Fight Aging!

At the high level, without delving into specific mechanisms, the consensus view on aging is that it exists in the shadow of natural selection. The selection pressure that drives the spread of changes in genes, systems, biology in general in any given species operates most strongly on early life reproductive success. This inevitably gives rise to systems that perform well initially, but which fall apart later. Expenditure of resources on long-term maintenance loses out to expenditure of resources on short-term reproductive fitness. Aging is a near universal side-effect of evolutionary competition, a race to the bottom that exists because early life reproductive success wins out over repeated reproductive success for a longer period of time.

That a given aspect of an individual's biochemistry can be beneficial in early life and harmful in later life is known as antagonistic pleiotropy. There are many examples at all scales, ranging from the structure and behavior of the adaptive immune system and its limited capacity for memory, to the well-known trade-off between developmental growth and later risk of age-related disease, to activities of specific proteins such VGLL3. There is a great deal of literature on this topic. Today's open access paper thus treads familiar ground in discussing aging as a side-effect of evolutionary pressures, attempting a modestly different framing of the situation.

Living Beyond Our Evolutionary Warranty: Why Non-Communicable Diseases May Be The Inevitable Costs of an Extended Lifespan

Despite decades of research, age-related non-communicable diseases (NCDs) remain prevalent even in populations with healthcare access. The conventional explanation invokes "evolutionary mismatch": modern lifestyles clash with ancestral biology. Yet a paradox persists: even individuals maintaining optimal health behaviours eventually develop NCDs. Hunter-gatherers living in ancestral conditions show moderate signs of atherosclerosis, metabolic dysfunction, and immune senescence past age 60-70. This raises the question, "Why are NCDs so difficult to prevent?"

We hereby propose an alternative framework where many NCDs represent not preventable consequences of modern lifestyle, but rather inevitable costs of adaptive mechanisms that were never "designed" to operate over 70 to 90-year lifespans. This "Adaptive Cost Hypothesis" (ACH) reframes NCDs as manifestations of evolutionary trade-offs largely, though not absolutely, between early-life fitness advantages and late-life pathology-trade-offs subject to sharply attenuated selection because they occur long after reproductive success. Late-life pathology is intrinsic to epigenetically programmed adaptive responses, manifesting even under matched environmental conditions. This is not mismatch. It is the inevitable cost of adaptive mechanisms operating beyond their evolved design duration.

One of the goals of the Dog Aging Project is to better establish that the characteristics of aging in dogs are close enough to the characteristics of aging in humans to make the results of interventions on dog life span relevant to the development of human medicine. Thus the paper here, in which researchers establish that comorbidity, the presence of multiple age-related conditions in the same individual, has much the same relationship with aging and mortality in dogs as it does in people. To have an age-related disease is to have a significant degree of dysfunction in some organ or tissue. The greater the burden of underlying cell and tissue damage resulting from aging, the more likely it is that multiple age-related conditions will emerge. Further, significant dysfunction in any one organ or tissue will tend to generate issues in other organs or tissues; everything connections everything else in our biology.

Multimorbidity, the presence of two or more conditions, is associated with a higher risk of death as individuals age. However, modeling multimorbidity in laboratory animals is difficult, if not impossible, because specific conditions are seldom individually diagnosed and treated in these settings. Because of their shared environment, physiology, and genetic diversity, and because they are medically managed as individuals, companion dogs have potential to serve as a translational multimorbidity model. Yet it is unknown how diagnoses accumulate over time, how these diagnoses are associated with mortality, and which multimorbid condition combinations are the most prevalent and hazardous.

Utilizing owner-reported data from over 50,000 dogs in the Dog Aging Project (DAP), we assessed how multimorbidities develop, learned which are the most prevalent, and evaluated their impact on survival. Like in humans, we show that the accumulation of conditions is associated with an increased risk of death in dogs. We also present data suggesting that future reported condition rates vary depending on the conditions a dog's owner already has reported. Not surprisingly, our analysis reveals that the overall canine aging process appears to be the driving factor behind disease development, more so than other covariates. Through classifying multimorbidities, we found that almost all either exhibit a synergistic effect or are driven by a single, predominant condition. In both cases, osteoarthritis, overweight, and cancer were highly prevalent throughout.

This analysis expands on previously conducted DAP work and further highlights the usefulness of the companion dog as a translational model for human aging.

Link: https://doi.org/10.1007/s11357-026-02342-4

In recent years, researchers have been gathering as much data as possible on the behavior of aging clocks of various sorts. The study here is an example of the type, in which multiple proteomic clocks were assessed in large epidemiological study populations. As one might expect, where there is age acceleration, meaning a higher clock age than chronological age, this correlates with a greater risk of age-related disease and mortality. Though as noted, clocks don't improve all that much on lifestyle indicators when it comes to the quality of the correlation. This sort of study helps to build a foundation of data as a reference for further exploration of clock behavior in response to interventions thought to affect the pace or state of degenerative aging.

Assessment of biological aging using proteomic clocks may enhance risk prediction and elucidate the molecular links between aging and chronic diseases. Here, among 17,473 participants of the European Prospective Investigation into Cancer and Nutrition, we examined associations of plasma SomaScan-based proteomic clocks, including organ-specific clocks, with risk factors, 24 incident chronic diseases and all-cause mortality, over up to 28 years of follow-up. Replication was conducted in the Whitehall II study.

We show that the global age gap, an age acceleration score combining proteomic clocks, was associated with smoking, alcohol consumption, physical inactivity and higher risk of mortality, cardiovascular diseases, dementia and cancers of the liver, upper aero-digestive tract, lung and kidney. Lung, kidney and stomach cancers were more strongly associated with related organ-specific age gaps. Predictive performance of proteomic clocks for mortality was comparable to that of classical lifestyle risk factors. In summary, proteomic clocks appear promising biomarkers of generalized age-related disease risk.

Link: https://doi.org/10.1038/s43587-026-01163-6

There are a good many affordable interventions that may well produce enough of an effect on aging to justify widespread use. At the more compelling end of the spectrum, based on a relatively large effect size in animal data and very limited supporting human data, we might consider the senolytic combination of dasatinib and quercetin, stem cell and exosome therapies, and fecal microbiota transplantation from a young donor to an old recipient. Somewhere in the middle lies rapamycin and some bisphosphonate therapies for osteoporosis. At the less compelling end of the list, based on an expectation of smaller positive outcomes and very mixed data for any effect on aging, we find widely used interventions such as hyperbaric oxygen therapy.

But we don't know with reasonable certainty for any of these interventions that it is in fact useful in the matter of aging, as that reasonable certainty requires at least a few fairly large clinical trials, summing to a patient population of high hundreds to low thousands at minimum. Interventions that only slow aging would also require those trials to last a long time, at least five years, in order to generate a meaning signal from incidence of age-related death and disease.

The challenge faced by all affordable interventions, capable of being readily implemented by most clinics, is that no-one has much of a motivation to fund a clinical program that would provide confidence in their ability to slow or reverse aging in specific ways. Regulators in the wealthier parts of the world, in collaboration with large pharmaceutical companies, have made the process of running a responsible clinical trial so very expensive that only a small fraction of the space of all possible therapies can possibly make enough of a profit to justify the investment. Anything that is hard to patent, and thereby obtain some degree of monopoly on the market, is not interesting to investors. Outside of the pharmaceutical and biotech industries, there is only limited funding for clinical trials from other sources, such as academia.

So we have the situation in which therapies potentially applicable to aging can exist in the market for decades without any sufficiently rigorous attempt being made to determine (a) whether they can treat aging, and (b) how good they are at treating aging. What can be done about this?

A variety of initiatives have been underway for some time, to some degree. Some groups want to reduce the cost of medical regulation. Thirty years of very aggressive lobbying, patient advocacy, and activism on this front have yielded just about nothing. Less than nothing, really, as the cost of putting a drug through the FDA regulatory system has more than doubled in recent decades, and the pace at which new drugs are approved keeps falling. It remains to be seen as to whether the present green shoots in the US regulatory system, such as Right to Try laws, will make any difference, but so far rhetoric from inside the system about accelerated approvals and reducing costs remains rhetoric.

A subset of those interested in reducing the cost of regulation are specifically engaged with the question of how to make clinical trials cost less. This is a complicated topic, and little progress has been made for many of the same reasons that regulation is expensive in the first place. Those in charge have little short term incentive to reduce the costs of the system; bureaucrats use it to diffuse blame for failures, while large pharmaceutical companies use the high cost of development as a moat to defend against upstart competitors. Everyone involves recognizes the flaws in the system, and no-one does anything about it because it is not in their immediate interest to do so.

Some groups devote themselves to making therapies available outside the major regulatory systems, via medical tourism. This has been relatively successful in the provision of therapies, albeit to a comparatively small number of people relative to those that could be reached if treatments were available in heavily regulated regions, but it has absolutely failed to generate an environment in which hard, reliable data on the efficacy of such therapies results. The medical tourism field is a black box; one roughly knows what therapies are available, but that is about it. Everything else is hidden, unavailable. First generation stem cell therapies have been widely used for more than 20 years, and we still know relatively little about efficacy in most use cases.

Some groups are trying to build systems and communities for self-experimentation and medical tourism participants that are specifically designed to yield higher quality data that might form the basis for synthetic clinical trials. So far this has not generated any meaningful success. It is a hard problem. All of the incentives are for patients and clinics not to share, and if one is paying enough to change those incentives, one is back to effectively running a less well organized form of expensive clinical trial.

Overall the problem of proving that an affordable therapy is or is not worthwhile as a treatment for degenerative aging is a challenging mess. For my part, I suspect that producing good data on low-cost interventions is going to require, at least at the outset, for the first dozen or so interventions, a community of dedicated, wealthy philanthropists who care more about this topic than they do about being wealthy. To my eyes, philanthropic support of clinical trials is the only short-term practical approach to bring change that might demolish the present set of perverse incentives, or at least lead to a few of the most interesting of the affordable potential interventions for aging being proven and quantified in clinical trials.

Exosomes are one category of extracellular vesicle secreted by cells, a membrane-wrapped package of molecules, one complex component of the extensive, incompletely mapped communication that takes place constantly between cells. Exosome therapies are conceptually similar to stem cell therapies, an attempt to favorably adjust the behavior of native cells via signaling. While the first exosome therapies are widely available via medical tourism, with a few organizations in the early stages of sponsoring clinical trials to allow use in more regulated regions, the research community is assessing approaches that involve engineering the contents or surface features of exosomes harvested from young donor blood, tissues, or stem cells. The example here is tested in a mouse model of Alzheimer's disease, producing favorable results.

In this study, the rabies virus glycoprotein-targeting peptide (RVG-29) was conjugated to the surface of young plasma-derived exosomes (EXOs) to construct RVG-engineered EXOs (RVG-EXOs). RVG-EXOs exhibit enhanced blood-brain barrier penetration and neuron targeting, thus offering an efficient delivery system for targeted Alzheimer's disease (AD) therapy. RVG-EXOs treatment markedly improved multiple cognitive behaviors in 3xTg AD mice, including spatial learning, working memory, and novel object recognition. RVG-EXOs effectively alleviated AD pathology by promoting amyloid-β clearance, suppressing Tau hyperphosphorylation, and preserving synaptic integrity and neuronal survival.

Mechanistic studies revealed that RVG-EXOs activates the autophagy pathway by inhibiting RPTOR expression, providing a molecular basis for the neuroprotective effects of young plasma exosomes. Single-cell RNA sequencing revealed that RVG-EXOs remodeled brain cellular landscape: increased neurons, rebalanced inhibitory/excitatory neurons, strengthened Ptn-Sdc3 neuroprotection, and attenuated APP-CD74 signaling, which suppressed disease-associated microglia (DAM) and promoted homeostatic microglia.

Link: https://doi.org/10.1016/j.bioactmat.2026.08.008

Some aspects of cognitive function exhibit marked declines relatively early in later life, by middle age. Here, researchers show that episodic and associative memory recall, meaning the ability to correctly link together and place in context specific individual memories, shows a sizable decline in 50-something participants versus their 20-something counterparts. The fine details of the storage of memories are understood to be fairly dynamic over time; accessing memory can change storage, as can mechanisms of aging operating on the organization of neural networks. Even outside the context of aging, memory is far from perfect even in the best of circumstances. We forget most of our personal histories quite quickly, retaining perhaps 2% of the past according to early research into memory and forgetting. There is a great deal of room for improvement.

Episodic memory is the ability to bind elements of an experience into coherent associations. This ability declines with age, often producing errors that can interfere with daily life. Memory distortions might arise from unstable hippocampal representations that cannot be maintained across encoding, storage, and later retrieval. However, whether aging disrupts the temporal continuity of these representations across memory phases has not been directly tested.

Here, adults aged 20-74 completed functional magnetic resonance imaging (fMRI) scanning during an associative memory task involving face-object and face-scene pairings, followed by post-encoding rest and a cued retrieval test. Using multivoxel correlation structure analyses, we quantified hippocampal pattern similarity across each memory stage. Increasing age was associated with increased category errors and reduced representational similarity across all transitions. Higher encoding-retrieval similarity predicted better associative accuracy in younger adults and was less predictive in middle-aged and diminished in older adults.

Uniquely among older adults, greater cross-phase similarity predicted elevated category-level binding errors, suggesting a shift from selective reactivation to misbinding with age. Baseline hippocampal organization and encoding-specific connectivity supported accurate reinstatement only in younger adults. Thus aging disrupts hippocampal stability, possibly representing a core mechanism of age-related decline in associative memory across the adult lifespan.

Link: https://doi.org/10.1093/cercor/bhag114

Many of the more sophisticated forms of medicine, including gene therapies and immunotherapies, are challenging to deliver to the brain. At the very least there are far fewer practical options for delivery, and it is possible that none of that that exist fit a given desired use case. The blood-brain barrier stands in the way of intravenous injection as a path for most approaches, blocking passage of most cells and molecules from circulation to brain tissue. While direct injection into the brain or into reservoirs of cerebrospinal fluid can be achieved, they are sufficiently invasive and challenging to rule out commonplace use.

The brain is made up of many different cell types, and more sophisticated approaches will want specificity to regions or cell types. Small molecules can readily pass everywhere in the body, but are a poor tool if the goal is to engineer selective activity in a given cell type. That selectivity is readily achievable via any form of gene therapy in which expression is keyed to a promoter only active in the cell type of interest. But gene therapies with that capability are largely very hard to get into the brain, or have other characteristics that present hurdles. Forms of AAV viral vectors now exist that can pass the blood-brain barrier, but AAV is restricted in size of payload, and payload size is required for promoter-driven selectivity, ability to turn off the therapy at any point, and other add-ons.

So it is always interesting to see people trying new approaches. Today's open access paper presents a way to selectively deliver antibodies via intravenous injection, through the blood-brain barrier, and into astrocytes in the brain. The astrocytes are reprogrammed into neurons that integrate into existing neural networks and reverse loss of cognitive function. The treatment is focused on Alzheimer's disease, and given the artificiality of the mouse models of this condition, it is always good to wait for a while before becoming too excited by any claimed advance. All too many approaches improve the mice, but do not work well in the human condition. More generally, a feasible approach to deliver antibodies to degrade a specific protein in a specific set of brain cells is quite an interesting technology, however.

Reverse the progression of Alzheimer's disease through Nano-ERASER-based adult neuroregeneration

The irreversible loss of neurons in key cognitive circuits highlights a central therapeutic challenge: neurodegeneration in Alzheimer's disease (AD) outpaces the brain's intrinsic capacity for repair. Astrocyte-to-neuron (AtN) reprogramming has recently emerged as an appealing regenerative strategy because astrocytes, which are abundant, regionally distributed, and proliferative, represent an endogenous cellular reservoir from which new neurons might be generated in situ. Among the molecular targets proposed to induce AtN conversion, polypyrimidine tract-binding protein 1 (PTBP1) has attracted particular attention. PTBP1 is an RNA-binding protein that maintains non-neuronal splicing programs; its downregulation is a hallmark of neuronal differentiation during development. Early studies reported that suppressing PTBP1 in astrocytes or other glia could initiate neuronal transcriptional programs and produce cells resembling functional neurons in models of Parkinson's disease and retinal injury, sparking strong enthusiasm for PTBP1 as a single-factor reprogramming node. However, subsequent lineage-tracing studies yielded conflicting results, suggesting that PTBP1 depletion alone may be insufficient to drive genuine AtN conversion in the adult mammalian brain, raising concerns that some reported conversions reflected viral promoter leakage into pre-existing neurons.

A major technical hurdle in translating PTBP1-based reprogramming for therapeutic use is precise, efficient, and cell-type-selective delivery of the reprogramming agent to astrocytes in vivo while avoiding off-target perturbation of neurons and other cell types. Conventional PTBP1 knockdown methods, including viral shRNA, CRISPR, and antisense oligonucleotides, struggle to achieve astrocyte-restricted suppression without off-target effects on neurons, microglia, or peripheral tissues.

Recently, our group developed a Nano-ERASER system that can downregulate a specific protein by intracellular delivery of its corresponding antibodies via proteasome-mediated degradation, achieving Trim-Away in adult animals and in a disease model for the first time. Thus, we designed a Nano-ERASER-based Trim-Away platform to (1) effectively deliver anti-PTBP1 antibodies (aPTBP1) into astrocytes in the adult brain and (2) trigger rapid intracellular degradation of endogenous PTBP1 via TRIM21-mediated proteasomal clearance. The Trim-Away mechanism depletes target proteins directly at the protein level, bypassing limitations of transcriptional or RNA-targeting approaches and offering temporally precise control over protein levels. By combining blood-brain barrier (BBB)-targeting ligands with a polymer nanocarrier engineered for efficient endosomal escape and intracellular antibody release, the system aims to achieve transient, localized PTBP1 depletion in astrocytes while minimizing exposure to neurons and peripheral tissues. In doing so, it provides a rigorous platform to test whether transient PTBP1 ablation at the protein level is sufficient to engage neuronal splicing programs and promote astrocyte conversion in adult mammalian brain regions relevant to AD pathology.

Treatment with our new system significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits in the 5XFAD mouse model of AD. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.

Researchers here suggest that increased ERBB4 expression in neurons is an important driving mechanism in the onset and progression of Alzheimer's disease. One has to be cautious with such findings, even given the effort made by the researchers to show that human data is compatible with the hypothesis, because the mouse models of Alzheimer's disease in which these sorts of discovery are made are very artificial. Mice do not normal exhibit anything like Alzheimer's disease, so the models induce forms of dysfunction that result in something resembling Alzheimer's in humans. The model embodies assumptions about relevant mechanisms that may not be correct, and this is one of the reasons why progress towards therapies has been slow and painful.

Single-nucleus RNA-sequencing analysis identified the emergence of early-responsive excitatory neurons (EREN), characterized by expression of ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4), as one of the earliest major alterations in Alzheimer's disease (AD) mouse models. Selective Erbb4 deletion in AD excitatory neurons abrogated abnormal neuronal network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition and cognitive deficits. Conversely, Erbb4 overexpression in wild-type excitatory neurons recapitulated these core AD-like phenotypes without amyloid plaques.

Mechanistically, these effects required mammalian target of rapamycin (mTOR) signalling downstream of ERBB4. Subsequent transcriptomic analyses showed that excitatory neuronal Erbb4 is both necessary and sufficient to induce EREN and reactive gliosis. Directed mediation analysis of human AD transcriptomic data further support a model in which excitatory neuronal ERBB4 contributes to a pathogenic cascade that links amyloid pathology to tau propagation and cognitive decline. These findings identify aberrant Erbb4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases.

Link: https://doi.org/10.1038/s41586-026-10964-z

This is far from the only study to indicate that the children of long-lived individuals tend also to be long-lived. The open question is the degree to which this is genetic versus cultural transmission. The construction of very large population databases over the past few decades has produced evidence for genetics to play only a small role in life expectancy for the vast majority of people. Similarly the weight of evidence for lifestyle choice, particularly physical fitness, to be the presently dominant influence on life expectancy is compelling. Against that background, the hypothesis that centenarians are centenarians because they have favorable gene variants that might form the basis for age-slowing therapies faces an uphill battle.

Centenarian lifespan extension is frequently accompanied by delayed onset of aging-associated diseases. Understanding the transgenerational patterns of this phenomenon is crucial for informing investigations of genetic and environmental factors that promote healthy aging. Three independent longitudinal cohorts were studied: LonGenity (2008-2024; New York City area), the New England Centenarian Study (NECS; 1995-2024; throughout the US), and the UK Biobank (2006-2022; throughout the UK). Participants were selected from the 3 studies based on their parental lifespan. Centenarians' offspring had at least 1 parent who reached age 100 years and were compared with control offspring of parents with shorter lifespans.

Differences in age at death and age at onset of 4 age-associated morbidities - cardiovascular disease (CVD), cancer, hypertension, and stroke - were evaluated within study cohorts using Cox proportional hazards regression modeling, estimating hazard ratios (HRs) and delays in expected age of incidence. Combined, centenarians' offspring and control participants numbered 480 in LonGenity (median enrollment age, 74 years [range, 65-94 years]; 262 women [55%]; 245 offspring of centenarians [51%]), 1566 in NECS (median enrollment age, 71 years [range, 39-100 years]; 923 women [59%]; 1082 offspring of centenarians [69%]), and 1984 in the UK Biobank (median enrollment age, 65 years [range, 42-71 years]; 1006 women [51%]; 992 offspring of centenarians [50%]).

Meta-analyses identified consistently reduced hazards in centenarian offspring for death, CVD, and hypertension, with aggregate HR estimates of 0.58 for death, 0.67 for CVD, and 0.68 for hypertension, and delays of 3.12 years for death and 5.21 years for hypertension. Stroke hazards were reduced only in LonGenity (HR, 0.27) and NECS (HR, 0.41). No significant associations with cancer were identified.

Link: https://doi.org/10.1001/jamanetworkopen.2026.30964

Senescent cells accumulate with age in tissues throughout the body, disrupting tissue structure and function with inflammatory secretions. The growing burden of senescent cells is an important contributing cause of degenerative aging. A cell becomes senescent in response to damage induced by some form of stress, or more often when a somatic cell reaches the Hayflick limit on cellular replication. In youth senescent cells are efficiently cleared by the immune system, but immune system aging allows senescent cells to linger and grow in number. Immune cells themselves are prone to reaching the Hayflick limit and entering replicative senescence because they respond to a variety of issues with greater replication to multiply their efforts.

Research into neurodegenerative conditions and the state of the aging brain has increasingly focused on maladaptive behavior on the part of microglia, innate immune cells resident in the central nervous system that are analogous to macrophages elsewhere in the body. Microglia do not just attack pathogens and malfunctioning cells, but also participate in normal tissue maintenance and aid in maintenance of neural circuits. When microglia become too inflammatory, whether or not this includes entering a senescent state, the brain suffers. Inflammatory microglia appear to be an important component of neurodegenerative conditions and age-related deterioration in cognitive function. As today's open access paper shows, senescent microglia are clearly harmful in specific ways.

Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and neuronal dysfunction

Critical shortening of telomeres by the end replication problem induces cell-cycle arrest and causes the cell to enter replicative senescence. Glial cells in the brain (e.g., microglia, astrocytes, and oligodendrocytes) retain proliferative capabilities after development and become more proliferative in response to damage to the central nervous system (CNS) and other stressors. Thus, glial cells are under heavy replicative stress, and telomere shortening is detected in the white matter, whereas telomere length in the gray matter remains relatively unchanged.

Glial senescence has been suggested to transform the brain from normal aging to pathological aging and to drive the buildup and spread of AD pathologies. Microglia are the resident macrophages in the CNS responsible for immune surveillance and innate immune responses to damage and pathogenic species. Microglia are susceptible to increased replicative stress associated with the reactivation of the proliferative program in response to neurodegenerative pathologies, including tauopathy and amyloid beta (Aβ) accumulation.

Here, we report direct evidence that senescent microglia exert detrimental influences on other cell types through an altered secretion profile. We investigated the brains of telomere-shortened mice and observed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single-nucleus RNA sequencing (snRNA-seq) revealed accelerated glial aging and elevated microglial senescence pathways. In a senescence model of human induced pluripotent stem cell (iPSC)-derived microglia, delta-like non-canonical Notch ligand 1 (DLK1) was identified as a novel senescence-associated ligand. Soluble DLK1 (sDLK1) was increased in the cerebrospinal fluid of telomere-shortened and naturally aged mice, and this increase was eliminated by microglial depletion.

In vivo elevation of sDLK1 caused hypomyelination and blocked oligodendrocyte lineage progression, and these effects demonstrate the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.

Long-lived bats are extreme outliers in the normal mammalian relationships between species body size, metabolic rate, and life span. They are small, have a high metabolic rate, and unlike near all other mammals with those characteristics, many bat species are long-lived. But bat species do exhibit a very wide range of life spans; near neighbor species can have very different paces of aging. Researchers here sequence the genomes of a number of different bat species in search of insight into the mechanisms driving longevity in bats. As is usually the case, the distant end goal of this sort of comparative biology of aging research is to find potential approaches to the development of longevity therapies. That is a long road, and little progress has been made beyond investigation. Only in recent years have the first speculative transfers of genes from long-lived species to short-lived species occurred, for example.

The genus Myotis is one of the largest clades of bats, and it exhibits some of the most extreme variation in lifespans among mammals, alongside unique adaptations to viral tolerance and immune defence. Here, to study the evolution of these phenotypes, we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation and functional experiments in primary cells, we identify patterns of adaptation contributing to longevity, cancer resistance, and viral interactions.

We demonstrate distinct modes of adaptation to DNA and RNA viruses compared with all other mammals, with bats exhibiting genome-wide over-representation of positive selection for DNA-virus-interacting proteins and elevated rates of copy-number variation for RNA-virus-interacting proteins. Characterization of Myotis-specific duplications of the key immune factor EIF2AK2 (also known as PKR) reveals multiple ancient segregating trans-species copy-number polymorphisms. We show that the recurrent evolution of longevity seen in Myotis is associated with positive selection in cancer pathways, and demonstrate a unique response to DNA damage in primary cells of the long-lived Myotis lucifugus. Together, our results suggest that bats' remarkable longevity and immunity are linked through pleiotropic adaptations to viruses and ageing-related disease.

Link: https://doi.org/10.1038/s41586-026-10932-7

Clonal hemotopoiesis is the emergence of patterns of potentially problematic mutations occurring in hematopoietic stem cells that then spread over time throughout the immune system, as these stem cells are the source of all immune cells. It is the most well studied form of the somatic mosaicism that occurs in all tissues, the spread of mutations originating in stem cell populations, with some correlational evidence for it to contribute to the development of other age-related conditions. Here researchers note that clonal hematopoiesis associates with idiopathic pulmonary fibrosis, an age related condition with causes that are poorly understood. The immune system is clearly important to health, but equally the research community is some way from fully understanding how exactly disruptive mutations cause downstream problems in tissues.

Clonal hematopoiesis (CH), defined as expanded somatic blood cell clones in persons without other hematological abnormalities, is also age related. CH at variant allele frequencies (VAF) ≥2% is associated with greater risk of chronic diseases, such as coronary heart disease or chronic obstructive pulmonary disease (COPD). Commonly mutated genes (e.g., DNMT3A and TET2) epigenetically control gene expression and are important regulators of disease-related immune responses. Given these shared risk factors, we hypothesized that incidence of CH is associated with idiopathic pulmonary fibrosis (IPF) progression.

DNA was extracted from whole blood after written informed consent was obtained from 123 patients with IPF. Clinical data, available at sampling and within 12 months after blood collection, was used to assign progression (n = 89) as follows: (a) ≥10% absolute forced vital capacity (FVC) 12-month decline alone; (b) ≥5% absolute FVC 12-month decline and radiologic progression; or (c) 12-month radiologic progression alone. CH-defining somatic mutations were analyzed with a targeted sequencing panel (ASXL1, CALR, CBL, DNMT3A, JAK2, MPL, PPM1D, SF3B1, SRSF2, TET2, TP53, U2AF2, and ZRSR2).

CH mutations were present in 38% of patients with IPF (overall median VAF = 6.2%). Significantly more CH-mutated patients were characterized as rapid progressors (53% vs. 25%) and had a greater 12-month loss in FVC compared with those without CH (280 vs. 90 mL).

Link: https://doi.org/10.1172/jci.insight.198458

The most common metabolic diseases, such as type 2 diabetes or fatty liver disease leading to metabolic dysfunction-associated steatohepatitis (MASH), a fibrotic condition of the liver, are consequences of the dysfunctional state of metabolism that results from being overweight and sedentary. These conditions are rare in thin, fit people, even in later life when the damage of aging makes metabolism more vulnerable and inflammatory. Excess visceral fat tissue is known to promote the accumulation of senescent cells. While cells become senescent throughout life, in youth they are promptly cleared by the immune system. That clearance falters with age, allowing senescent cells to linger and accumulate. The metabolic dysfunction produced as a consequence of being overweight accelerates this process.

In today's open access paper researchers review what is known of the bidirectional relationship between metabolic dysfunction and the burden of senescent cells. Metabolic dysfunction promotes senescence, and in turn the inflammatory secretions of senescent cells further disrupt the operation of metabolically active tissues such as the liver. While a fair number of companies are presently developing senolytic drugs capable of clearing a meaningful fraction of senescent cells from the body, and while cheap first generation senolytic treatments, such as the dasatinib and quercetin combination, are readily available for anyone willing to put in a little effort to obtain them, metabolic disease is fairly low on the research and development communities' priority list. It seems unlikely that clinical trials will take place any time soon, but an increasing number of people are choosing to use senolytics off-label, an option that unfortunately generates very little solid data on whether or not a therapy is effective in any given use case.

Metabolically Active but Dysfunctional: The Impact of Senescent Cells and SASP

Cellular senescence and its secretory phenotype (SASP) have emerged as important contributors to chronic inflammation and metabolic dysfunction across multiple tissues. In adipose tissue, a combination of telomere attrition, oxidative stress, and pro-inflammatory signals pushes preadipocytes and mature adipocytes into premature senescence. These senescent adipocytes secrete a complex SASP, rich in cytokines, chemokines, and matrix-remodeling enzymes, that perpetuates local "metaflammation," impairs insulin signaling, and promotes systemic lipotoxicity.

In the liver, hepatocyte and stellate cell senescence similarly contribute to the progression of steatosis to MASH and cirrhosis, as SASP factors drive fibrosis, immune cell infiltration, and metabolic reprogramming. In the pancreas and skeletal muscle, senescence undermines β-cell function and glucose uptake, respectively, further exacerbating insulin resistance and hyperglycemia. Collectively, the cumulative burden of senescence and chronic SASP underscores a feed-forward cycle: metabolic stress induces senescence, and persistent SASP amplifies tissue dysfunction and accelerates disease progression.

Despite the protective role that acute, transient senescence can play in wound healing and tumor suppression, the accumulation of senescent cells in aged or obese individuals creates a pathogenic SASP milieu, often termed "inflammaging", that underlies obesity, type 2 diabetes, MASLD/MASH, and related cardiometabolic disorders. In rodent models, reducing senescent-cell marker burden has been associated with improved metabolic parameters, reduced fibrosis, and improved insulin sensitivity. These findings suggest translational potential for senotherapy in metabolic disease, although whether it can delay or reverse disease onset in humans remains to be established.

The research community remains very interested in finding novel ways to promote muscle growth with minimal side effects. Therapies that inhibit myostatin or upregulate follistatin signaling are under development, and follistatin gene therapies have been available via medical tourism for some years. But most of the research community is focused on pharmacology, the use of small molecules to influence muscle metabolism. As an example of this type of work, researchers here report on a small molecule that mimics adiponectin signaling to promote muscle growth in rats.

Skeletal muscle atrophy is a hallmark of ageing and chronic diseases, yet effective pharmacotherapies remain unavailable. Adiponectin signalling through receptors AdipoR1 and AdipoR2 regulates skeletal muscle metabolism, regeneration and oxidative capacity, but the therapeutic use of adiponectin is limited by its large size and complex multimeric structure. Small-molecule AdipoR agonists, therefore, represent an attractive therapeutic strategy.

Here, we report the discovery and pharmacological characterization of medicarpin, a previously described osteogenic phytoalexin and its water-soluble sodium salt (Med), as dual AdipoR1/R2 agonists, and demonstrate the efficacy of Med in vitro and in rodent models of skeletal muscle atrophy. Med enhanced myogenic differentiation, evidenced by increasing myotube formation and expression of MyoD, myogenin and MyHC. Med also enhanced oxidative capacity by increasing fatty acid oxidation and Med-treated cells showed elevated oxidative fibre markers.

Oral administration of Med significantly attenuated muscle atrophy in both rat models, evidenced by improved muscle morphology, suppressed atrogenes, enhanced myogenic markers and increased muscle adiponectin expression and corresponding downstream signalling. Med markedly improved muscle function, including grip strength, wire hanging, rotarod performance, and toe-spread ability of denervated limbs.

Link: https://doi.org/10.1002/jcsm.70364

Parkinson's disease and Lewy body dementia are synucleinopathies, characterized by the spread of misfolded α-synuclein through the central nervous system. The presence of misfolded α-synuclein provokes harmful changes in cell behavior and ultimately cell death in important populations of neurons. Researchers here explore differences in the vulnerability of different parts of the brain to the pathology produced by misfolded α-synuclein. They conclude that more complex parts of the brain, characterized by increased mitochondrial activity and greater connectivity between neurons, are more fragile in the face of the pathological mechanisms of syncleinopathy.

A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and identified genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process.

Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body- and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABAA, serotoninergic 5-HT1A, 5-HT1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity.

In conclusion, MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.

Link: https://doi.org/10.1186/s12929-026-01267-6