Fight Aging!

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

Researchers have established a number of interventions in short-lived species that extend life as a result of degrading the function of a cellular component, usually the mitochondria. Some forms of degraded function induce the cell to increase maintenance activities and otherwise alter its behavior to produce a net benefit to function, resistance to damage, and other line items that combine to reduce the level of age-related dysfunction in tissues and thereby extend life span. Where alterations touch on aspects of the complex processes of gene expression in the cell nucleus, the full effects on cell function are usually unclear. Tinkering with the machineries of gene expression typically has sweeping effects on cellular biochemistry, and it is usually a surprise to find that breaking something in the nucleus yields an increase in life span.

The first step in gene expression is the production of RNA, a step known as transcription. RNA molecules in the cell nucleus are produced by structures that read gene sequences in the genome and assemble the matching RNA piece by piece from the raw materials of nucleotide molecules. An RNA molecule is finalized by giving it a 5` structure at one end and a 3` structure and poly(A) tail of trailing adenine nucleotides at the other. This decoration is managed by a different set of machinery than that responsible for reading and assembling RNA. One of these molecular machines is the Integrator, and in today's open access paper researchers report that degradation of Integrator function results in slowed aging in nematode worms. They believe that this occurs because the chain of cause and consequence spreading out from impaired RNA 3` processing in the cell nucleus leads to mild mitochondrial dysfunction, and thus an improved cell maintenance. Given the breadth of changes, however, this has to be taken as an initial suggestion rather than an answer to the question.

Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing

Identifying strategies to mitigate age-related physiological decline remains a central challenge. During ageing, the transcriptome undergoes extensive remodelling, but how this affects organismal health and lifespan is not well understood. The Integrator complex plays a central role in RNA polymerase II transcription and RNA 3` end processing. Surprisingly, we find that depletion of most Integrator subunits specifically in adults extends lifespan and healthspan in the nematode C. elegans. We show that loss of the catalytic subunit INTS-11 disrupts 3′ end formation of small nuclear and spliced leader RNAs, impairing trans-splicing and promoting outron retention in a subset of transcripts enriched for spliceosomal and nucleocytoplasmic transport genes.

These RNA-processing defects lead to altered levels of endogenous small interfering RNAs (siRNAs), which are required for the longevity and healthspan benefits of INTS-11 depletion. In parallel, outron retention disrupts nuclear-encoded mitochondrial gene expression and protein production, inducing mitochondrial dysfunction and promoting lifespan extension. We also demonstrate that loss of INTS-11 perturbs transcription elongation at genes where Integrator is present at promoters, and that upregulation of enhancer elements within intragenic regions can affect the expression and isoform usage of nearby genes. Together, our findings identify Integrator as a key upstream regulator of non-coding RNA transcription, which in turn impacts protein-coding gene expression and mitochondrial function to shape the ageing process.

All cells release and take up extracellular vesicles. This includes the bacteria present in the body, both the beneficial commensal species resident in various locations such as mouth and gut and the undesirable invasive pathogens. An extracellular vesicle is a lipid membrane wrapped package of molecules; much of the communication that takes place between cells consists of vesicle contents. Here, researchers theorize on the involvement of bacterial vesicles in the development of neurodegenerative conditions, particularly Alzheimer's disease. A body of evidence suggests a connection between infection, particularly persistent infections, and risk of neurodegenerative conditions. The underlying mechanisms remain a topic of ongoing research, with the side-effects of chronic inflammatory reactions of the immune system as one point of focus, but it seems likely that bacterial signaling has other, less immediately evident consequences.

Alzheimer's disease is a complex neurodegenerative condition characterized by progressive cognitive decline, neuroinflammation, metabolic dysregulation, and abnormal protein deposition. While genetic factors and amyloid-beta-focused hypotheses have been extensively investigated, they fail to fully account for the prolonged prodromal phase or the early susceptibility of olfactory and limbic regions. Emerging evidence suggests chronic peripheral and mucosal infections may influence disease risk; however, mechanisms by which microbial activity outside the central nervous system contributes to persistent neuropathology remain poorly understood.

This review explores the emerging concept that bacterial outer membrane vesicles act as mobile, lipid-rich vectors linking peripheral microbial reservoirs to neuroimmune and metabolic dysfunction in the aging brain. We discuss evidence suggesting vesicles originating from oral, olfactory, and upper airway niches can access the central nervous system via vascular routes and direct neural pathways, including olfactory and trigeminal nerves, where they influence glial and endothelial cell function.

We also propose the Accumulative Vesicle Load Hypothesis, which describes how cumulative lifetime exposure to bacterial vesicles shapes disease onset, anatomical vulnerability, and progression, and incorporates components of other hypotheses proposed for Alzheimer's disease. This offers a system-level perspective for early diagnosis and upstream therapeutic strategies, including minimally invasive vesicle profiling in nasal fluid, saliva, blood, and cerebrospinal fluid. This work is a conceptual review that summarizes current evidence in a hierarchically organized manner and proposes a testable model; it does not assert causality where direct human evidence is currently limited.

Link: https://doi.org/10.3390/cells15080690

The study noted here is one of many to show that the effects of lifestyle choice and environmental exposure far outweigh the effects of genetic variants when it comes to late life survival. Yes, there are a few very rare genetic variants and mutations that produce effect sizes of at least several years, but for the vast majority of individuals mortality risk in old age is overwhelmingly determined by lifestyle and environment. Did you stay relatively thin and relatively fit? Were you unlucky in your exposure to infectious pathogens, particularly persistent infections? Did you self sabotage by smoking? And so forth.

In this prospective cohort study of 1,545 participants aged 80 years and older from the China Hainan Centenarian Cohort Study, we investigated the independent and joint associations of modifiable risk factors and genetic predisposition with life expectancy. A weighted modifiable risk factor score (MRFS) based on 11 factors and a polygenic risk score (PRS) for longevity were constructed.

A favorable modifiable risk factor profile (low MRFS) was associated with a 40.7% lower death risk (hazard ratio, HR = 0.593) compared with high MRFS. Genetic predisposition to longer lifespan (high PRS) conferred a 13.0% lower risk (HR = 0.870). Participants with both low MRFS and high PRS had the lowest mortality (HR = 0.544), with a borderline significant multiplicative interaction. Life expectancy gains from a low MRFS were more pronounced in those with high PRS (6.92 years at age 80) than low PRS (5.35 years).

In conclusion, among the oldest-old Han Chinese, favorable modifiable risk profiles and genetic predisposition independently and jointly contribute to substantially longer life expectancy. Importantly, an unfavorable modifiable profile may largely negate genetic longevity benefits, emphasizing the critical role of managing these factors even in advanced age and irrespective of genetic inheritance.

Link: https://doi.org/10.1038/s41514-026-00393-7

Researchers have in recent years undertaken considerable effort to demonstrate that the biochemistry of obesity overlaps with the biochemistry of Alzheimer's disease. Setting aside motivations relating to linking two large pools of research funding (obesity researchers would love to be able to write Alzheimer's grants, and vice versa), it is certainly possible to point to a great many interesting findings in this context: circulating choline; microglial lipid accumulation; changes in extracellular vesicle profiles; links between visceral fat specifically and protein aggregation in the brain; the commonality of insulin resistance to both conditions; and so forth. From a cellular biochemistry point of view, it looks quite compelling.

Inconveniently, however, the epidemiological data from large study populations just doesn't support as direct a role for obesity in Alzheimer's risk as it does for, say, type 2 diabetes. Type 2 diabetes is very, very clearly a consequence of being overweight for the vast majority of patients, and losing that weight makes the condition go away. GLP-1 receptor agonists produce involuntary calorie restriction and weight loss, and have positive effects on patients with type 2 diabetes. So does voluntary calorie restriction achieved without the use of fancy modern drugs. GLP-1 receptor agonists do not slow the progression of Alzheimer's disease, however. To my eyes the question is more one of why so many obese people do not go on to develop Alzheimer's disease, particularly given the existence of so many plausible connecting mechanisms evaluated by the research community in recent years.

From Lipids to Mitochondria: Shared Metabolic Alterations in Obesity and Alzheimer's Disease

The number of individuals aged 65 and older will grow significantly over the next few years. This demographic shift is expected to increase the economic burden on society and, importantly, to elevate the prevalence of age-associated disorders such as Alzheimer's disease (AD), a neurodegenerative condition characterized by memory impairment and progressive cognitive decline. According to estimates from the Alzheimer's Society, 11% of individuals over the age of 65 in the U.S. are diagnosed with AD. At the same time, obesity - a chronic condition characterized by excessive fat accumulation and a major driver of metabolic disorders such as type 2 diabetes, liver disease, and cardiovascular disease - has risen markedly across the lifespan. Notably, its prevalence among older adults nearly doubled from 22% to 40% between 1988 and 2018.

Growing evidence indicates that obesity and AD are mechanistically linked through overlapping metabolic disturbances that contribute to structural and functional alterations in the brain and increase the risk of cognitive decline. Based on the evidence presented in this review, AD and obesity share convergent metabolic disturbances that often emerge early, preceding overt clinical manifestations. Key shared mechanisms include mitochondrial dysfunction, with coordinated impairments in the TCA cycle and electron transport chain leading to reduced adenosine triphosphate (ATP) production and excessive reactive oxygen species (ROS) generation; oxidative stress, which damages macromolecules and promotes pathological cascades such as amyloid-β aggregation and tau phosphorylation in the brain; dysregulation of adipokine signaling in adipose tissue; and systemic metabolic inflammation, linking peripheral energy imbalance to neurodegenerative vulnerability.

Given the concurrent rise in both conditions, elucidating their shared metabolic mechanisms has become increasingly important. This review focuses on the interplay between mitochondrial dysfunction, oxidative stress, and lipid dysregulation as converging mechanisms that connect peripheral metabolic imbalance to neurodegeneration. Furthermore, because adipose tissue functions as an endocrine organ, these systemic alterations can influence central nervous system (CNS) function. Accordingly, this review examines how adipose tissue dysfunction influences neurodegeneration, emphasizing the role of metabolic health in shaping cognitive decline.

Cardiovascular disease and cancer receive much of the public and scientific attention devotes to causes of human mortality, but it might surprise many people to know just how prominent respiratory conditions are in the list of causes of death. The various forms of damage and dysfunction accompanying aging predispose the lungs to all of the common fatal respiratory conditions, and incidence rates increase with age, even when the cause of disease is external, such as respiratory infections. Here, researchers take a tour of the present state of research into the aging of the respiratory system. Unlike past years, such a review now usually contains a discussion on the development of means to target mechanisms of aging and their potential relevance to the treatment of age-related conditions. It is a welcome change.

The respiratory system undergoes substantial ageing-related changes. The loss of function comes with a reduced adaptability to the ever-changing demands of the body, and more importantly, to an increase in disease states, such as sleep apnoea. The reduction in defences such as mucociliary clearance, coughing, and macrophage function causes increased respiratory infections. A reduction in autophagy, alongside replicative senescence and with chronic inflammation, contributes to age-related diseases such as COPD and pulmonary fibrosis. Sequential spatial analysis of biopsies or resection samples in individuals with airway disease will reveal altered structural and immune cell interactions associated with pathophysiological changes.

Much of what we know about lung ageing comes from the study of ageing in other systems or later-onset diseases, rather than a direct assessment from lung tissue sampled across all time periods of the life course from healthy individuals. The inference from other organ systems is particularly evident in the epigenetics and comes mainly from studies on blood cells or individuals with respiratory disease, rather than from studies on healthy lung tissue. In parallel, much of the genetic and molecular mechanisms are drawn from studies using tissue from individuals with COPD. Although COPD might represent a form of accelerated lung ageing, whether the mechanisms that underlie COPD are entirely replicative of normative ageing of the lung remains uncertain and cannot be elucidated without further study. Furthermore, a large proportion of our current understanding of lung ageing comes from animal models rather than human populations, and several areas of great importance remain almost completely unexplored. For example, research on the ageing of the mucociliary system in humans is restricted to only three studies, with one dating back to 1979.

Advances in genetic studies such as GWAS and whole-genome sequencing have been revolutionary in understanding the complexities of molecular alterations associated with diseases, and in uncovering new molecular targets. However, distinguishing which associations arise from direct effects of biological ageing on an organ system and which arise indirectly through other ageing-related pathologies is difficult. For example, GWAS on lung function found associations with genes that are related to confounding factors such as cancer and hypertension and genes related to environmental stressors, in addition to biological factors such as adult body size and BMI; whether these associations are genuine or arise due to overmatching remains to be elucidated.

Drugs that target the ageing process (senotherapies) could be of clinical value in treating respiratory diseases. Senotherapies include drugs that reduce the development of cellular senescence (senomorphics) and those that result in removal of senescent cells from lung tissue (senolytics). Several senotherapies have shown promising results in experimental models of age-related lung diseases, but only few clinical studies have been reported to date. Clinical studies of geroprotective therapies in lung diseases are challenging because the slow progression in these diseases is difficult to measure in clinical trials. However, changes in markers of senescence, such as p16INK4a and p21CIP1, and SASP mediators, are feasible. There is a need to know clinical biomarkers of lung ageing to identify the most suitable individuals for clinical trials and to monitor anti-ageing interventions.

Link: https://doi.org/10.1016/j.lanhl.2026.100842

Researchers continue to identify compounds that marginally affect aging in short-lived species. The Interventions Testing Program at the NIA continues to show that most of these have no effect on life span when rigorously assessed in mice. The few points of comparison we do have between mice and humans suggest that effects on life span in mice resulting from manipulation of metabolism become much smaller in humans. Long lived species do not have the same flexibility in metabolic determination of the pace of aging as exists in short lived species. This entire branch of longevity science, focused on exercise mimetics, calorie restriction mimetics, and other similar approaches, should not be expected to deliver meaningful results to human medicine in terms of years of life gained. Nonetheless, these efforts persist.

Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.

This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction. We analyzed age-stratified muscle transcriptome data from various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. Subsequently, myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction.

Celastrol, a bioactive triterpenoid, was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6%, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.

Link: https://doi.org/10.1016/j.jare.2026.01.079