Fight Aging!

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

On the one hand there is a modest amount of evidence for GLP-1 receptor agonist drugs to produce beneficial effects on an aged metabolism that are unconnected to weight loss. On the other hand, when Big Pharma has a very successful drug, it will attempt to use that drug for every condition it can that is associated with a sizable market, whether or not the expected effects are marginal. So it isn't necessarily indicative of support for these non-weight-loss mechanisms that leads the clinical trial of a weight loss drug for patients with Alzheimer's disease. Cynically, it is that Alzheimer's is an enormous market.

The present state of regulation makes it more cost-effective for companies to push existing drugs into new marginal uses than it is to develop new drugs that are actually effective for that new use. At times, it seems that the entire world cares nothing for how well a drug, a supplement, any intervention actually works at its given task. Effect sizes are boring, a dead letter. Drugs that do relatively little and only marginally slow progression of a condition are marketed aggressively and have huge sales. Big Pharma is far from the only culprit in this matter, of course. Just look at the supplement industry.

That a weight loss drug produces weight loss but at the same time fails to slow Alzheimer's disease might be taken as another data point to illustrate that the relationship between obesity and Alzheimer's disease is very different in character to, say, the robust and very direct relationship between obesity and type 2 diabetes. Yes, being overweight appears to be a risk factor that plays into Alzheimer's disease, but it isn't as strong a relationship, indicating a great deal more complexity and variation from individual to individual in the mechanisms involved.

Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer's disease progression

Novo Nordisk today announced the top-line results from the 2-year primary analysis of evoke and evoke+ phase 3 trials in early-stage symptomatic Alzheimer's disease. The two trials were randomised, double-blinded, enrolled a total of 3,808 adults and evaluated the efficacy and safety of oral semaglutide compared to placebo on top of standard of care. The decision to pursue an Alzheimer's disease indication with semaglutide was based on real-world evidence studies, pre-clinical models as well as post-hoc analyses from diabetes and obesity trials.

The evoke and evoke+ trials did not confirm superiority of semaglutide versus placebo in the reduction of progression of Alzheimer's disease, as measured by the change in Clinical Dementia Rating - Sum of Boxes (CDR-SB) score compared to baseline. While treatment with semaglutide resulted in improvement of Alzheimer's disease-related biomarkers in both trials, this did not translate into a delay of disease progression.

The chemistry of molecules in solution is dynamic and complex, such as the spontaneous liquid-liquid phase separation in which a solution divides into regions of greater and lesser concentrations to form droplets. This process is important in the formation of protein aggregates involved in neurodegenerative disease. Here, researchers show that the α-synuclein that misfolds and aggregates to cause Parkinson's disease does not undergo liquid-liquid phase separation on its own, but rather is dragged into the liquid-liquid phase separation and droplet formation of another protein, UBQLN2. This suggests possible novel targets to interfere in this chemistry.

Some neurodegenerative disease-associated proteins form liquid droplets via liquid-liquid phase separation (LLPS). Over time, these droplets transition from a highly labile liquid state to a hydrogel state, and eventually to a solid-like condensate, via self-interaction and oligomerization of the proteins within, thereby leading to the formation of amyloid fibrils. Recently, α-synuclein (α-syn) has been reported to be one such protein. However, the precise molecular events involved in the early stages of α-syn aggregation remain controversial.

In this study, we show that α-syn aggregation is promoted by droplets formed by ubiquilin-2 (UBQLN2), rather than by α-syn LLPS itself. During the liquid-gel/solid transition of UBQLN2 droplets, α-syn within the droplets transforms into pathogenic fibrils both in vitro and in cells. Immunohistochemistry of brain sections from sporadic Parkinson's disease patients revealed UBQLN2 in substantia nigra Lewy bodies, implicating UBQLN2 in α-syn aggregation in vivo. Furthermore, the small molecule 1,2,3,6-tetra-O-benzoyl-muco-inositol (SO286) inhibited both UBQLN2 self-association and its interaction with α-syn by binding to the STI1 domain, thereby suppressing α-syn aggregation.

These findings demonstrate that UBQLN2 droplets catalyze α-syn fibrillization and suggest that small molecules targeting fibril-catalyzing proteins such as UBQLN2 may represent a promising therapeutic approach for neurodegenerative diseases.

Link: https://doi.org/10.1038/s44318-025-00591-1

Brown fat, or adipose tissue, is responsible for generating heat to maintain body temperature. Research has shown its presence and activity to be beneficial in the context of aging, in that the presence of more brown adipose improves long-term health. However, like all tissues, brown adipose tissue becomes dysfunctional with age. Here, researchers investigate what appears to be an important mechanisms in this process, in which brown fat adipocyte cells and macrophage cells of the innate immune system interact in ways that provoke inflammation and dysfunction.

Loss of brown adipose tissue (BAT) activity observed during ageing, obesity, and living at thermoneutrality is associated with lipid accumulation, fibrosis, and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances.

Mechanistically, we demonstrate that brown adipocytes secrete adenosine triphosphate (ATP) in response to imbalanced thermogenic activation, which activates the P2X4 and P2X7 receptors of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction, and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality, or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT degeneration.

Link: https://doi.org/10.1038/s44319-025-00642-y

Stem cells exist in order to minimize the number of cells capable of unrestricted replication; most cells in the body are limited in the number of times that they can divide. This limit serves to reduce the risk of cancer - and other severe disruptions that could result from unlimited replication of a malfunctioning cell - to an acceptably low level to enable evolutionary success. Stem cells provide a supply of daughter somatic cells to replace those that are lost over time, due to limited somatic cell replication. In actuality, stem cells spend much of their time in a state of quiescence, without replicating. This is necessary to preserve their function and minimize damage over the course of a lifetime. When forced into excessive activity, stem cells risk a state of exhaustion, becoming dysfunctional and displaying harmful alterations in behavior.

Hematopoietic stem cells reside in the bone marrow and are responsible for generating immune cells and red blood cells. The dysfunctions that arise with aging in this cell population, such as a growing bias towards the production of myeloid cells at the expense of lymphoid cells, appear similar to the dysfunctions that arise when hematopoietic stem cells are forced into exhaustion by excessive replication. In today's open access paper, researchers explore the relevance to hematopoietic stem cell aging of IL-10 signaling intended to bring an end to an acute episode of inflammation, such as in response to an infection that is now defeated. Hematopoietic stem cells must be ever ready to produce large numbers of immune cells to help defend the body, but at the same time they must also return to quiescence when that danger is passed. The chronic inflammation of aging may well sabotage this balance, driving ever greater dysfunction in the production of immune cells.

Impaired IL-10 Receptor Signaling Leads to Inflammation Induced Exhaustion in Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are maintained in quiescence, which protects this pool from the damaging effects of excessive proliferation. Quiescence is tightly regulated by intrinsic programs, including FoxO3a, p53, and cyclin-dependent kinase inhibitors, and by extrinsic cues such as TGF-beta and Notch. Under homeostatic conditions, HSCs remain largely dormant but can rapidly activate in response to inflammatory stimuli, such as infection, to support emergency hematopoiesis. A timely return to quiescence after activation is essential to prevent stem cell exhaustion, which occurs if cycling persists.

Many hallmarks of stem cell exhaustion, including impaired regenerative capacity, expansion of phenotypic HSCs with reduced function, increased inflammatory signaling, and a shift toward myeloid-biased differentiation, mirror features of aged hematopoiesis. Aging is associated with chronic, low-grade inflammation that stresses the HSC pool, driving both functional decline and selective pressure for clones that resist inflammation-induced exhaustion.

Although much is known about maintaining HSC quiescence under steady-state conditions, the signals that govern the return to quiescence after inflammatory activation remain poorly defined. In other cell types IL-10 is an anti-inflammatory cytokine that restrains excessive immune activation by suppressing responses downstream of Toll-like receptor (TLR) stimulation. We identify IL-10 receptor (IL-10R) signaling as critical for returning HSCs to quiescence. IL-10R blockade prolongs HSC cycling and sustains activated transcriptional programs after acute inflammation. With chronic exposure, blockade increases cumulative divisions and accelerates aging hallmarks, including myeloid bias, loss of polarity, and functional defects, under conditions that do not otherwise exhaust HSCs when IL-10R signaling is intact. Our findings identify IL-10R signaling as a key coordinator of post inflammatory return to quiescence and suggest that modulating this axis could preserve HSCs and shape clonal hematopoiesis.