammalian species that exhibit a variety of different type of social organization, and find a correlation with species longevity. While thinking about this, one might also look at the evidence for mating strategies to drive the evolution of longevity; one might think that social organization has a large impact on mating strategy. At root, one might ask how all of these various parameters and their outcomes affect the trade-off between growth and maintenance in individuals; as a rule, species that mature faster can achieve reproductive success more reliably in an uncertain environment, but at the cost of a shorter life span and less opportunities to reproduce over time.

Extrinsic mortality, largely driven by predation, imposes strong selective pressures on ageing and longevity. Body size is perhaps the most important factor: larger mammals generally face fewer predators, allowing them to allocate more resources to maintenance and repair, thereby extending their lifespans. Comparative analyses of bats and marsupials similarly support reduced environmental vulnerability as a driver of longer lifespan. Furthermore, lifespan is correlated with other traits, including age at maturity and parental investment, consistent with the trade-off between energy allocation for reproduction and cellular repair. Increasingly, behavioural factors such as sociality are recognised for their impact on lifespan dynamics, adding another dimension to our understanding of longevity evolution.

Social groups protect their members from predation and starvation. Reduced risk of death from such extrinsic causes is expected to promote the evolution of longer lifespans. Since group-living similarly aids predator avoidance, resource defence, and foraging efficiency, we might expect a positive relationship between group-living and lifespan in comparative analyses. However a broad-scale quantitative study of 253 mammalian species failed to detect this relationship. To investigate this unexpected lack of support, we present a re-analysis of the topic, expanding the sample size to include a greater diversity of mammal species.

We analysed maximum recorded lifespan, body mass, and social organisation data for 1,436 mammal species using Bayesian phylogenetic comparative methods, confirming that group-living and pair-living species exhibit longer lifespans than solitary species after controlling for body mass and phylogeny. Pair-living species showed slightly longer lifespans than group-living species (though credible intervals overlapped), while body mass slopes did not differ substantially among social categories and activity period showed weak associations with lifespan. These results provide independent corroboration of recent findings linking sociality to longevity in mammals and suggest that while group-living may reduce predation risk, pathogen transmission costs in larger groups may constrain longevity benefits. Our findings, based on the largest comparative dataset analysed to date, strengthen the evidence that social organisation is a key factor shaping mammalian life-history evolution alongside body size and ecological adaptations.

Link: https://doi.org/10.1002/ece3.73587