Fight Aging!

A number of distinct cellular processes are labeled as forms of autophagy. These are ways in which a cell identifies unwanted structures and molecules, conveys those unwanted structures and molecules to a lysosome, and there breaks down the unwanted structures and molecules into raw materials. Autophagy is necessary for cell function, and has attracted attention in the aging research space for a number of reasons. Firstly the efficiency of autophagy appears to decline with age, secondly a number of ways to alter metabolism to modestly slow aging, such as calorie restriction and mTOR inhibition, appear to primarily function via increased efficiency of autophagy, and thirdly a few strategies to directly and selectively improve the efficiency of autophagy, such as LAMP2A upregulation, have also been shown to slow aging.

Today the focus is on chaperone mediated autophagy, in which unwanted proteins bind to a chaperone protein such as HSC70 that in turn binds to features such as LAMP2A on the surface of a lysosome, allowing the unwanted protein to be engulfed and then broken down. A pair of recently published papers from a team that has been working on LAMP2A for twenty years or so caught my attention. The work implicates an age-related decline in the efficiency of chaperone mediated autophagy in the aging of muscle tissue. The researchers show that maintaining efficient chaperone mediated autophagy in later life, achieved via upregulation of LAMP2A in a genetically engineered mouse lineage, can slow the age-related loss of muscle mass and strength. This approach likely works via helping to maintain muscle stem cell function into later life.

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise, and tissue repair, but declines in ageing and obesity.

Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.

Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration.

Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.

As a brief introduction to the way in which the statistical tools used by policy makers exhibit important disconnections from reality, one can start with the quality-adjusted life year (QALY) and value of statistical life (VSL). Sadly we live in a world in which medicine is ever more centralized and regulated, with an ever greater fraction of decisions made by regulators based on statistics rather than by the individual patient based on their preferences. The paper here is an interesting glance at the relationship between the value of QALY and the VSL as used in practice, in this course of arguing that the value of QALY used in policy decisions should change with age (and other circumstances) because the VSL changes with age (and other circumstances).

In the healthcare sector, cost-benefit analysis (CBA) using measures such as the value of statistical life (VSL) and quality-adjusted life years (QALY) is commonly employed to guide policy interventions and the efficient allocation of healthcare resources. The VSL is calculated based on willingness to pay for mortality risk reduction and is widely used in CBA to evaluate the economic benefits of a policy. The QALY, which considers both quality of life (QoL) and life expectancy, equates one QALY to one year of life in perfect health (QoL = 1).

The VSL and QALY are considered to be closely related, and research on their relationship has been active in recent years. This measure allows for cross-sectional comparisons of different healthcare policies and is widely used in many countries as a standard metric for public health policies and resource allocation decisions. By employing QALY-based CBA, policymakers can quantitatively assess the effectiveness of healthcare interventions based on scientific evidence, thereby facilitating informed decision-making. For instance, the UK's National Institute for Health and Care Excellence (NICE) uses QALY to assess pharmaceutical and medical technologies, providing guidelines for the effective use of limited healthcare resources.

However, the QALY has several limitations. For example, it applies uniformly across different age groups, despite significant differences in health status and life expectancy between younger and older individuals. The current QALY-based CBA may not adequately account for age-specific differences, potentially leading to biased results. Additionally, QALY values are often derived based on practices from other countries without fully considering regional characteristics such as population, economic conditions, and age distribution.

This study aims to present a QALY metric that considers age-specific health status (QoL) and life expectancy by deriving QALY from VSL. We model the VSL-based QALY and demonstrate its effectiveness through a scenario and policy evaluation analysis. In this study, we focus our analysis on the monetary value of a QALY that arises solely from life extension without incorporating QoL improvements and present the results of VSL, QALY, and policy cost reduction, using socioeconomic data from Japan.

Link: https://doi.org/10.1038/s41598-025-29794-6

Stressing cancer cells to induce a senescent state is a secondary goal of cancer therapy, after inducing cell death, as senescence brings a halt to replication. Senescent cell burden is an important component of degenerative aging, and so clearance of the senescent cells created by treatment following the completion of cancer therapy should be beneficial to patients. There is a complex relationship between the presence of senescent cells and the ability of a cancer to grow, however. Senescent cells draw the attention of the immune system, but also secrete signals that can help to support the growth of cancerous cells. There is some debate over whether one should expect clearance of senescent cells during cancer treatment to help or hinder the goal of eliminating the cancer. Here, researchers provide animal model data to suggest that removing senescent cells hinders cancer growth to some degree.

Immunologically mediated clearance of senescent cells has been demonstrated in several model systems. Given increasing evidence for these cells promoting tumor pathology and immune escape, we sought to examine whether a vaccine against senescent cells can lead to tumor regression. A senolytic dendritic cell (DC) immunotherapy ("SenoVax") was created by pulsing DC with cell lysate from senescent fibroblasts, producing DCs that expressed co-stimulatory molecules, stimulated T cell proliferation, and expressed the senescence antigen p16.

SenoVax induced prophylactic and therapeutic tumor regression in Lewis Lung Carcinoma (LLC) primary and metastatic murine tumor models. T cell proliferative and cytokine recall responses towards senescent cells but not to control stromal cell pulsed DCs were detected in vaccinated mice. Additionally, reduction in senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 were observed. Adoptive transfer experiments revealed a role for CD8+ T cells in transplanting protection.

When SenoVax was administered in combination with anti-PD-L1 or anti-CTLA-4 antibodies, the data showed synergistic effects in reducing tumor growth. SenoVax also demonstrated reduction of glioma, pancreatic cancer, and breast cancer cell growth. No significant activation of complement or induction of autoantibodies was observed. The data provide mechanistic support for advancement of senolytic immunotherapy as a novel form of cancer therapy.

Link: https://doi.org/10.1186/s12967-025-07393-3

Cells become senescent constantly throughout life, in tissues throughout the body, for a variety of reasons. Some senescence is a response to damage or stress or inflammatory signaling, some cells become senescent to help coordinate regeneration following injury, but most senescence is the result of cells reaching the Hayflick limit on replication. A senescent cell ceases to replicate, becomes larger, primes itself for programmed cell death, and secretes a potent mix of pro-growth, pro-inflammatory signals that attract the attention of the immune system.

In youth, senescent cells are efficiently removed by the immune system. In later life, this process slows as damage and stress increases, leading to the accumulation of senescent cells over time. Senescent cell signaling sustained over the long term by this growing, lingering population becomes increasingly disruptive to tissue structure and function, an important contribution to degenerative aging.

The research community is engaged in finding ways to selectively destroy senescent cells, reverse the normally irreversible senescent state, or shut down senescent cell signaling. A range of programs are scattered across the length of the slow and expensive path that leads towards clinical trials and eventual regulatory approval. At the same time, researchers continue to expand on the presently understanding of how exactly senescent cells cause harm to their host tissues. Today's open access paper is an example of this sort of work, focused on skin aging. As is usually the case in biology, nothing is direct and simple.

Endothelial senescence drives intrinsic skin aging via the neuroimmune CGRP-mast cell axis in mice

Endothelial cells (ECs), lining the inner surfaces of blood vessels, are particularly vulnerable to senescence, a state of irreversible cell cycle arrest triggered by telomere dysfunction, oxidative stress, and chronic inflammation. Senescent ECs secrete a senescence-associated secretory phenotype (SASP), a pro-inflammatory mix of cytokines, chemokines, and matrix-degrading enzymes that disrupt tissue homeostasis and propagate senescence. Although EC senescence has been implicated in age-related pathologies such as neurodegeneration, metabolic disorders, and pulmonary dysfunction, its contribution to skin aging remains poorly understood.

Skin aging is classified into two distinct types: extrinsic aging, driven primarily by environmental stressors such as ultraviolet (UV) radiation and pollution, and intrinsic (chronological) aging, mediated largely by genetic, metabolic, and vascular factors. While extrinsic aging manifests as epidermal hyperplasia, elastosis, and pigmentation, intrinsic aging is characterized by dermal thinning, collagen degradation, and impaired wound healing. Given the high vascular density within the dermis, microvascular dysfunction may contribute significantly to intrinsic skin aging by disrupting tissue homeostasis. However, the precise molecular mechanisms underlying the relationship between vascular dysfunction and intrinsic skin aging remain unknown.

Here we show that EC senescence contributes to intrinsic skin aging through immune dysregulation. Using an EC-specific senescent mouse model, we observe mast cell activation driven by the neuropeptide calcitonin gene-related peptide (CGRP), independent of traditional immunoglobulin E mediated pathways. Senescent ECs secreted pro-inflammatory SASP factors, activating dermal neurons to produce CGRP, leading to mast cell degranulation and subsequent skin aging phenotypes. Pharmacological stabilization of mast cells or inhibition of the EC-SASP-CGRP pathway significantly attenuate dermal thinning, collagen degradation, and delayed wound healing, which are hallmarks of intrinsic skin aging. These findings identify vascular senescence as an upstream regulator of skin aging through a neuroimmune mechanism and suggest potential therapeutic targets for age-related skin deterioration.

Vaccination for the herpes zoster virus that causes shingles is generally done after age 50. Evidence from widely used vaccines suggests that many forms of vaccination produce long-term trained immunity effects, which include increased resistance to unrelated pathogens, and a reduction in innate immune system inflammatory signaling in older individuals. Insofar as vaccination is connected with reduced incidence of an inflammatory disease, this may well be the important mechanism. Equally, in the case of Alzheimer's disease, some evidence suggests that persistent viral infection may be an important contributing factor in the onset and progression of this condition for other reasons. None of this is completely cut and dried - there are contradictory findings and clinical trial outcomes. But on balance, the evidence leans towards a protective effect of vaccination.

Clinical and subclinical reactivations of the neurotropic herpesvirus (the varicella zoster virus) that causes chickenpox and shingles may constitute a chronic immune stressor that drives inflammatory pathways in both the peripheral and central nervous system, interfering with neuroimmune homeostasis in older age. The varicella zoster virus has also recently been linked to amyloid deposition and aggregation of tau proteins, as well as cerebrovascular disease that resembles the patterns commonly seen in Alzheimer's disease. Reducing clinical and subclinical reactivations of the virus through herpes zoster (HZ) vaccination might thus have a beneficial impact on the development or progression of dementia, as well as neuroimmune health and cognitive reserve in older age more broadly.

Moreover, it is possible that HZ vaccination, and potentially vaccinations in older age more generally, act on the dementia disease process through a pathogen-independent immune mechanism. Such an effect might counteract immunosenescence and would add to the growing body of evidence suggesting that vaccines frequently have broader health benefits beyond their intended target.

Using natural experiments, we have previously reported that live-attenuated HZ vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had their eightieth birthday just after the start date of the HZ vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. The key strength of our natural experiments is that these comparison groups should be similar in all characteristics except for a minute difference in age. Our findings suggest that live-attenuated HZ vaccination prevents or delays mild cognitive impairment and dementia and slows the disease course among those already living with dementia.

Link: https://doi.org/10.1016/j.cell.2025.11.007

TDP-43 is one of the few proteins known to form persistent aggregates in the aging brain. When this aggregation becomes excessive it is a cause of neurodegenerative conditions, notably ALS and LATE, but it is worth remembering that every aged brain exhibits some degree of this problem. Here, researchers show that TDP-43 is involved in regulating a form of DNA repair, and depletion of the functional TDP-43 protein by aggregation leads to increased DNA damage and consequent dysfunction in cells.

TDP43 is an RNA-binding/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons.

Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include changes in MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability.

We furthermore find that aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and in post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Link: https://doi.org/10.1093/nar/gkaf920

Since around the time at which the goal of extending life through improvements in medical technology became a respectable goal, let us say somewhere a little after 2010, perhaps around the time that the first demonstration of clearing senescent cells in mice was conducted, the official message from the academic research community to the public and politicians has been that the goal of the field is to extend healthspan, but not lifespan. Extending the healthy period of life is great, but extending overall lifespan is shady and disavowed. Why did the prominent figures of aging research so enthusiastically embrace this public messaging?

Today's open access paper provides one view on that question, but I don't think that it touches closely enough on what seems the actual answer. It seems quite clear to those of us who lived through that period of time that this messaging was a way to distance the dominant factions in academia, who are ever sensitive to any threat that might impact their perceived status and thus ability to raise funds, from the growing voices of patient advocates and a minority faction of researchers who had started to achieve some success in talking up radical life extension and the medical control of aging, while funding research into technologies to repair cell and tissue damage thought to cause aging. The "healthspan but not lifespan" messaging was a rush to conservatism undertaken in fear of reduced funding from conservative institutions. This is, after all, what happened in the field of aging research following the anti-aging advocacy and birth of the supplement industry in the 1970s. The leaders of the field disavowed any attempt to intervene in aging. It was an exclusion of those not following the orthodoxy, and a rebranding and message intended to distinguish the orthodox form the newcomers, all conducted to protect existing status and sources of funding.

But make your own mind up! One could also argue, much as is done in the paper here, that it was a reaction to the data obtained from decades of efforts to treat age-related diseases. Since those efforts did not in fact target causes of aging, they produced very little gain in life span, but heroic efforts in development and clinical practice had managed to incrementally extend healthspan. It takes enormous effort to coax a failing machine into continued function if repair is off the table, but it can be achieved to some degree. Still, some researchers may have felt that this outcome represented the bounds of the possible, and thus the newcomers who aimed to extend life span by changing the strategy to medicine to one of repairing causative damage were mistaken.

Against "Extending Healthspan but Not Lifespan" as a Goal for Biogerontology

Extending human healthspan is of course highly desirable. However, within the biogerontology field one increasingly encounters this view that our goal should be to extend healthspan but not lifespan. This view has been stated explicitly, for example by Jay Olshansky, who argued that "life extension should no longer be the primary goal of medicine when applied to people older than 65 years of age. The principal outcome and most important metric of success should be the extension of healthspan." From some perspectives, this is a strange position to take. What is wrong with extending lifespan? We suggest that this anomaly has arisen from conflation of the goals of two distinct disciplines, namely geriatric medicine, that addresses the health needs of older adults, and biogerontology, the study of the biology of aging.

A challenge for geriatricians is that all of their patients will inevitably die from the condition that ails them, namely the process of senescence (aging). Faced with this, laudable and inspiring goals for geriatric medicine were set out in the early 1980s in a vision that accepts the harsh fact that, as in most animal species, there exists an upper ceiling for human longevity. Thanks to improvements in public health during the last century or so, an increasing proportion of the population are living longer lives, coming closer to the longevity ceiling. This is reflected in an increasing rectangularization of population survival curves. It was argued that the goal of late-life medicine should be to reduce the proportion of later life in poor health: "The rectangularization of the survival curve may be followed by rectangularization of the morbidity curve and by compression of morbidity."

By contrast, the vision of biogerontology is very different. Central to it is the possibility of decelerating or even reversing the aging process as a whole, or in its greater part. That this is feasible is suggested by the existence of numerous interventions that extend both healthspan and lifespan in animal models, particularly rodents. In terms of medical applications, the main, ultimate goal of biogerontologists is much the same as that of most of medical research: to alleviate illness, reduce disease burden, and save lives. Anti-aging treatments will always reduce disease, and may extend lifespan, but whether they increase healthspan and compress morbidity is to a large extent a matter of chance. For a biogerontologist to say that their goal is to increase healthspan but not lifespan is as strange as for a practitioner of any other medical specialism (say, oncology) to say it.

The arguments for healthspan rather than lifespan originated in the field of geriatrics, in which they are cogent, but were subsequently imported into biogerontology, where they are not. Possibly this partly reflects efforts by biogerontologists to align themselves with the agenda of the broader and better funded biomedical field, particularly as part of the geroscience agenda. In the end, medical interventions that save lives and postpone death may or may not cause an expansion of morbidity. Whether they do or not, such interventions are beneficial to the patient, and a good thing. The prospect of a doctor denying a patient a life-saving treatment on grounds that they will remain alive for an extended period in poor health is not part of any ethical reality. We advocate that biogerontologists frankly state their goals of understanding and intervening in aging, to make any gains possible in terms of improvements to late-life health and saving of lives (i.e. life extension).

In discussions of aging, references to klotho usually mean α-klotho, a transmembrane protein, and specifically the fragment of α-klotho that projects beyond the cell membrane and is shed to circulate in the body, also known as soluble α-klotho. Soluble α-klotho interacts with cell receptors to produce beneficial changes in cell function in a range of tissues. Klotho has long been of interest to researchers because increased expression of α-klotho slows aging, whereas reduced expression accelerates aging. Past research has focused on beneficial effects resulting from soluble α-klotho in the kidney and brain. Improved function in these organs might be enough to explain systemic benefits throughout the body, but as shown here soluble α-klotho likely has direct effects on cells in other tissues as well.

We investigate the effects of α-Klotho, an anti-aging hormone, on cell proliferation across three tissues with varying regenerative capacities in the context of aging. Using young and old wild-type mice, alongside old heterozygous Klotho-deficient mice, we administered soluble α-Klotho (sKL) daily for 10 weeks to elucidate the impact of α-Klotho deficiency and its supplementation. Our investigation spanned three organs: the small intestine, the kidney, and the heart.

We measured cell cycle markers (BrdU, Ki-67, and phospho-histone-3), Sirtuin-1, DNA-damage response pathways (gamma-H2Ax, ATM, CHK2), and the aging phenotypes. Supplementation of sKL significantly enhances proliferative markers and attenuates many aging changes. Mechanistic studies show that sKL acts through the Sirt1-CHK2 pathway to promote cell proliferation. In summary, Klotho deficiency exacerbated aging phenotypes, reduced regenerative capacity, and impaired cellular proliferation. Supplementation with sKL effectively counters these age-related declines across multiple tissues by enhancing cellular proliferation and attenuating aging phenotypes through the Sirt1-CHK2 signaling pathway.

Link: https://doi.org/10.1038/s41514-025-00286-1

Myelin is a protein that forms an insulating sheath around the axons that connect neurons, enabling the effective transmission of nerve impulses. It is essential for the normal function of the nervous system and brain, and thus demyelinating diseases such as multiple sclerosis that cause extensive loss of myelin are particularly debilitating. A lesser but still significant loss of myelin integrity occurs with aging, and thus forms of therapy that encourage myelin formation that are under development as potential treatments for multiple sclerosis may eventually find more widespread use in the aging population. Myelin is maintained by a population of specialized cells called oligodendrocytes, and all aspects of aging that degrade cell function in the brain and nervous system thus contribute to a progressive loss of myelin integrity. The example here for cardiovascular disease is likely connected to a number of mechanisms, from reduced blood flow to the brain to the inflammation and high burden of cell and tissue damage that contributes to both cardiovascular and nervous system degeneration.

A new study applied a novel multivariate approach to brain assessment using 12 separate metrics. The researchers compared test results and MRI scans of 43 patients with coronary artery disease (CAD) to those of 36 healthy individuals. All participants were over age 50. The multivariate approach of bundling individual white matter metrics into one overarching metric provides advantages over past studies. It allows the researchers to simplify complex aspects of brain health into a single metric that can be compared to the same metric in healthy controls.

The researchers found that individuals with CAD had widespread structural changes in their white matter compared to their healthy counterparts. The changes were particularly noticeable in the parts of the brain fed by the middle cerebral artery and anterior cerebral artery. Both regions are key for cognitive and motor functions.

The researchers found that the changes were mainly linked to reduced myelin content - the fatty coating that insulates nerve fibers and allows signals to travel quickly through the brain. Myelin loss can slow communication between brain cells and is often an early sign of cognitive aging. Interestingly, participants with higher measures of myelin integrity performed better on tests of processing speed, a key aspect of thinking and attention. However, no significant differences were observed between groups in overall cognitive scores, suggesting that brain changes may precede noticeable symptoms.

Link: https://www.concordia.ca/news/stories/2025/11/25/concordia-researchers-identify-key-marker-linking-coronary-artery-disease-to-cognitive-decline.html

Evolution produces species that exhibit stochastic metabolic variation from individual to individual. Any species or subpopulation of a given species lacking this individual variation might be more successful in a specific ecological niche, but would vanish due to competition the moment that niche changed in any way. And change is a feature of the world we live in. Given a long enough time scale, everything shifts in character. The species we see today are the descendants of the survivors of change, that survival enabled by individual metabolic variation within the species.

This adds to the growing list of complexities faced by any group attempting to find ways to adjust metabolism in order to slow aging. What works in one person may not work in the same way, or anywhere near as well, in another. We can see how this will likely turn out in the long run by looking at the past few decades of preventative clinical practice in cardiovascular disease. Individual variation in cholesterol metabolism has complicated attempts to reduce cardiovascular disease by lowering circulating LDL cholesterol. People exhibit a high degree of variance in the relationship between LDL cholesterol, other circulating atherogenic factors such as Lp(a), the pace at which atherosclerotic plaque grows in blood vessels with age, and the structure of that plaque. Most people presenting with a first heart attack or stroke do not have elevated LDL cholesterol, and it seems likely that only a subset of the population is benefiting meaningfully from LDL lowering drugs.

Today's open access paper notes that one can take a set of genetically identical nematode worms, raise them in identical ways, and still find that this population naturally produces stochastic differences in metabolism during development. These differences then affect the degree to which age-slowing interventions that attempt to alter metabolism into a more favorable state actually manage to achieve a slowing of aging.

The efficacy of longevity interventions in Caenorhabditis elegans is determined by the early life activity of RNA splicing factors

Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using RNAseq analysis of young, isogenic, subpopulations of Caenorhabditis elegans selected solely on the basis of the splicing pattern of an in vivo minigene reporter that is predictive of future life expectancy, we find a strong correlation in young animals between predicted life span and alternative splicing of messenger RNAs related to lipid metabolism.

The activity of two RNA splicing factors, Reversed Polarity-1 (REPO-1) and Splicing Factor 1 (SFA-1), early in life is necessary for C. elegans response to specific longevity interventions and leads to context-specific changes to fat content that is mirrored by knockdown of their direct target POD-2/ACC1. Moreover, POD-2/ACC1 is required for the same longevity interventions as REPO-1/SFA-1. In addition, early inhibition of REPO-1 renders animals refractory to late onset suppression of the TORC1 pathway. Together, we propose that splicing factor activity establishes a cellular landscape early in life that enables responsiveness to specific longevity interventions and may explain variance in efficacy between individuals.

Collagen supplementation has an interesting history, and as is often the case in these matters there is all too much hype and marketing in relation to the amount of actual data. But even looking at only the clinical trials, it seems likely that collagen supplementation can produce small beneficial results in a number of aspects of aging and age-related conditions. Here, researchers demonstrate in cells, worms, mice, and a human clinical trial that one can supplement the amino acids used in the production of collagen, in the right ratio, in order to produce these benefits. The human dose used was 8400 mg glycine, 1700 mg proline, and 1700 mg hydroxyproline, taken daily for six months. The biological age measure used was TruAge, a DNA methylation clock.

Collagen supplementation has gained attention with increasing claims regarding its beneficial effects on healthy aging based on clinical observations and lifespan extension in pre-clinical models; however, how and which part of an ingested collagen promotes healthy longevity is unknown. Here, we identified the minimal required unit of ingested collagen, which consists of the proper ratio of three glycine to one proline to one hydroxyproline that was sufficient to increase the healthspan and lifespan of C. elegans, as well as collagen homeostasis in human fibroblasts in vitro.

Supplementation in 20-month-old mice improved grip strength and prevented age-related fat accumulation. In a clinical observational trial (ISRCTN93189645), oral supplementation in humans demonstrated improved skin features within three months and a reduction in biological age by 1.4 years within 6 months. Thus, a ratio of three amino acids elicits evolutionarily conserved health benefits from ingested collagens.

Link: https://doi.org/10.1038/s41514-025-00280-7

Sizable regeneration of damaged or lost cartilage remains impossible in practice, but also a highly desirable goal given the prevalence of osteoarthritis. The best that has been achieved to date in clinical practice results from one specific implementation of stem cell therapy, Cartistem. Other stem cell therapies haven't done as well in this context. You may recall that inhibition of 15-PGDH was shown to improve muscle function in old mice. That work has since moved on to initial clinical trials of a small molecule drug, developed by Epirium Bio. Here, researchers show that the same approach can produce some degree of cartilage regrowth, also in old mice.

Blocking the function of 15-PGDH with a small molecule results in an increase in old animals' muscle mass and endurance. Conversely, expressing 15-PGDH in young mice causes their muscles to shrink and weaken. 15-PGDH has also been implicated in the regeneration of bone, nerve, and blood cells. In each of these tissues, regeneration is due to increases in the proliferation and specialization of tissue-specific stem cells.

Osteoarthritis occurs when a joint is stressed by aging, injury, or obesity. The chondrocytes begin to release pro-inflammatory molecules and to break down collagen, which is the primary structural protein of cartilage. When collagen is lost, the cartilage thins and softens; the accompanying inflammation causes the joint swelling and pain that are hallmarks of the disease. Under normal circumstances, articular cartilage rarely regenerates. Although some populations of putative stem or progenitor cells capable of generating cartilage have been identified in bone, attempts to identify similar populations of cells in the articular cartilage have been unsuccessful.

When researchers compared the amount of 15-PGDH in the knee cartilage in young versus old mice, they saw that, as in other tissues, levels increased about two-fold with age. They next experimented with injecting old animals with a small molecule drug that inhibits 15-PGDH activity - first into the abdomen, which affects the entire body, then directly into the joint. In each case, the knee cartilage, which was markedly thinner and less functional in older animals as compared with younger mice, thickened across the joint surface. Further experiments confirmed that the chondrocytes in the joint were generating hyaline, or articular, cartilage, rather than less-functional fibrocartilage. Similar results were observed in animals with knee injuries.

Link: https://med.stanford.edu/news/all-news/2025/11/joint-cartilage-aging.html

One of the most interesting areas of research into aging at the moment is the question of whether detrimental epigenetic changes that occur in cells throughout the body with age, altering cell behavior for the worse, are caused by the operation of DNA repair processes in response to stochastic damage to nuclear DNA. The concept and animal study evidence are recent enough that it should be considered speculative, and any of the details published to date subject to revision.

If true, however, this relationship in which DNA repair causes epigenetic aging would neatly resolve a range of challenges in the understanding of the role of nuclear DNA damage in aging. For example that mutational damage to nuclear DNA doesn't appear to cause enough harm to cell function to explain the major changes that occur with age. Most nuclear DNA damage occurs in somatic cells with few cell divisions remaining, limiting the spread of the mutation, and occurs in gene sequences that don't much matter or are not even used.

Somatic mosiacism, the spread of mutations over time from stem cell populations out into the tissues they support via the vector of daughter somatic cells, can somewhat salvage this situation by amplifying a tiny number of mutations into widespread existence. However, present investigations of the role of clonal hematopoiesis of indeterminate potential, the name given to somatic mosaicism in hematopoietic cells and the immune system, suggest that it isn't harmful enough to explain very much of aging. It raises risks, it isn't driving degeneration.

Today's open access paper is a recent exploration of epigenetic change induced by DNA damage, employing a mouse model generated a few years ago. Here, this model is crossbred with an Alzheimer's disease model in order to look at relevance to that condition. Cynically, one should assume that this choice of direction in research is driven as much by the funding incentives as the reasonable scientific rationale for the relevance of a mechanism of aging to any specific age-related condition, as work on Alzheimer's disease represents a sizable fraction of all public funding for aging research. Still, all significant new work on this issue of DNA repair and epigenetic change is welcome.

DNA Break-Induced Epigenetic Alterations Promote Plaque Formation and Behavioral Deficits in an Alzheimer's Disease Mouse Model

The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift.

We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess amyloid-β pathology and neuroinflammatory markers.

Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters amyloid-β plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage-induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.

Butyrate is one of the better known metabolites generated by microbial populations within the gut microbiome, a product of the fermentation of dietary fiber. Butyrate has been shown to produce beneficial effects in a range of tissues, such as via increased BDNF signaling to improve brain and muscle health. Production of butyrate declines with age, a consequence of harmful shifts in the composition of the gut microbiome that take place with age. Here, researchers show that butyrate is senomorphic, in that is reduces the number of cells entering a senescent state. This sort of effect is thought to be beneficial over time, as it allows the normal mechanisms of senescent cell clearance, impaired with age but still operating, to catch up and reduce the age-related burden of senescence.

Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs).

Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial reactive oxygen species (ROS) accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB.

Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.

Link: https://doi.org/10.1111/acel.70257

Scar tissue is formed by excess deposition of extracellular matrix molecules such as collagen. It obstructs complete healing. In aged tissues, fibrosis is a form of inappropriate scarring and consequent loss of function produced by the disruption of normal tissue maintenance. Researchers here provide evidence for scarring following injury to be driven by a subpopulation of monocytes and macrophages, types of myeloid immune cell. The pro-fibrotic behavior of these cells is triggered by mechanical cues. Mechanosensing is a complex set of regulatory pathways by which cells react to the mechanical properties of the surrounding environment, such as degree of tissue stiffness or mechanical stresses placed upon the tissue. These regulatory pathways can be manipulated via drugs and genetic engineering, just like others, and this opens the door to a novel approach to reducing scar formation following injury.

In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation.

Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations.

In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.

Link: https://doi.org/10.1038/s41551-025-01479-5