Fight Aging!

Epigenetic control over nuclear DNA structure determines which sequences of DNA are exposed to transcription machinery in the cell nucleus, and thus which genes are expressed. As epigenetic decorations to DNA and its structural helpers are constantly added and removed, structure changes and so does gene expression. Which proteins are produced from their genetic blueprints, and in what amounts, is an important determinant of cell behavior. Epigenetic patterns and the structure of DNA changes with age, and so does gene expression. There are any number of examples of age-related changes in the level of expression of a specific protein that are clearly harmful, as animal studies have shown that health improves when the change is reversed.

If one thinks that aging is essentially epigenetic aging, which many people do judging from the vast funding flowing into the development of partial epigenetic reprogramming therapies intended to reset epigenetic decorations to a youthful pattern, then one should probably be very interested in which other interventions are known to reduce epigenetic age in human trials. People with other opinions on the nature of aging should still find the list interesting. Still, it has to be said that it is far from clear that there is a usefully comprehensive mapping of aging to epigenetic aging, or that even the better epigenetic clocks are actually measuring biological age, or measuring aspects of it in a way that will accurately reflect any given specific change to biochemistry produced by potential treatments for aging. There are clearly mechanisms of aging that cannot be fixed by reprogramming, such as accumulation of metabolic waste that cannot be effectively broken down by even youthful cells, or mutational damage to DNA.

Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans

Epigenetic aging clocks estimate age from DNA methylation patterns and have become central tools in longevity research. More recently, next-generation clocks have been developed to better compensate for the known divergence between chronological age and epigenetic age in ways that relate to lifestyle, health, and age-related disease. Although epigenetic clocks represent investigational biomarkers, these newer models are more strongly associated with all-cause mortality risk than first-generation clocks. As such, interventions that modify them are of interest. To test this, we performed a series of systematic searches and identified 41 human studies reporting the effects of interventions on at least one next-generation epigenetic clock.

Our data suggest that a diverse range of pharmaceutical, lifestyle, supplementation, non-pharmaceutical clinical, and psychosocial interventions can decrease epigenetic age, including exercise, a plant-rich diet, the GLP-1 receptor agonist semaglutide, caloric restriction, ketamine, omega-3 fatty acids, a multivitamin-multimineral supplement, umbilical cord plasma, and the cholesterol-lowering drug pitavastatin. Nicotinamide riboside, rapamycin, senolytics, and several other interventions showed no detectable effect, whereas plasmapheresis and other therapeutics accelerated epigenetic aging. We also summarize reported effect sizes and compare next-generation clocks with respect to their frequency of use and responsiveness to intervention.

Mitochondria are power plants, hundreds of them in every cell working to create the chemical energy store molecule adenosine triphosphate (ATP) used to power cellular processes. They are the evolved descendants of ancient bacteria, and still act like bacteria in many ways. They are also very complex, and while a great deal is known of their structure and biochemistry, a complete and detailed answer as to why exactly their function declines with age is lacking. It is well established that exercise improves mitochondrial function, both in the short term and over the long term of maintaining physical fitness. This in turn explains some fraction of the beneficial effects of exercise and fitness when it comes to slowing the pace of degenerative aging.

Brain aging is a complex biological process characterised by progressive neuronal and synaptic decline, in which disruption of mitochondrial quality control plays a central role. This system encompasses multiple synergistic components, including mitochondrial biogenesis, dynamic equilibrium, autophagic clearance, and energy metabolism. Aging induces dysfunction across these processes, precipitating mitochondrial fragmentation, functional decline, and energy crises, ultimately driving cognitive deterioration.

Exercise is a promising non-pharmacological intervention for preserving brain health during aging, and its benefits may be mediated, at least in part, through modulation of mitochondrial quality control. Specifically, exercise has been shown to activate key signaling pathways such as AMPK/SIRT1/PGC-1α, thereby promoting mitochondrial biogenesis and metabolic adaptation. It may also regulate mitochondrial dynamics and mitophagy via pathways including cAMP/PKA/Drp1 and AMPK/mTOR. In addition, emerging evidence indicates that exercise may influence brain mitochondrial function through activity-dependent regulation of mitochondrial gene expression and systemic signaling factors.

Link: https://doi.org/10.3390/biology15110854

Members of the life insurance industry have typically been far ahead of the rest of the general public outside the life sciences when it comes to an appreciation of progress towards therapies to treat aging as a medical condition. It is a very large industry, and thus has significant funding to direct towards analysis and prediction of trends in medicine. The prospect of increasing healthy human longevity, of a change in the way in which aging is addressed by medical research and development, is both an existential threat and opportunity for the life insurance industry. Those who predict correctly will thrive, and those who do not will suffer.

Thus it is always interesting to see how insurance industry researchers and analysts react to developments in the medical life science space. Here, the focus is on aging clocks, ways to combine biological data that predict mortality risk across populations. If biological age could be measured accurately for an individual via any specific variety of aging clock, and thus a good estimate of intrinsic mortality risk derived that individual, one would imagine that the life insurers would adopt this technology very rapidly. They have every motivation to do so. The reasons why they have not so far done are the same reasons as to why clocks are not yet the gold standard for assessing the quality of potential rejuvenation therapies: the clocks are not accurate for individuals, and their underlying connections to biological age are not fully understood.

Biological Clocks: Ready for Prime Time?

John Smith is a 50-year-old male applying for a life insurance policy. His medical history is unremarkable, and his recent medical visits record good health. He exercises regularly and is an enthusiastic member of several wellness programs. A recent test from a longevity company reports a biological age of 46, and records that he is aging at 0.7 years per year. Both the company and Mr. Smith are excited that his life expectancy is well above normal. Are they right? And if they are, should life insurers be excited too?

Chronological age is the widely accepted starting point of mortality assessment. It is also time-honored, having first appeared in insurance life tables in the 17th century. Yet it is a blunt metric: two 50-year-olds may have quite different health statuses and life expectancies. Biological age is a term that is widely used in the aging literature. But curiously, it has no accepted definition. This reflects both the complexity of aging and the lack of any gold-standard metric. It reflects how old the body has become, functionally and biologically. It incorporates dimensions of health, such as current physiological state, and the cumulative molecular and cellular damage that has accrued over time. Thus, at face value, biological age would seem to provide more useful underwriting information than chronological age. If one of our 50-year-olds had a biological age of 46 and the other 54, mortality projections would be quite different, and premiums could reflect these.

So, where did John Smith's biological age determination come from? It was likely provided by an "epigenetic clock." which is an algorithm that estimates chronological age from patterns of cellular DNA methylation. Epigenetic clocks are statistical models, trained on methylation status of selected subsets of CpG sites - typically ranging from a few hundred to a few thousand - chosen to optimize predictive performance.

What are the rubs against epigenetic clocks? There are quite a few. Epigenetic clocks are not trained to provide reliable predictions at the individual level. Rather, they are statistical models designed to minimize error across thousands of samples. Consequently, when applied to a single person, their estimates are biologically noisy. Epigenetic age is not a traditional biomarker, such as BMI or serum glucose, which can generate reliable individual-level information. Thus, to equate a younger predicted epigenetic age with a younger biological age, even though this is common practice, is an overextension. Epigenetic clocks are highly dependent on the training data and the populations from which they are derived. If a clock is applied to different populations - such as the very fit (Mr. Smith) or self-selected individuals (those likely to buy a commercial test) - the predictions may be inaccurate.

Are epigenetic clocks of value to life insurers? Not at present. While biological age, to the extent it is equated with epigenetic age, does predict mortality, it does not outperform traditional mortality risk predictors such as age, sex, smoking, blood pressure, BMI, and medical history. Similarly, pace-of-aging, although an outwardly attractive metric, does not outperform traditional measures of current health status. One exception might be the young or apparently healthy, where traditional risk factors are absent, and early deterioration might be captured. Another might be the small number of older individuals where all traditional risk markers are negative; epigenetic clocks may provide better insight into current health. But both scenarios would require longitudinal analyses to prove clock utility.

Researchers have for some years been casting a very broad net in terms of trying to understand how centenarians, people who survive to age 100 and beyond, are different from those who die at earlier ages. There is plenty of evidence for a fairly distinct biochemistry, such as better immune function and lesser degrees of chronic inflammation. Centenarians are still greatly impacted by the processes of aging, are frail, and exhibit a high mortality rate, so it is not a state to emulate, but it is hoped that this sort of research could help to better understand which aspects of aging are the most important in terms of driving declining function and rising mortality, and thus merit greater attention from the research community.

Centenarians exhibit remarkable longevity and compression of morbidity making them an ideal population for uncovering proteins associated with successful aging. Using proteomics, we characterized the immune and cardiometabolic profiles of centenarians' plasma from the SWISS100 cohort. We identified 583 differentially expressed proteins (DEPs) by centenarians when compared with hospitalized geriatric patients (age 80-90 years) and younger healthy participants (age 30-60 years). We replicated the association of 23 proteins with a standard set of aging proteins (APs) developed by the Targeting Aging with Metformin (TAME) consortium.

By comparing the centenarian signature to an independent centenarian proteomics study, we identified 135 DEPs in both studies with identical aging directions, establishing a robust set of APs in centenarians. Applying fractional polynomial regressions, we uncovered proteins with linear and non-linear profiles associated with age and identified a subgroup of 37 proteins with a younger signature in centenarians. Protein-protein interaction and pathway enrichment analyses of 37 proteins point to programmed cell death, metabolic enzyme pathways, regulation of extracellular matrix stability, immune and inflammatory responses, and neurotrophic signaling pathways. This novel approach to aging research has uncovered new proteins and pathways, which may present promising targets to understand processes associated with longevity and healthy aging.

Link: https://doi.org/10.1111/acel.70409

I expressed some skepticism on the approach of Sentcell. The claim is that under defined circumstances CD4+ T cells will secrete structured extracellular telomere fragments (named "telomere rivers") that produce broadly beneficial effects to extend life span in mice. The very large size of reported extension of life and the small number of mice in the published study were red flags - we've seen this sort of thing before and it doesn't tend to replicate. To the team's credit, it appears that they are moving towards an academic phase 1 trial of this technology to commence this year, so someone is sufficiently convinced to fund this exercise.

A first-in-human clinical trial of an immune rejuvenation therapy developed by biotech company Sentcell and designed to restore the function of worn-out T cells is expected to begin later this year, building on research into the mechanisms of immune ageing. The Phase 1 trial will focus on exhausted or senescent T cells, which accumulate with age and in chronic disease and become less effective at coordinating immune protection. The treatment is administered by intramuscular injection, similar to many commonly used vaccines. Once delivered, it is designed to reprogramme key pathways that drive immune dysfunction, helping immune cells regain characteristics of younger, healthier cells.

The trial builds on research suggesting that some dysfunctional T cells - a type of white blood cell that helps coordinate the body's immune response - can be restored to a more youthful, functional state. Researchers are focusing on CD4+ T cells, often described as the "conductors" of the immune system because they help direct other immune cells to respond to infection, cancer, and disease. Previous laboratory studies suggest that rejuvenated CD4+ T cells may be able to release telomere-containing structures into the bloodstream. Researchers have termed these structures "telomere rivers" and are investigating whether they could help explain how rejuvenated immune cells influence the health and function of other tissues throughout the body. This idea remains under active investigation and has not yet been demonstrated in humans.

Researchers are preparing for Phase 1 of the trial, which will carefully select adult participants and is expected to focus initially on people with evidence of immune dysfunction, including immune ageing and chronic viral infection. Participants will undergo detailed immune profiling before and after treatment. Investigators will look at whether the therapy can restore features of healthy immune function. As an early-stage trial, the primary goals are safety and biological activity rather than demonstrating clinical benefit.

Link: https://www.eurekalert.org/news-releases/1132420

The platelets found in blood are membrane-wrapped cell fragments generated by a specialized population of megakaryocytes. As such, platelets can contain most of the molecules and structures that are present inside a cell, and exhibit behavior and surface features that reflect their parent cell's state. The primary purpose of platelets is to induce coagulation of blood and formation of a clot, or thrombus, where needed, such as following injury. With age, there is a tendency for clotting to be maladaptively triggered, particularly around areas of damage and dysfunction in blood vessel walls, such as where atherosclerotic plaques have developed. But even without atherosclerosis and other damage to the innner endothelial layer of blood vessels, there are still other changes to platelets themselves that make inappropriate clotting more likely.

This is the background that led to the development of widely used anti-thrombotic drugs that suppress the enhanced tendency towards clotting. Unfortunately, these drugs act on the same regulatory systems that are employed during useful, necessary clotting, such as following injury. Bleeding is a problematic side-effect. This is a common story in attempts to intervene in problems that occur with age, with chronic inflammation providing another example. The obvious paths to suppress unwanted behavior in system run awry turn out to also suppress desired behavior in that system. As biotechnology and the capabilities of the life science community advance, however, we start to see the first signs of improvement, of the ability to begin to manipulate these complex systems more adroitly, finding ways to suppress the unwanted outcomes with lesser effects on the desired outcomes.

Researchers discover a new therapeutic target to prevent thrombi with a lower bleeding risk

Antiplatelet drugs are one of the main tools used to prevent thrombus formation in people who have had a heart attack or stroke or who have cardiovascular diseases with a high thrombotic risk. These treatments work by reducing platelets' ability to aggregate and form clots that can obstruct the arteries. However, their use also increases the risk of bleeding, a common complication that limits their use in certain patients and remains one of the major challenges in cardiology today.

Now, a study dentifies a new protein involved in platelet activation that could help advance toward safer antithrombotic therapies. The work shows for the first time that the LRP5 protein, known for its role in the WNT signaling pathway, is directly involved in platelet aggregation and in arterial thrombus formation. "We have observed that both the genetic deletion of LRP5 and its pharmacological inhibition very significantly reduce platelet activation and thrombus formation in preclinical models, but with a much lower bleeding impact than that of classic antiplatelet agents such as aspirin or clopidogrel."

LRP5, a WNT signalling pathway receptor, and platelet activation

Human platelets, as well as platelets isolated from wild-type (Wt) and Lrp5-deficient (Lrp5-/-) mice, were challenged with ADP, collagen, LRP5-specific inhibitors, and standard platelet inhibitor drugs. Both platelet aggregation and flow-dependent platelet deposition on collagen-coated surfaces were significantly lower in Lrp5-/- than in Wt mice. In vivo carotid artery occlusion time measured by real-time blood flow monitoring was significantly prolonged in Lrp5-/- mice. Human platelets express high levels of LRP5 and flow-mediated human platelet deposition and aggregation was highly reduced by LRP5 inhibition. Under the experimental conditions tested, LRP5 deletion did not significantly affect coagulation nor induce bleeding.

These findings reveal for the first time that LRP5 plays a critical role in platelet adhesion and thrombus formation. Genetic deletion and biochemical inhibition of LRP5 markedly impair platelet aggregation and thrombosis in preclinical models, without major effects on haemostasis. Although further research is needed to evaluate its clinical applicability, LRP5 appears as a novel and actionable target to modulate platelet reactivity and thrombosis.

Researchers here report on a novel a way to improve kidney regeneration following injury, using a technique that was developed as a treatment for an injured heart. It is interesting to consider whether it might work on other tissues as well. Perhaps more relevant is the question of whether the therapy would improve ongoing tissue maintenance in an aged organ in the absence of injury; that rather depends on the fine details of the biochemistry, and could go either way.

A drug developed to help heart tissue repair itself after a heart attack might also help kidney tissue repair and regenerate, researchers have found. The drug, called AD-NP1, which was recently approved by the FDA for a Phase 1 clinical trial in humans, works in heart tissue by blocking a protein that disrupts healing and prevents internal organs from fully recovering. Researchers have now found that blocking this protein in kidney tissue speeds repair after kidney injury in mice.

An injured kidney produces a protein called ENPP1 that initiates a metabolic chain of events, disrupting energy production and function of multiple cells in the injured region, impeding tissue repair. The researchers found that blocking ENPP1 enhanced kidney repair and reduced scar tissue formation, thereby improving kidney function. Researchers previously determined that blocking ENPP1 in heart tissue improved healing.

fed mice a diet toxic to the kidneys and administered drugs that cause kidney damage to normal mice and mice with genes knocked out for producing ENPP1. Blood tests showed that these mice all had significant increases in serum creatinine, BUN, and cystatin C, which are signs of renal dysfunction. But after four weeks, these levels were greatly reduced in mice unable to produce ENPP1 compared with control mice, indicating that their kidneys were healing.

AD-NP1 is a monoclonal antibody engineered in the laboratory to mimic the function of natural antibodies produced by our immune system. Just as our immune system can produce specific antibodies to bind and inactivate specific pathogens, the monoclonal antibody AD-NP1 has been engineered to target human ENPP1 and no other human protein.

Link: https://newsroom.ucla.edu/releases/ucla-researchers-damaged-kidneys-drug

The accumulation of senescent cells in aged tissues is harmful because these cells generate a potent mix of inflammatory signals known as the senescence-associated secretory phenotype, disruptive to tissue structure and function when sustained over the long term. Researchers are interested in finding ways to selectively suppress this signaling, which involves better understanding the mechanisms that promote it. Here, researchers find a way in which senescent cells provoke the well studied cGAS-STING inflammatory pathway, a system that reacts to mislocalized or foreign DNA in the cell cytoplasm, via export of R-loop DNA structures from the cell nucleus.

Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS-STING innate immune pathway to drive the SASP.

We identify the exportin-1 (XPO1)-DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.

Link: https://doi.org/10.1038/s43587-026-01147-6

The primary scientific impulse is to accumulate data and extract knowledge from that data. Application of that knowledge to the production new technologies is a distant afterthought. So too in the life sciences specifically. When it comes to cellular senescence as a driving mechanism of aging, the primary focus of the research community is to employ modern omics tools to build as great a body of data as possible regarding the burden of cellular senescence in aged tissues. In particular this includes the ways in which the state of senescence differs between cell types, or even within the same cell type. Senescence appears to be much more a collection of distinct subtypes than initially suspected.

None of this changes the potential utility of early senotherapeutics, such as the low cost senolytic combination of dasatinib and quercetin that selectively pushes senescent cells into programmed cell death. Clearing even a third of lingering senescent cells from aged tissues produces dramatic benefits in aged mice, meaning a clear reversal of many different age-related diseases and dysfunctions. Yet relatively little effort has been made to rigorously assess this and other early senolytic drugs in humans. A few small academic clinical trials at a few doses have been undertaken when it comes to dasatinib and quercertin, too small a sample to say anything other than the results seem promising, and one company has made it as far as phase 2 trials for a poor choice of senolytic strategy before failing. One would think that the quality of the animal data demands a greater effort when it comes to dasatinib and quercetin.

Scientists Develop First Comprehensive Atlas of Human Cellular Senescence in Aging

A massive scientific initiative to decode how aging reshapes the human body reached a major milestone this month. The National Institutes of Health (NIH) Cellular Senescence Network (SenNet) published its first wave of discoveries. Together, they represent the first coordinated effort to map senescent cells - damaged or aged cells that stop dividing but refuse to die - at single-cell and spatial resolution. When cellular senescence occurs, these "zombie cells" accumulate over time. They secrete harmful chemicals that trigger inflammation and damage surrounding tissue. This process drives aging and fuels chronic diseases like arthritis, cancer, and Alzheimer's disease.

Charting human cellular senescence in aging and disease

Cellular senescence was first recognized in long-term in vitro cultures, where cells eventually ceased dividing yet remained metabolically active. Later studies revealed that senescence also occurs in vivo as a distinct cellular state induced by stress, damage, or other stimuli, resulting in permanent cell-cycle arrest alongside widespread alterations in intracellular and extracellular signaling, including the senescence-associated secretory phenotype (SASP). However, in the human body, we still know surprisingly little about which cell types undergo senescence, their abundance, their spatial distribution, and the impact on the microenvironment across different organs and tissues.

Without such a comprehensive "blueprint" of senescent cells in human tissues and organs, it is nearly impossible to address fundamental questions about their roles in maintaining tissue homeostasis, driving age-related physiological decline, or contributing to chronic diseases. Moreover, emerging evidence suggests that senescence is not a single, uniform program but a highly heterogeneous process. It may manifest differently depending on the initiating trigger, its duration, the tissue microenvironment, the cell type affected, and the individual's age or life stage. Yet, this diversity has been documented primarily in cell culture or animal models, with very limited characterization in human tissues.

The NIH SenNet consortium aims to build the first comprehensive human reference framework for heterogeneous senescent cell states, defined as "senotypes," providing the resources and tools needed to finally ask and answer the deep and meaningful questions about how senescent cells influence human aging and disease. The SenNet publication collection highlights some of the progress made in generating the human cellular senescence atlas during healthy aging of whole lymph nodes, lung parenchyma, prefrontal cortex tissues of the brain, and 14 other tissues; during disease in the liver and human chronic wounds from aged skin; and during the COVID-19 pandemic. Some of the manuscripts highlight the senolytic therapies identified and tested within the SenNet consortium. We envision that mapping senescent cells across human tissues will enable the development of precise diagnostics and senolytic therapies that selectively target harmful senescence while preserving its beneficial roles, transforming the management of aging and chronic diseases.

Researchers have discovered many correlations between age-related diseases that occur in very different tissues at opposite ends of the body and, at first glance, appear to have little to do with one another. These correlations arise because the many varied outcomes of aging emerge from a much smaller set of underlying mechanisms of damage, such as mitochondrial dysfunction and accumulation of senescent cells. The patterned burden of these these forms of damage, amount and distribution in the body, will tend to favor the emergence of some forms of age-related disease over others. Regardless of how this all progresses, these underlying forms of damage are the real target that should be addressed by potential therapies to treat aging.

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss among the elderly in industrialized countries. Neovascular AMD (nAMD), characterized by choroidal neovascularization, represents the most vision-threatening form of AMD and is uniquely dependent on vascular endothelial growth factor (VEGF)-driven angiogenesis. While the ocular consequences of nAMD are well-established, mounting evidence suggests potential links between AMD and systemic diseases, including cancer. AMD and cancer may share several common risk factors and biological mechanisms, such as advanced age, smoking, oxidative stress, chronic inflammation, and dysregulated angiogenic pathways, notably involving VEGF.

Beyond angiogenesis, nAMD may also reflect broader systemic aging biology. Increasing evidence suggests that nAMD is associated with processes such as chronic low-grade inflammation ("inflammaging"), immune dysregulation, and extracellular matrix remodeling. Cellular senescence, while an important component of aging, has been suggested to play dual roles: tumor-suppressive early via growth arrest, but tumor-promoting later through the senescence-associated secretory phenotype (SASP). In the context of AMD, several studies have demonstrated involvement of senescent retinal pigment epithelial cells and their SASP signatures.

These mechanistic lines of evidence provide a framework in which nAMD might not only share angiogenic pathways with cancer but also intersect with systemic aging processes, potentially helping to explain its selective associations with certain malignancies. Recent genome-wide studies have revealed that both AMD and various cancer types exhibit polygenic susceptibility involving complement activation, lipid metabolism, and extracellular matrix regulation-pathways that are also implicated in tumor microenvironments and cancer progression-raising the possibility that such systemic vulnerability could extend beyond the eye.

Link: https://doi.org/10.18632/aging.206383

Increased FGF21 expression is essential to the life extension produced by the practice of calorie restriction. It is a part of the regulatory system governing the beneficial reaction to low levels of protein intake, an evolved response that helps to increase the odds of individuals surviving long winters and other periods of famine. Here, researchers report on the use of an FGF21 AAV gene therapy in mice to produce the sweeping improvements in health that are characteristic of most calorie restriction mimetic strategies.

The decline of organ function during aging limits healthspan. Despite the potential of lifestyle interventions to improve health, sustained maintenance of healthspan is challenging, and no gerotherapeutic drugs have been approved. Here, we demonstrated that aged and geriatric male and female mice treated with muscle-directed adeno-associated viral (AAV) vector-mediated fibroblast growth factor 21 (FGF21) gene therapy extended healthspan and lifespan with sustained organ benefits. This treatment normalized body weight and adiposity, improved insulin sensitivity and glucose homeostasis, preserved hepatic detoxification capacity, counteracted age-related kidney disease, promoted cardiac health and muscular function, and enhanced cognition.

Transcriptomic and histopathological analyses indicated improved whole-body energy homeostasis and cellular fitness, which were mediated by tissue-specific adaptations, including enhanced mitochondrial function, restored proteostasis, and reversion of inflammation, fibrosis, and amyloidosis. AAV-FGF21 treatment also activated AMPK signaling. These results highlight FGF21 gene therapy as a potential strategy to promote healthspan and delay age-related deterioration.

Link: https://doi.org/10.1016/j.ymthe.2026.05.025

Any sufficiently complex set of biological data assessed in a large population of various ages can be used as a basis to create an aging clock. Machine learning techniques are used to find algorithmic combinations of measurements that map to chronological age or observed mortality risk within the reference population. That algorithm then predicts age or mortality risk when used in people outside the reference population; where a person's predicted age is higher than chronological age this is thought to represent a higher burden of damage and dysfunction, and thus a greater biological age. Aging clocks have been show to work pretty well at a population level, but it remains difficult to establish how the measured parameters are determined by mechanisms of aging, and whether a clock assessment is of any practical use for one individual in the health and medical contexts.

Nonetheless, researchers are creating new clocks at a fair pace. Most omics based clocks use immune cells from a blood sample, and there has been some discussion over the years as to how relevant this is to aging in other tissues. Another point of interest has been how to separate variations in immune function that arise from stress, infection, and other transient causes from those arising from mechanisms of aging. With this background context in mind, today's open access paper reports on the use of a single cell assessment of chromatin accessibility in many different immune cell subtypes. Chromatin is structured nuclear DNA, with different sections either spooled and compact to prevent gene expression, or unspooled and accessible for gene expression. This structure is controlled by epigenetic decorations, and determines the behavior of the cell by determining which proteins are manufactured.

sc-ChromAging: A Single-Cell Chromatin Accessibility-based Clock Decodes Cell-Type-Specific Epigenetic Aging Trajectories

The aging process in humans constitutes a complex progression that exerts widespread effects across various organ systems, with the immune system displaying particularly significant dysregulation. This deterioration of immune integrity, often termed immunosenescence, is intrinsically linked to an attenuated capacity for tissue regeneration, a heightened vulnerability to infectious diseases, and the disruption of systemic homeostasis, all of which facilitate the pathogenesis of age-associated morbidities. While chronological age serves as a rough proxy for these changes, it often fails to capture the substantial heterogeneity in health trajectories among individuals. Consequently, the quantification of biological age through molecular biomarkers has emerged as a pivotal strategy to assess aging status and predict health outcomes. Among the hallmarks of aging, epigenetic remodeling is considered a primary driver of the aging process.

The concept of an epigenetic clock was pioneered using DNA methylation data. However, the majority of existing DNA methylation clocks rely on bulk tissue profiles, which makes it difficult to discern whether observed changes arise from alterations within specific cells. Chromatin accessibility, measured by single-cell assay for transposase-accessible chromatin-sequencing (scATAC-seq), reflects the regulatory potential of the genome. As an upstream layer, chromatin state provides unique mechanistic insights into how the aging process rewires the regulatory network of immune cells, yet high-resolution clocks based on scATAC-seq remain unexplored.

To decode the epigenetic heterogeneity of immune aging, the cell-type-specific chromatin accessibility aging clock sc-ChromAging were constructed using a high-quality scATAC-seq dataset derived from the Chinese Immune Multi-Omics Atlas (CIMA) cohort. The predictive performance of sc-ChromAging was evaluated across five major immune cell types. Significant heterogeneity in predictive performance was observed, and the CD4+ T cells exhibited the highest predictive accuracy. To further investigate the epigenetic signatures of aging at higher granularity, the analysis was extended to 25 immune cell subtypes. Consistent with the lineage-level findings, subtypes within the T cells displayed higher predictive accuracy. Notably, CD4+ naïve T cells showed the highest accuracy among subtypes.

The relatively high predictive accuracy observed in CD4+ naïve T cells suggested that their chromatin landscape may effectively reflect the biological aging process. Mechanistically, this high precision may be related to the intrinsic program of thymic involution. Unlike memory or effector subsets whose epigenomes are mainly remodeled by antigen exposure, naïve T cells may maintain a relatively quiescent state where chromatin accessibility changes are driven primarily by the intrinsic aging program. Notably, although CD8+ naïve T cells also showed relatively good predictive performance, their accuracy remained lower than that of CD4+ naïve T cells. This distinction suggests that a quiescent phenotype alone does not necessarily confer the same degree of age predictability across naïve T-cell compartments. One possible explanation is that the chromatin state of CD8+ naïve T cells may be more susceptible to extrinsic regulatory influences associated with their survival and maintenance, including cytokine-dependent homeostatic signals and other environmental stimuli.

Alongside calorie restriction, exercise represents the gold standard of proof for an intervention to slow degenerative aging. Sadly the research community has demonstrated all too few approaches that can robustly improve on exercise and physical fitness in the matter of aging, and none of those yet have compelling human data to support the extensive animal studies. Rapamycin and senolytics spring to mind as those with the greatest amount of data. Partial epigenetic reprogramming is also interesting but still too new to have gathered a very large body of animal work, despite the vast funding devoted to it in recent years. Thus pharmacological mimicry of the response to exercise continues to interest researchers, and programs in this part of the field continue to emerge.

Global declines in physical activity have contributed to an acceleration in immune aging, characterized by systemic inflammation (inflammaging) and impaired immune regulation (immunosenescence). This narrative review provides an overview of the evidence in both preclinical and clinical models supporting exercise as a critical intervention to counteract immune aging and its related diseases.

Regular physical activity modulates systemic inflammation, reduces neutrophil extracellular trap (NET) formation, and promotes favorable shifts in immune cell populations, including T cell and natural killer (NK) cell subsets. Exercise interventions have been associated not only with maintaining immune health but also in mitigating autoimmune disease progression, improving metabolic regulation, enhancing tumor immune surveillance, and reducing neuroinflammation. Emerging studies highlight the role of exercise in promoting vascular normalization within the tumor microenvironment, alleviating tumor hypoxia and acidosis, and restoring T and NK cell function.

In the elderly, appropriately prescribed multimodal exercise regimens may lower infection risk without clear evidence of immunodepression, supporting exercise as a potentially safe and effective strategy for immune rejuvenation. Furthermore, novel mechanistic insights, including the modulation of NET burden, IGF-1 signaling, kynurenine metabolism, and microbiome composition, suggest that exercise influences key biological pathways underlying age-related immune decline. While exercise offers broad clinical benefits, future research should prioritize mechanistic studies to optimize exercise prescriptions and inform the development of exercise-mimetic therapeutics.

Link: https://doi.org/10.3389/fragi.2026.1832962

The functional connectome is a map of connections between brain regions, produced via MRI imaging. Features tend to be fairly distinct from individual to individual, and change over time. Researchers here show that the functional connectome can be used to predict handgrip strength in patients exhibiting age-related frailty, which is quite interesting. One tends to think of loss of hand strength as emerging from degeneration of local musculature and local neuromuscular junctions. The results suggests that there is a component of physical frailty localized in the brain, though it is also possible that this reflects downstream issues resulting from the underlying mechanisms of aging occurring distinctly in both locations.

Physical frailty, which refers to a decline in physical strength and energy, is prevalent in older adults and has been attributed to impaired cognitive function and adverse health outcomes. The strength of a contraction on a handgrip, known as isometric handgrip strength, has been used as a marker of physical frailty. While handgrip strength can partially be explained by muscle properties (e.g., cross-sectional area and architecture), it may also be influenced by neural adaptations, such as intermuscular and intramuscular coordination.

There is a growing use of imaging-derived data from different modalities to predict clinical phenotypes and disease risk. In this context, handgrip strength has been attributed to resting-state functional connectivity within motor and salience networks. For example, within healthy older adults, researchers found that higher functional connectivity of the motor cortex to putamen, insula, and cerebellum was associated with higher handgrip strength. Another study investigated whole-brain functional connectivity (i.e., connectome) and observed that higher handgrip strength was associated with greater functional segregation of the salience ventral attention network in older adults at rest.

Because the connectome is unique for each person, akin to a "brain fingerprint", it may also serve as a personalized marker that can be used to predict their individual behavioral measures. A predictive model can be developed using connectomes from tasks involving motor components. Such tasks shift the brain into a more alert, motor-relevant state, offering greater sensitivity to motor-related conditions like frailty compared to resting-state connectivity. In this study, we focused on healthy older adults and had them perform two perceptual discrimination tasks on two different functional MRI sessions, both of which involved a non-dominant handgrip manipulation. We aimed to test the identifiability of the task-based connectomes across the sessions and identify the key functional connections (FCs).

We measured participants' maximum isometric voluntary contraction (MVIC) of their non-dominant hand as an indicator of frailty and neuromuscular health. We identified FCs predictive of MVIC, which may partly explain motor-related impairments in frail older adults. Finding such brain-based biomarkers for grip strength could identify potential target sites for motor rehabilitation programs.

Link: https://doi.org/10.3389/fnins.2025.1697908

Klotho is one of the few robustly longevity-associated genes. The effects of increased klotho expression on life span in mice that are arguably large enough to be interesting even if one prefers more of a focus on damage repair in the treatment of aging. A number of companies are developing therapies based on either the delivery of klotho fragments shown to improve function in aged animals, or using gene therapies to promote klotho expression and secretion. While klotho is important in the aging kidney, it is the ability of circulating klotho to promote function in the aging brain that has attracted greater interest, perhaps in large part because the biochemistry of its influence on the brain is less well understood.

Brain aging is accompanied by progressive disturbances in calcium signaling, mitochondrial function, redox balance, neuroimmune regulation, and barrier-fluid homeostasis, collectively increasing susceptibility to neurodegenerative diseases. Therefore, identifying physiological regulators that stabilize these interconnected processes is central to understanding brain aging. Klotho, an antiaging protein initially characterized by its systemic roles in mineral metabolism and lifespan regulation, has emerged as a key modulator of cellular and tissue homeostasis across multiple organs, including the central nervous system.

In the brain, Klotho is predominantly expressed in the choroid plexus and selectively in neuronal and oligodendroglial populations, positioning it at the interface of barrier physiology and neural function. Experimental studies have indicated that Klotho contributes to cerebrospinal fluid homeostasis, synaptic plasticity, neurogenesis, myelination, and resistance to metabolic and oxidative stress. Rather than acting through disease-specific pathways, Klotho stabilizes the core physiological axes that govern neuronal resilience, including Ca2+ signaling, mitochondrial-redox homeostasis, neuroimmune balance, growth factor signaling, and barrier integrity. Consistent with these physiological roles, reduced Klotho availability is associated with cognitive decline and multiple neurodegenerative disorders.

This review positions Klotho as a central determinant of cognitive reserve and neuro-resilience, providing a unifying physiological framework that links systemic homeostasis to brain aging and explains how disruption of Klotho signaling amplifies vulnerability to neurodegenerative disease, whereas its preservation supports lifelong brain integrity.

Link: https://doi.org/10.4196/kjpp.26.015

Senescent cells accumulate with age, a situation that appears more a result of the aging immune system failing to achieve timely clearance of newly senescent cells rather than a significant increase in the pace at which cells become senescent. Senescence occurs in response to cellular damage and stress, but also when somatic cells reach the Hayflick limit on replication. A senescent cell becomes larger, ceases replication, and devotes its energies to the secretion of pro-growth, pro-inflammatory signals. In the short term and in youth this is usually beneficial, helping to coordinate tissue maintenance, regeneration, and suppression of potentially cancerous cells. When sustained for the long term, the signaling of senescent cells is disruptive to tissue structure and function, however, contributing to the damaging chronic inflammation of aging.

In principle, clearing out lingering senescent cells should improve the ability of other classes of rejuvenation therapy to produce benefits. This is particularly thought to be case for stem cell and exosome therapies that rely upon generating favorable signals to improve the behavior of a patient's cells, thereby dampening chronic inflammation and hopefully enhancing regeneration and tissue maintenance. Senescent cells and signaling therapies stand in opposition, and it makes sense that a reduced burden of senescent cells should improve outcomes for signaling therapies.

This has to be tested, of course. Today's open access paper reports on the results from one example of this sort of study. Unfortunately the researchers involved chose to employ accelerated aging mouse models rather than naturally aged mice, so one can't take the results entirely at face value. Still, it is supportive of the consensus view on the opposition between senescent cells and signaling therapies. Interestingly, the researchers used a senolytic vaccine rather than a small molecule; you might recall an earlier study that employed this specific vaccine to slow cancer progression in mice.

Synergistic senolytic-regenerative therapy significantly extends healthspan and lifespan

Regenerative medicine, particularly through stem cell-based therapies, holds immense potential for treating chronic diseases and mitigating the effects of aging by restoring tissue function and homeostasis. Mesenchymal stem cells (MSCs), have been extensively investigated for their paracrine effects, immunomodulatory properties, and capacity to promote tissue repair via secretion of growth factors. Personalized MSC (pMSC) are a type of autologous stem cells developed by Immorta Bio which can be produced in an "age-specific" manner by controlling the extent of differentiation during generation from pluripotent stem cells. MSC are attractive from an anti-aging perspective because of the studies showing young MSC can suppress and in some cases even inhibit characteristics of aging.

Despite promising preclinical outcomes, and one FDA approval for an orphan disease, clinical translation of MSC therapeutics remains limited, with many trials demonstrating modest efficacy in conditions characterized by fibrosis, inflammation, and organ failure. A key barrier to successful regeneration is the accumulation of senescent cells, a hallmark of aging and chronic pathology that actively impedes stem cell function. Senescent cells, induced by stressors such as oxidative damage, telomere attrition, or chemotherapeutic agents, enter a state of irreversible cell cycle arrest and secrete a constellation of pro-inflammatory cytokines, chemokines, and matrix-degrading proteins collectively known as the senescence-associated secretory phenotype (SASP). SASP components not only perpetuate local inflammation but also directly antagonize regenerative processes by inhibiting stem cell proliferation, differentiation, and survival.

Experimental models of organ failure and accelerated aging, including carbon tetrachloride (CCl4)-induced hepatotoxicity and doxorubicin chemotherapy, reliably recapitulate this senescent environment, manifesting as increased aging markers and impaired physical capacity alongside biochemical evidence of tissue damage. Here, we investigate the hypothesis that senescent cells and their SASP directly impair pMSC-mediated regeneration in models of liver failure and accelerated aging. Using SenoVax, a novel senolytic immunotherapy, in combination with pMSCs, we evaluate synergistic effects on biochemical markers of liver function, aging and regenerative biomarkers, survival, and physical fitness attributes of aging. Combined senolytic and pMSC therapy outperformed monotherapies and produced clear synergistic benefits, including significant biochemical improvement of liver failure parameters, reversal of accelerated aging features, and restoration of regenerative signaling pathways. These findings support the concept that clearance of senescent cells can act as a critical adjuvant to regenerative therapies for chronic disease and aging.

Producing new aging clocks is easier than overcoming the hurdles to the practical use of existing aging clocks, so the research community is generating new clocks at a fair pace while failing to make much concrete progress on the challenging problem of how to use clocks to assess novel potential rejuvenation therapies. An aging clock measures some combination of parameters that at least appears to reflect biological age. Given that clocks are reverse engineered from epidemiological data via machine learning techniques and the research community has not established clear links between biological age and any of the specific parameters used in a clock, it is entirely unclear as to whether any given clock will accurately reflect the outcome of an actual rejuvenation therapy. Will it understate or overstate the effects of repairing some form of cell and tissue damage? Will its predictions regarding mortality risk turn out to be correct? They only way to find out at present is qualify a specific clock for a specific intervention via the slow and expensive life span studies that everyone wants to avoid. Some way to fix this present situation is needed, and building more clocks seems unlikely to achieve that goal.

Accurate quantification of biological age is essential for early risk stratification and intervention of chronic diseases. Here, we present StackAge, an ensemble-based biological aging clock that integrates large-scale plasma proteomic and metabolomic profiles from 30,376 participants in the UK Biobank. StackAge demonstrated high accuracy in age prediction (Pearson r ≈ 0.93 with chronological age) and substantially enhanced risk prediction for 12 chronic diseases, achieving area under the curve (AUC) exceeding 0.90 for type 2 diabetes, Alzheimer's disease, and chronic kidney disease. Notably, the incorporation of estimated aging rates consistently improved disease prediction beyond conventional omics and demographic features.

Feature interpretation and pathway enrichment analyses revealed that aging-associated biomarkers were enriched in inflammation, metabolic stress, and extracellular matrix remodeling pathways. Mediation analysis further indicated that modifiable lifestyle factors may accelerate biological aging, thereby increasing susceptibility to cardiovascular, neurological, immune, and musculoskeletal disorders. Together, these findings establish a robust multi-omics framework for quantifying individual aging trajectories and highlight biological age as a clinically actionable indicator for precision prevention and health management of age-related diseases.

Link: https://doi.org/10.1093/bib/bbag271

Adjusting the operation of metabolism to modestly slow aging has long formed the bulk of fundamental research into intervention in aging. All living organisms exhibit some plasticity of life span when subject to mild stresses, such as lack of nutrients, heat, cold, and so forth. Unfortunately this strategy seems unlikely to lead to therapies that greatly improve upon the effects of exercise and lifestyle choice, particularly given the evidence for metabolic adjustment to produce ever smaller gains in longevity as species life span increases. Nonetheless, this form of research persists, driven by the scientific urge to obtain complete understanding of the way in which aging progresses in detail. Here, for example, researchers provide evidence for there to be multiple options for the adjustment of metabolism to slow aging, not just one path.

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process, that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived C. elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial reactive oxygen species (ROS), and mild mitochondrial impairment.

We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense, and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms.

Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

Link: https://doi.org/10.64898/2025.12.29.696944

Macrophages are innate immune cells found throughout the body, important not just for their ability to defend against infectious pathogens, but also deeply involved in tissue maintenance and regeneration. Macrophages can adopt different packages of behaviors - known as polarizations - in response to circumstances. The simple model, which likely glosses over many lesser differences that are important in some contexts, divides the macrophage population into M1 and M2 polarizations, distinguished by surface features as well as by behaviors. M1 macrophages generate inflammation and aggressively hunt down pathogens. M2 macrophages resolve inflammation and engage in tissue maintenance activities, such as ingesting cellular debris and waste products. Both polarizations are necessary, but aging brings imbalance, often characterized as too many M1 macrophages where M2 macrophages are what is needed.

Thus the research community is interested in developing the means to adjust macrophage polarization for therapeutic benefit. At the outset, this involves better understand the regulation of polarization, and the many distinct influences that contribute to a macrophage adopting one state or another. Today's research materials focus on an aspect of the regulation of circadian rhythm that is known to influence macrophage behavior, and the authors report on their efforts to dig more deeply into how this actually works. This sort of fundamental research is necessary to identify possible points of intervention for the later development of therapies.

Body clock found to control inflammatory responses in macrophages

When our body encounters an injury or infection, the immune system sends out cells known as macrophages to initiate an inflammatory response that begins the healing process. These macrophages can exist in two different states: a pro-inflammatory (M1) state, which promotes inflammation, and an anti-inflammatory (M2) state, which helps resolve inflammation and repairs the tissue. The balance between these two states is important, as disruptions can lead to uncontrolled inflammation, which in turn can give rise to chronic inflammation-associated diseases, including cancer, liver disease, diabetes, and autoimmune disorders.

Previous studies have revealed that macrophage activity is closely linked to the circadian clock, with BMAL1 playing a central role in regulating this process. Researchers have now found that BMAL1 drives macrophages toward a pro-inflammatory M1 state by activating inflammatory signaling pathways in the cell nucleus. Researchers observed that normal mice showed a marked increase in pro-inflammatory M1 macrophages along with elevated inflammatory signals after exposure to a chemical carcinogen. In contrast, mice lacking BMAL1 in their macrophages showed significantly reduced inflammation and suppressed liver tumor development.

Experiments revealed that BMAL1 binds to multi-functional protein 2 (MFP2), a fatty acid-oxidation enzyme normally found in cellular compartments called peroxisomes, and transports it into the cell nucleus. Notably, nuclear MFP2 levels fluctuate according to the time of day in a BMAL1-dependent manner. Once inside the nucleus, MFP2 increases acetyl-CoA levels, which drives acetylation of key proteins including p65, a component of the transcription factor NF-κB, a key regulator of inflammatory genes. This activates NF-κB, which functions as a switch for inflammatory genes, thereby driving macrophages into the pro-inflammatory M1 state. These findings suggest that targeting or blocking nuclear MFP2 and administering drugs at an optimal time of the day could become a new therapeutic strategy for chronic inflammatory diseases and enhance treatment efficacy while minimizing side effects.

The circadian clock component BMAL1 enhances macrophage inflammation by nuclear translocation of peroxisomal β-oxidation enzyme MFP2

The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previously unrecognized mechanism by which the core circadian clock component BMAL1 enhances the inflammatory response of macrophages through the nuclear translocation of the peroxisomal β-oxidation enzyme multi-functional protein 2 (MFP2). BMAL1 drives MFP2 accumulation in the nucleus, where MFP2 contributes to acetyl-CoA production and acetylation of the NF-κB subunit p65, thereby facilitating M1 polarization and inflammatory chemokine expression. Nuclear MFP2 levels oscillate in a diurnal manner in the liver, but this rhythmicity is abolished in Bmal1-deficient mice. Macrophage-specific deletion of BMAL1 alleviates diethylnitrosamine-induced hepatic inflammation and tumorigenesis, concomitant with reduced inflammatory gene expression. These findings uncover a BMAL1-dependent nuclear metabolic pathway that links circadian regulation of macrophage inflammation and suggest that targeting nuclear MFP2 may offer a therapeutic approach for inflammatory diseases and tumorigenesis.

Researchers here report on an interesting in vitro exercise in the comparative biology of aging. They took fibroblast cells from ten difference mammalian species with widely divergent life spans and chemically induced DNA damage in the cells. Modern DNA sequencing approaches allow an accurate measure of the amount of mutational damage produced by this chemical treatment, which in turn allows a comparison of the degree to which cells from different species can resist such damage via the operation of DNA repair systems. Long-lived species have more efficient DNA repair mechanisms, as determined by this approach.

We test the hypothesis that excess mutations induced in primary fibroblasts by a low dose of N-ethyl-N-nitrosourea (ENU) are inversely correlated with species-specific maximum life span. To measure excess mutations induced by ENU we treated primary cells of 10 mammalian species, greatly differing in life span. We treated all cells with a low dose, non-toxic dose of ENU (20 ug/ml). We then extracted DNA from all treated and untreated cells and quantified somatic mutation burden by single-molecule sequencing. We measured excessive mutations by calculating the increase in single nucleotide variants (ΔSNVs) and we analyzed this across species with linear regression.

The average values for ΔSNV were found to range from 0.773 in mice to 0.367 in whale, resulting in a modest inverse correlation with species-specific maximum life span (R^2 = 0.2067). We conclude that DNA repair accuracy, the main determinant of genome sequence integrity, modestly correlates with life span suggesting that longer lived species have better repair capacities compared to shorter-lived species, which is in keeping with genome instability being a primary hallmark of aging and highlights its important role for longevity.

Link: https://doi.org/10.70401/Geromedicine.2026.0023

Researchers here identify mechanisms downstream of faulty calcium metabolism that drive the harmful signaling of senescent cells that accumulate in aged tissues. Calcium metabolism is well studied in a number of contexts, and various drugs exist to adjust its operation in one way or another. Applying one of those drugs to aged mice results in a reduction in the harms done by senescent cells, improved health, and a 17% extension of life span. There will be many ways in which the presence of senescent cells in aged tissues could be made less harmful. At present most efforts are focused on the development of new drugs to selectively destroy senescent cells, but it seems likely that these research groups and companies will soon be joined by those seeking to alter the behavior of these cells instead.

Cellular calcium (Ca2+)-regulating systems are compromised during aging-related disorders. Here, we show that disruption of Ca2+ homeostasis leads to the cytoplasmic accumulation of Ca2+ binding protein S100A6, which promotes Hutchinson-Gilford progeria syndrome (HGPS) and natural aging. S100A6 recruits CacyBP to facilitate the ubiquitination and degradation of PARP1, leading to DNA damage and the formation of cytoplasmic chromatin fragments (CCF), activing cGAS-STING-NF-κB pathway and the secretion of senescence-associated secretory phenotype (SASP) factors.

Mianserin (MIA), a tetracyclic antidepressant, attenuates senescence in cells derived from HGPS patients and naturally aging humans by antagonizing serotonin receptors HTR2B/2 C to lower Ca2+ concentrations. MIA also improves a range of aging phenotypes and significantly extends the lifespan of both progeroid and naturally aging mice. Together, our findings uncover the mechanism of Ca2+ homeostasis disruption during premature and natural aging, and suggest MIA as a potential therapeutic strategy to extend healthy lifespan by augmenting Ca2+ homeostasis.

Link: https://doi.org/10.1038/s41467-026-74021-z

As yet the life sciences have provided no way to definitively, robustly measure biological age in an individual. In part this stems from a lack of consensus as to a useful definition of biological age, or indeed of aging more broadly. Researchers have long agreed upon sensible definitions at the high level, such as that aging is an increase with time in the risk of mortality due to intrinsic causes. That definition is validated, measurable over populations, but helps little when it comes to assessing the mortality risk or age of any given individual. At the low level, there are many specific forms of damage and dysfunction that can be measured, albeit not always without invasive sampling. Burden of senescent cells, loss of mitochondrial function, reduced average telomere length, slowed pace of cell replication, reduced grip strength, changes in a thousand biomarkers relating to immune function, and so forth. We have the general sense of trends, but again one cannot use these measures to say definite things about biological age and mortality risk for any given individual.

We live in a world in which measurements and algorithmic combinations of measurements that reflect aging in populations are proliferating alongside the interest in treating aging as a medical condition. This is particularly true for the aging clocks, such as epigenetic clocks, derived from machine learning techniques applied to large bodies of biological data. A slow, incremental ongoing process is underway to find out whether this landscape forms a suitable foundation for the discovery and development of a true consensus measure of biological age that can be applied usefully to individuals. At present that largely involves assessing as many people as possible using as many different measurement approaches as possible, and searching for patterns in the data. Data informs the way in which researchers think about definitions of aging, which inspires new approaches to measurement of biological age, and use of those approaches produces new data. It is a circular road.

Today's open access paper is a snapshot of part this ongoing dialog between theory and data. It is well known that socioeconomic status correlates with life expectancy across populations. Does this mean that low socioeconomic status produces accelerated aging? By what mechanisms, and how does the relative importance of these mechanisms inform our definitions of aging? Looking at epigenetic clock data derived from study populations with different socioeconomic circumstances doesn't answer these questions, but having that data is one step further towards a future in which those answers do exist.

The mediating role of DNA methylation clocks in associations of race, ethnicity, education, income, and occupation with mortality: findings from NHANES 1999-2002

For most documented contexts and time periods, there is a strong association between lower socioeconomic position and risk of higher mortality. The theory of social stratification posits that social stratification caused by a combination of factors, particularly race, ethnicity, and socioeconomic position, would influence health outcomes through differential access to resources, power, and opportunities. These adverse effects even can undermine the beneficial effects from other social exposures such as social cohesion and social resistance. These health disparities are reflected in key social stratification factors such as race and ethnicity, educational attainment, income, and occupation. Studies report notable differences in life expectancy across these dimensions. For instance, according to recent estimates, White Americans who reach age 15 have a life expectancy of 63 years, compared to 59 years for Black Americans and 66 years for Hispanic Americans. Likewise, individuals with an income at or above 400% of the poverty threshold have a life expectancy of 60 years at age 18, while those living below the poverty line have just 49 years. Similar disparities are also observed across different education levels and occupational groups

Aiming to systematically examine the mediating role of DNA methylation clocks in the associations between race, ethnicity, education, income, and occupation and mortality, this study uses nationally representative data to demonstrate that DNA methylation clocks, particularly GrimAge2 and DunedinPoAm, mediate a substantial proportion of racial/ethnic and socioeconomic disparities in mortality. GrimAge2 exhibited significant mediation on all-cause mortality disparities, accounting for 21% of the difference between participants with a high school diploma or GED and those with a college degree or higher, up to 52% of the difference between individuals in high-skilled blue-collar occupations and those in white-collar and professional positions. Similarly, the DunedinPoAm pace of aging mediated 11% of the mortality disparity between high school graduates and individuals with a college degree or above, and 28% of the disparity between Hispanic and White participants. Notably, these mediation results, particularly for GrimAge2, were greater than those observed for traditional clinical biomarkers. These findings suggest that DNA methylation clocks and biomarkers could serve as valuable tools for future research investigating the mechanisms underlying health disparities.

Across mammalian species, resting metabolic rate roughly inversely correlates with species life span and body weight. Larger species are on average longer lived and have lower metabolic rates. There are, of course, a number of interesting outliers that exhibit very long lives relative to similarly sized mammalian species, such as a few bat species and the naked mole-rats that are the subject of this paper. The prevalent thinking on the matter of metabolic rate and longevity is that this relationship says something about the amount of oxidative damage an individual's cells can sustain, or the capacity of those cells to resist that form of damage. Greater metabolic rate implies greater generation of oxidative molecules by mitochondria. The membrane pacemaker hypothesis on species life span suggests that the degree to which the lipid composition of cell membranes can resist oxidative damage is important. There is a great deal of complexity under the hood here, however, and every neat and compact theory on important mechanisms in this matter has its exceptions and outlier species.

This study offers a detailed analysis of resting metabolic rate (RMR) in naked mole-rats, incorporating individual, social, and colony-level factors to clarify how energy expenditure is organised within a eusocial mammal. Body mass consistently emerged as the primary predictor of RMR, aligning with the well-established allometric scaling of metabolic rate across mammals. This follows widely accepted convention that body mass explains the majority of variation in mammalian metabolic rates.

Notably the absolute RMR values recorded here are substantially lower than those predicted for mammals of similar size, further supporting the characterisation of naked mole-rats as possessing an unusually low metabolic profile. Predicted RMR values from 10 different studies and their associated approaches show a range of RMRs from 51.6 ml O2/hr to 71.1 ml O2/hr, compared to an average RMR of 45.5 ml O2/hr in the present study. This metabolic depression is commonly viewed as an adaptation to their subterranean environment, where relatively stable burrow temperatures lessen thermoregulatory demands, and energetic efficiency is advantageous given the high energetic and water costs of excavation alongside constrained resource availability. Within this ecological framework, reducing maintenance energy expenditure is likely to contribute both to colony stability and to the species' exceptional longevity.

Age did not significantly predict RMR once body mass was accounted for. The absence of an age effect is particularly notable given the exceptional lifespan of naked mole-rats. In many mammals, aging is accompanied by measurable shifts in metabolic maintenance; here, basal metabolism appears remarkably stable across age classes. This stability is consistent with the species' negligible senescence phenotype and suggests that aging does not impose detectable energetic costs at the level of resting metabolism.

Link: https://doi.org/10.1242/bio.062586

Thrombospondin-1 is a component of the senescence-associated secretory phenotype (SASP) produced by senescent cells. It has been shown in the past to induce blood-brain barrier dysfunction, but here researchers show that it also degrades mitochondrial function in macrophages, biasing those cells into the inflammatory M1 state. This in turn contributes to chronic inflammation and dysfunctional bone regeneration. The accumulation of senescent cells with age is known to be an important aspect of degenerative aging, and the SASP is known to change bystander cell behavior for the worse. There are likely countless mechanisms of this nature taking place in the aging body, all of which could be suppressed via reduction of the burden of senescent cells.

The aging bone marrow microenvironment is characterized by chronic low-grade inflammation ("inflammaging"), which disrupts skeletal homeostasis and impairs bone regeneration. However, the stromal-immune crosstalk mechanisms sustaining this pathological state remain poorly defined. Here, transcriptomic analysis identified thrombospondin-1 (Thbs1) as a key upregulated component of the senescence-associated secretory phenotype (SASP) in aged bone mesenchymal stromal cells (BMSCs).

We demonstrate that BMSC-derived Thbs1 drives pro-inflammatory M1 macrophage polarization by suppressing PINK1/Parkin-mediated mitophagy. Mechanistically, Thbs1 binds to the TGF-β type II receptor (Tgfbr2) on macrophages to activate Smad3 signaling, which transcriptionally represses the mitophagy regulator Pink1. This repression leads to mitochondrial superoxide accumulation and redox imbalance, thereby skewing macrophages toward an M1-like phenotype.

These Thbs1-activated M1 macrophages, in turn, secrete IL-6, which activates the JAK/STAT3 pathway in BMSCs to inhibit osteogenic differentiation. Crucially, activated Stat3 directly binds the Thbs1 promoter, establishing a self-amplifying loop that perpetuates inflammaging and osteogenic decline. In vivo, AAV9-mediated Thbs1 knockdown in aged rat bone defects restored mitochondrial homeostasis, promoted an M2 macrophage transition, and significantly enhanced bone repair.

In summary, our study reveals a vicious cycle involving the Thbs1/TGF-β/Smad3/PINK1-IL-6/JAK/STAT3 axis that sustains inflammaging and osteogenic decline, highlighting Thbs1 as a promising therapeutic target for age-related bone regeneration.

Link: https://doi.org/10.1111/acel.70575

A cell becomes senescent given sufficient stress, molecular damage, or on reaching the Hayflick limit on replication. A senescent cell ceases replication, grows in size, and secretes a potent mix of pro-growth, pro-inflammatory signals. In a young individual, senescent cells are rapidly removed by the immune system, but this clearance slows with age. Senescent cells accumulate as a result in tissues throughout the aging body. The greater the number of senescent cells, the more disruptive their signaling becomes, changing the behavior of surrounding cells for the worse, degrading tissue structure, and rousing the immune system into a harmful state of constant inflammatory behavior. Studies have shown that selective clearance of senescent cells in older mice improves health, extends life, and turns back many aspects of age-related disease.

Today's open access paper reviews what is know of the bidirectional relationship between the burden of cellular senescence and state of the aging immune system. Senescent cells degrade the performance of the immune system, while the aging of the immune system allows greater numbers of senescent cells to accumulate. Like many of the interacting aspects of aging, each side exacerbates the other in a feedback loop that accelerates over time. Under the hood, the details are far more complex than this simple summary of the situation, of course, and there much is yet to be mapped and understood. Still, what is known more than justifies a far greater level of attention and funding to be given to clinical trials of senolytic therapies to clear senescent cells.

Immunological consequences of senescence in physiology and pathology

Cellular senescence is a sublethal stress response characterized by a durable cell-cycle arrest and the acquisition of a complex secretory program known as the senescence-associated secretory phenotype (SASP), which can profoundly influence local and systemic immunity. In physiological contexts - including embryonic development, tissue repair, and acute tumour suppression - senescent cells coordinate the recruitment and activation of immune cells, enabling their timely immune-mediated clearance and facilitating tissue remodelling and restoration of homeostasis. However, during aging and chronic disease, immune surveillance mechanisms frequently become compromised, allowing senescent cells to accumulate and persist within tissues.

The persistence of senescent cells results in sustained SASP signalling that promotes chronic inflammation, immune dysfunction, and tissue remodelling processes linked to fibrosis, metabolic impairment, tumour progression, and defective tissue repair. In parallel, increasing evidence indicates that immune cells themselves can acquire senescent or senescence-like states, thereby weakening immunosurveillance and generating self-reinforcing feedback loops that further amplify senescent cell accumulation and tissue dysfunction.

The relationship between senescent cells and the immune system is reciprocal. Immune surveillance governs whether the senescence response is resolved or persists, yet immune cells themselves can adopt senescence-associated features that remodel tissue environments and propagate senescence systemically. Age-related decline or dysfunction within immune compartments can amplify inflammatory signalling, shift immune tolerance and generate niches that favour senescent-cell persistence, establishing feedback loops between immune aging and cellular senescence. Together, these observations position senescence not as an isolated cell-intrinsic programme but as a process shaped by continuous dialogue with the immune system. The strength of this senescence-immune crosstalk is shifting the therapeutic paradigm from classical senolytics toward immuno-senolytic strategies aimed at reactivating endogenous immune surveillance or deploying engineered immune cells to selectively eliminate senescent populations.

Machine learning approaches can be used to create aging clocks from near any set of biological data collected from people of various ages. The techniques are well established and many new clocks are published every year. A clock is really an age predictor (or a mortality predictor, or a predictor of some other outcome) trained on a single dataset. When the clock algorithm is applied to any given individual not in that data set, it is thought that the predicted age or mortality risk or other outcome is some reflection of biological age. It is hard to validate this proposition, as there is very little concrete connection between any easily measured biomarker and mechanisms of aging, and indeed all too little consensus on how to measure biological age in the first place. To my eyes more effort should go towards understanding the clocks we have and less to producing new clocks.

Biological aging is a key determinant of liver disease and mortality, but there is little evidence on noninvasive index for assessment of liver biological aging. We developed the Liver Aging Index (LAI) in the China Kadoorie Biobank (CKB, N = 21,629) using Cox-Gompertz proportional hazards model. The LAI incorporated three clinical factors (body mass index, systolic and diastolic blood pressure), eight plasma biomarkers (glucose, total cholesterol, triglycerides, high-density and low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase), and two imaging biomarkers (fat attenuation parameter and liver stiffness measurement).

External validation was conducted in the National Health and Nutrition Examination Survey (NHANES; N = 3412) and the VCTE-Prognosis cohort (N = 12,170, 16 global centers). Across all cohorts, the LAI demonstrated strong discrimination for all-cause mortality (area under the receiver operating characteristic curve: 0.764 in NHANES; 0.759 in VCTE-Prognosis), outperforming chronological age. Liver aging acceleration (LAA), defined as the difference between LAI and chronological age, was associated with substantially elevated risks: each 1 standard deviation increase in LAA conferred a 22%-85% higher risk of all-cause mortality and a 34%-170% higher risk of liver-related event or mortality.

Using genetic instruments identified in CKB, we found genetic predisposition to accelerated liver aging was associated with higher risks of cirrhosis and liver cancer (hazard ratios = 3.94 and 7.82), further validated in Biobank Japan. Integrating genetics and proteomics revealed novel pathophysiological involvement of amyloid-beta clearance pathway and amyloid precursor protein in liver aging. These findings demonstrate the feasibility of a noninvasive, liver-specific biological aging index and provide new insights into mechanisms underlying liver aging.

Link: https://doi.org/10.1111/acel.70565

The public health side of the cardiovascular community has undertaken a range of messaging programs for physicians and the public at large over the years, attempting to convince more people to make the lifestyle choices that will reduce cardiovascular mortality in later life. Life's Essential 8 is a more recent example of this sort of messaging, a fairly simplistic packaging of what are known to be the largest lifestyle risk factors for cardiovascular disease, starting with diet and exercise and moving on to avoidance of self-sabotage via smoking and excess weight. The study noted here pays particular attention to the effects of lifestyle on mortality in centenarians, finding that effect sizes are relatively large in this age group. Maintenance of fitness and lifestyle doesn't stop producing benefits, in other words.

While Life's Essential 8 (LE8) provides a comprehensive measure of cardiovascular health (CVH), its association with mortality among the oldest-old, including centenarians, remains unclear. This study evaluated the relationship between LE8-defined CVH and all-cause mortality across adulthood using data from the China Kadoorie Biobank (Hainan cohort) and the China Hainan Centenarian Cohort Study, including 31,473 individuals aged 30-116. Participants were categorized by life stage and CVH score (low, moderate, high).

Higher CVH scores were associated with significantly reduced mortality risk at all life stages, including among centenarians, who experienced a 54.8% lower risk with high CVH. A near-linear dose-response relationship was observed. Population-attributable fractions for mortality reached 36.8% in centenarians. Physical activity and body mass were particularly important in reducing mortality among centenarians. These findings challenge therapeutic nihilism in the oldest-old while underscoring the need for age-specific strategies tailored to distinct physiological profiles is crucial for extending healthy lifespan across the adult life course.

Link: https://doi.org/10.1038/s41514-026-00395-5

Today's open access paper combines a few interesting topics. Firstly, the researchers involved describe a way to deliver a short-lived messenger RNA gene therapy selectively to the innate immune cells known as macrophages. Macrophages are normally responsible for engulfing all sorts of unwanted structures in the cell, and many of the specific features that induce that behavior have been identified. Encapsulating messenger RNA into lipid nanoparticles that mimic some of the surface features of cells undergoing programmed cell death results in aggressive uptake by macrophages. Macrophages arguably make a good target for gene therapies in which the goal is to manufacture a secreted molecule of some sort, such as an antibody, and have it fairly widely and evenly distributed throughout the body. For many secreted molecules, this is quite unnecessary; injecting a single subcutaneous fat depot with a small amount of a non-targeted vector can and does work. Distribution in the body is enough of a challenge in gene therapy for any and all alternatives to be welcomed, however.

The application of this novel approach to messenger RNA therapy is in this case a reduction of circulating MMP9. The secreted molecule generated by the targeted macrophages is an anti-MMP9 antibody, directly binding to and allowing clearance of MMP9. Increased circulating MMP9 is characteristic of aging, and here researchers demonstrate that it is the cause of further issues by clearing it and observing benefits. Targeted depletion of MMP9 from circulation achieved via this antibody manufacturing approach improved the function and structure of bone and cartilage tissue in treated mice. It is of course a long road from preclinical proof of concept to therapy in the clinic, and many such demonstrations are never further developed. One might hope that this will at least attract more attention to the production of novel drugs that can much more effectively and selectively reduce circulating MMP9 than is the case for present small molecule drugs known to affect MMP9 levels.

In vivo circRNA-engineered macrophages mediate localized MMP9 neutralization to rejuvenate aged bone

Age-related bone disorders (e.g., osteoporosis, impaired fracture healing, and osteoarthritis) rank among the most common and debilitating complications in elderly populations. However, current treatment strategies are predominantly palliative, focusing on symptom management rather than addressing the underlying causes or halting disease progression. Growing evidence suggests that these disorders share a common pathophysiological foundation, driven by chronic low-grade inflammation, cellular senescence, and dysregulated tissue remodeling.

Through transcriptomic analysis of serum and bone samples from elderly human individuals, we identified matrix metalloproteinase-9 (MMP9) as a potential central and consistently upregulated effector in age-related bone dysfunction. MMP9 is well-known for its role in extracellular matrix degradation, but its persistent elevation in aged individuals and osteoporotic bone suggests a broader pathological role in skeletal aging. Despite this, its mechanistic contribution to age-related bone loss and its potential as a therapeutic target remain unexplored.

Effective clearance of MMP9 in the blood and bone microenvironment as a therapeutic target could be a highly efficient strategy for treating degenerative bone diseases. Clearly, the introduction of neutralizing antibodies is the most direct approach. However, neutralizing antibodies have limitations in terms of safety and cost-effectiveness and lack effective bone-targeting capabilities. In recent years, mRNA-based protein replacement strategies have brought revolutionary breakthroughs to the field. While mRNA-based therapeutics have revolutionized vaccinology and oncology, their clinical application in age-related degenerative diseases, particularly within orthopedic settings remains elusive.

Here, we developed an in vivo messenger RNA based antibody-engineering strategy that specifically targets macrophages, converting them into biofactories for anti-MMP9 antibodies. Central to this therapy is an apoptosis-mimicking lipid nanoparticle incorporating phosphatidylserine with an optimized formulation (aMMP9-LNP), which enhances macrophage-specific recognition and endocytosis. Leveraging inflammation-guided chemotaxis, this approach enables systemic, targeted MMP9 neutralization. In aged mice, aMMP9-LNP injected intravenously reduced stem cell senescence, boosted osteogenesis, accelerated fracture repair, and mitigated cartilage degeneration. Mechanistically, MMP9 blockade dampened the senescence-associated secretory phenotype, restored osteoblast-osteoclast balance, and lowered p21/MMP3. Biodistribution confirmed bone-targeted delivery with preserved tissue homeostasis, supporting translational potential.

Weight loss drugs are a major focus of the pharmaceutical industry at present. It remains to be seen as to what will emerge as the next big class of weight loss drugs following GLP-1 receptor agonists. Since the primary effect of GLP-1 receptor agonist drugs is a reduction in calorie intake, all of the gathered data in humans is really just a sizable confirmation of the harms done by the presence of excess visceral fat tissue, and the benefits gained from losing that fat via dieting. It wouldn't much matter how these patients achieved that outcome, the resulting benefits would look much the same - and have in the past as a result of other strategies for weight loss.

Researchers analyzed data from a previously published clinical trial of 108 adults with HIV-associated lipohypertrophy, a condition in which excess fat builds up around the abdomen. About half of the participants received weekly injections of semaglutide, with the rest receiving placebo injections. The team used a set of biological "epigenetic clocks" to track cellular aging over the 32-week treatment period. These clocks detect DNA methylation, chemical marks on DNA that help regulate how genes are turned on or off without changing the genetic sequence itself. By measuring changes in these marks, the team could assess whether the treatment was associated with a slower or faster biological aging pattern.

Participants treated with semaglutide exhibited a broad pattern of slower biological aging across epigenetic clocks linked to inflammation and blood, brain, heart, kidney, liver and metabolic health. The drug slowed the pace of biological aging by 9%, as measured by the DunedinPACE epigenetic clock. The drug significantly slowed biological processes associated with the risk of all-cause mortality and age-related disease, as measured by the PCGrimAge epigenetic clock. Research suggests there are several mechanisms by which semaglutide may influence biological aging. By reducing inflammation and metabolic stress, GLP-1 drugs decreased chronic immune activation, a primary driver of accelerated aging in people with HIV. They also reduce visceral and ectopic fat that accumulates around the abdomen and organs, which may help curb the inflammatory and metabolic signals that promote aging.

Link: https://today.ucsd.edu/story/study-popular-glp-1-drug-may-slow-down-biological-aging

Here researchers report on a novel form of pathological protein aggregation in the aging brain and evidence for it to contribute to mitochondrial dysfunction in Alzheimer's disease. This phosphorylated GRK2 aggregation is argued to be a downstream effect of the other well-known forms of protein aggregation in the condition, those involving amyloid-β and tau, though that remains to be definitively proven. Certainly, given the inability of clearance of amyloid-β to produce sizable effects on the progression Alzheimer's disease, one might imagine other mechanisms are more involved in triggering GRK2 aggregation. Regardless, reducing GRK2 aggregation improves function in mouse models of Alzheimer's disease, suggesting some value in targeting this process.

The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L.

Aggregated phospho-S670-GRK2 triggers aggregation of TOMM6 (translocase of outer mitochondrial membrane 6), promotes mitochondrial dysfunction, and enhances beta-amyloid. Transgenic expression of inactive GRK2-K220R or a GRK-inhibitory peptide proves that neuropathological features are caused by GRK2 inactivation. Restoration of TOMM6 by neuron-specific TOMM6 expression reduces beta-amyloid plaques but enhances soluble beta-amyloid and increases mortality. In contrast, reconstitution of monomeric GRK2 and proteasomal phospho-S670-GRK2 degradation by small molecules counteracts neuropathological AD features, prevents neuronal loss, and improves survival. Thus, targeting of pathological GRK2 aggregation slows aging-induced neurodegeneration.

Link: https://doi.org/10.1016/j.xcrm.2026.102707

The medical biotechnology and pharmaceutical investment market was always very risk averse, giving rise to the valley of death between preclinical seed funding and early clinical stage funding; there are all too few investors willing to fund companies to move from late preclinical stage to early clinical stage. They would rather let promising companies die out and pick from the few that somehow find funds to run a first clinical trial in human patients than take the risk on a preclinical program. Further, investment is a herd industry, it polarizes to a few hot areas, fads, and sure things. In the recent years of various flavors of poor market environment for biotechnology and pharmaceutical drug development it seems that these tendencies have grown more exaggerated. A sizable fraction of all biotech investment pours into a small number of cellular reprogramming initiatives, a hot area of research and development, while investors have largely retreated from preclinical funding more generally. It will be interesting to see how long this lasts, as it is clearly unsustainable for every initiative in the field other than reprogramming.

This year alone has seen sizable funding devoted to Retro Bio and NewLimit for reprogramming efforts, though in fairness Retro Bio does have a number of other programs on the go. Life Biosciences raised a relatively smaller but still sizable amount in the grand scheme of things for their clinical trials in reprogramming. Couple all of this to the even greater funding still possessed by Altos Labs, and it seems fair to say that partial epigenetic reprogramming is the one area of aging-related biotechnology that needs no further assistance from patient advocates and other folk. Over the next decade or so we should expect the development community to establish answers to all of the fundamental questions regarding the construction of viable therapies based on reprogramming.

It remains strange to me that partial reprogramming captured the market and the interest in this way rather than senolytic therapies to clear senescent cells, given that senolytics were first on the scene by some years, and senolytic research continues to boast a far larger and more impressive portfolio of animal data for reversal of age-related disease and dysfunction. There is no accounting for how things turn out sometimes. Once enough funding flocks to a cause, there is a tipping point, and its popularity becomes a self-fulfilling prophecy. The funding carves a channel for more funding.

No limits: NewLimit lands $435m ahead of human trials

NewLimit believes it has found a way to help older liver cells behave more like younger ones. That idea sits within a growing area of longevity science known as epigenetic reprogramming. The company has raised $435 million in a Series C financing round led by Founders Fund, with participation from Thrive Capital, Greenoaks, Quiet Capital and existing investors including Kleiner Perkins, Eli Lilly Ventures and Human Capital. More notably, the company says it plans to bring its first age-reprogramming medicine into human clinical trials next year - a milestone it once thought was more than a decade away. Just a year ago, NewLimit closed a $130 million funding round and was still talking about the long road toward a clinic-ready therapy. Then something changed. According to NewLimit, a promising candidate emerged from the company's research platform far sooner than expected, prompting the company to accelerate its plans.

Retro Biosciences: Next Phase

Today, we're announcing the initial close of our next financing round at a pre-money valuation of $1.8 billion, led by 4P Capital alongside a group of investors who believe Retro is uniquely positioned to translate the biology of aging into a new generation of medicines. In three years, Retro moved from its first lab to a clinical candidate. In 15 months, that candidate RTR242 went from indication selection to first-in-human dosing. Alongside that progress, we've built cell therapy, tissue reprogramming, and AI-enabled protein engineering programs, all designed to support a growing pipeline of therapeutics targeting the underlying drivers of aging and age-related disease.

Everyone develops atherosclerotic plaque that narrows and weakens blood vessel walls in later life. A sizable fraction of all human mortality derives from the consequences of that plaque, such as rupture of unstable plaque to cause a stroke or heart attack. The maladaptive formation of blood clots within or attached to the plaque structure greatly reduces the stability of these structures, and is an important contribution to mortality. Here, researchers show that cells driven into a senescent state by the toxic plaque environment generate the circumstances that provoke inappropriate clot formation in and around an atherosclerotic plaque. Of note, other work has suggested that those same senescent cells may be structurally important to a plaque, and removing them may also cause loss of plaque stability. After a certain point, it becomes hard to resolve the issues a plaque presents. Here, as elsewhere in medicine, prevention is far more desirable than resolution.

Researchers have discovered a molecular pathway that drives certain stressed or aging cells to become abnormally active, causing inflammation inside blood vessel plaques. This results in disturbed blood flow and high-risk lesions that can lead to blood clots that cause heart attacks or strokes. The researchers studied senescent cells, which are stressed or aging cells that have stopped dividing but don't die. They discovered that losing key regulatory proteins, LATS1 and LATS2, in these cells activates the CD38 enzyme, which reprograms how these cells use energy and makes them more unstable. This leads to inflammation and an increased risk of blood clot formation inside plaques, a process known as atherothrombosis.

The researchers used advanced molecular profiling on preclinical models to show how endothelial cells - the cells lining blood vessels - change with the loss of LATS1/2 proteins, which usually help with healthy cell stabilization. Removing LATS1/2 in endothelial cells caused them to become senescent but also abnormally active. This led to instability, leaky vessels, inflammation, abnormal vessel growth and plaques that could form clots, all of which are pro-thrombotic features.

Further analyses showed that these senescent cells had a dramatic increase in CD38 levels, highlighting their potential role as key drivers of this hybrid state. Preclinical models demonstrated that overexpressing CD38 rewired the metabolic pathways and energy sources for endothelial cells, leading them to consume enough additional energy to drive inflammation. This destabilized plaques and led to the formation of blood clots. Inhibiting CD38 reversed these effects both in vitro and in vivo.

Link: https://www.mdanderson.org/newsroom/research-newsroom/researchers-uncover-how-aging-cells-may-trigger-heart-attacks-and-strokes.h00-159856134.html

Microglia are innate immune cells resident in the brain, responsible for defense against pathogens, destruction of senescent and potentially cancerous cells, and assistance with regeneration and tissue maintenance. In recent years, increasing attention has been given to changes in the behavior of microglia, particularly increased inflammatory signaling, as a contributing cause of age-related neurodegenerative conditions. Here, researchers make use of modern omics technologies to assess distinct states in subpopulations of microglia that associate with the presence or absence of Alzheimer's disease in older individuals. This sort of research sets the stage for later efforts to alter the behavior of microglia in order to improve brain function, such as via clearance of damaged or inflammatory microglia, or forcing overly inflammatory microglia into a more regenerative pattern of behaviors.

Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs.

This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.

Link: https://doi.org/10.1038/s41591-026-04393-8

In recent years, greater attention has been given to efforts that push back against the present broad acceptance of established data on human life expectancy, particularly for the oldest surviving cohorts. It has been suggested, and the evidence for this assertion is broadly supportive, that the published data for exceptional longevity is largely of poor quality, and much of what has been hyped over the years (such as Blue Zones or Jeanne Calment's alleged life span of 122 years) is simply not real.

What is observed in the data is a selection effect for error, fraud, and outright falsehood that grows stronger at advancing ages. We should be quite confident that a small number of humans can survive into their 110s, as individual cases have been well vetted, but we should be much less confident about the accuracy of demographics of survival much past age 90.

Does any of this really matter? From the perspective of building therapies to treat aging, I think probably not. It doesn't affect the need for better ways to measure biological age than exist at present, and it doesn't change the list of programs and targets that should be undertaken to produce potential rejuvenation therapies. People do get somewhat up in arms about the demographics of aging, but it seems a tempest in a teacup to me, somewhat irrelevant to the real issue of making progress in the treatment of aging as a medical condition. Other people may see it differently, of course.

How long can humans live? We simply don't know

Many errors are undetectable and, therefore, we do not know their underlying frequency. This has prompted a rather absurd response from demographers, who say that, sure, some errors occasionally escape detection, but these errors must be rare. I usually ask them: if you cannot detect particular errors, how do you know that they are rare? The core problem is that age relies on one measurement system: paperwork. If a person's paperwork is consistent but wrong, there is no reproducible way of knowing. You often see a famous case discussed, the details exhaustively validated and all of the paperwork examined. But after decades, the case turns out to be false. It has passed every test that demography has, and it is still wrong.

I did not just observe this in individual cases. I found it in entire populations. In Greece, for example, at least 72% of centenarian records were cases of pension fraud. The person was left alive on paper while their younger relatives collected the pension cheques. That was the secret to longevity in Greece, and nobody in demography saw it for decades.

There are several overlapping error processes. Pension fraud is one. Clerical error is another, and that can be undetectable. People who have paperwork with incorrect details often do not know, because literacy rates a century ago were low. Some people purposefully increase their age to escape military service, others to marry or work earlier when they are young, and some just inherited paperwork from older relatives because it was easier than travelling or paying to register a new birth. Then there are identity substitutions. Imagine a room with 100 people over 100, all holding valid paperwork. Replace one of them with a younger sibling. How do you detect the swap? The paperwork is real. The person knows enough about their sibling to answer questions.

Even if you understand the social and administrative context, there is still no reproducible method to test whether the age on a person's paperwork is correct. That is the central issue. There are also broader patterns. Extreme longevity often appears in places with weak record systems, low incomes and low historical levels of birth certification. That pattern runs against expectations if the signal were biological.

The mathematical process for small errors to dominate at very old ages is counter-intuitive but simple. Normally, rare errors can be ignored. But in this case, they grow non-linearly. Take a large population at age 50. Introduce a small number of people whose true age is younger than this recorded age. These individuals are biologically younger than the rest, so they die at lower rates as the cohort ages. Each year, the proportion of people with an error in their records increases because people with an inflated age are more likely to survive than are people with accurate data. Even with tiny starting error rates, you can end up with a population that has a 100% rate of errors at very old ages.

This is a universal problem. Five to ten per cent of people in the United States misstate their age in the census. Often, they simply do not know. Nearly one-quarter of the world's children still do not receive a birth certificate. Add that to the slow historical roll-out of birth registration and you get widespread uncertainty. There has been a 40-year debate about whether there is a limit to human lifespan. Both sides seem to be wrong, and the data seem to be junk. Demographers have been drawing shaky inferences from bad data for decades.

Mitochondrial function is clearly important in the development of Parkinson's disease. The mutations associated with increased risk of Parkinson's are related to mitochondrial quality control and function. Greater mitochondrial dysfunction makes the dopaminergic neurons most vulnerable to Parkinson's pathology that much more vulnerable, though it is an open question as to whether this is more a matter of disrupted energy metabolism or increased inflammatory signaling, both of which result from the presence of failing mitochondria in cells. Here, researchers report that expression of IFNAR1 is reduced in Parkinson's disease. That reduced IFNAR1 expression causes mitochondrial dysfunction via impairment of the quality control mechanisms of mitophagy, the same sort of issue as accelerates Parkinson's in genetic cases. Establishing whether or not this discovery may lead to a viable therapy to delay onset and progression of Parkinson's disease via increased IFNAR1 expression will require further research and development.

Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinson's disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets. Baseline IFNAR1 expression varies among major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls.

Neuron- and astrocyte-specific transcriptomic and proteomic alterations in IFNAR1 knockout mice implicate mitochondrial defects, defective mitophagy, and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, IFNAR1 knockout mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1.

Link: https://doi.org/10.1186/s12929-026-01257-8

It seems perhaps overly reductionist to summarize the panoply of current efforts to treat aging into two camps of (a) things that affect the burden of cellular senescence and (b) things that affect metabolism. One has to cut out or diminish the importance of a fair number of line items that may be useful irrespective of their effects on cellular senescence. An increased burden of cellular senescence is only one of the major issues that drive aging. Nonetheless, that is the approach to categorization taken in this review paper.

Aging is a complex biological process characterized by progressive functional decline, driving the incidence of age-related diseases such as neurodegeneration, metabolic disorders, and cardiovascular diseases. Therapeutic strategies targeting aging hallmarks can delay aging and mitigate disease risk. Emerging interventions focus on modulating core aging mechanisms, including cellular senescence, metabolic dysfunction, epigenetic alterations, and mitochondrial impairment, etc.

Recent advances have focused on three strategies: senolytics (eliminating senescent cells, e.g., dasatinib + quercetin), senomorphics (inhibiting the senescence-associated secretory phenotype, e.g., rapamycin), and senoreversion (rejuvenating senescent cells via epigenetic reprogramming). Additionally, metabolic interventions such as caloric restriction mimetics (e.g., spermidine, α-ketoglutarate, ergothioneine) enhance mitochondrial function, activate autophagy, and reprogram energy metabolism, demonstrating lifespan extension and healthspan improvement in preclinical models. Collectively, these approaches hold promise for delaying aging and alleviating age-related pathologies, facilitating the transition to precision longevity medicine.

Link: https://doi.org/10.1038/s41392-026-02662-z

That part of the life science research community focused on better understanding and treating the panoply of age-related neurodegenerative conditions is increasingly focused on chronic inflammation in the brain. Aging, and neurodegenerative disease, is characterized by excessive, unresolved inflammatory signaling in brain tissue. A sizable focus is given to increased inflammatory behavior in microglia, for example, and how these innate immune cells of the central nervous system might be adjusted to reduce this problem. But much of the ongoing portfolio of fundamental research seeks to understand how the underlying biochemistry of aging gives rise to a state of chronic inflammatory signaling in various cell populations in the brain, including microglia, but not only microglia.

The authors of today's open access paper review review a topic of increasing interest in this context, the maladative overactivation of cGAS-STING signaling in aged brain cells. This is actually a global phenomenon throughout the body, so much of what is said here applies to other tissues as well. STING is a central hub in the regulation of inflammatory signaling, and is activated by a range of sensor proteins that react to various different circumstances in the cell. cGAS detects double-stranded DNA in the cytosol of the cell, where no double-stranded DNA should exist. This is an evolved defense against invasive pathogens such as bacteria and viruses, but it is is also triggered in a cell that has become dysfunctional enough to allow leakage of DNA fragments from the nucleus or mitochondria.

Aged cells are characterized by excessive cGAS-STING activation in particular due to mitochondrial dysfunction allowing mitochondrial DNA fragments to escape the mitochondria. This is one of the reasons why addressing mitochondrial dysfunction in the aging brain may help with neurodegeneration. It isn't just a matter of a dysfunctional energy metabolism allowing cells to run down, but also a matter of tidying up mitochondrial DNA to reduce cGAS activity.

Expanding roles of cGAS-STING signaling in neuroinflammation

The sensing of nucleic acids is a central component of innate immunity, enabling host defense against infection while shaping inflammatory responses within the central nervous system (CNS). Pattern recognition receptors (PRRs) function as molecular sentries that detect both pathogen-derived nucleic acids and endogenous danger signals. Among these, DNA is an important signal of infection and inflammation. Several PRRs act as DNA sensors, and cyclic GMP-AMP synthase (cGAS) has the unique ability to directly and sequence-independently detect double-stranded DNA (dsDNA) in both the cytosol and nucleus. The dsDNA inside cells sensed by cGAS originates from diverse sources, ranging from foreign viral or bacterial DNA to endogenous self-DNA caused by mitochondrial damage or chromatin instability. Upon binding to dsDNA, cGAS activates the adaptor protein STING and elicits a strong interferon (IFN) response. cGAS is highly evolutionarily conserved from bacteria to mammals, underscoring its fundamental role in innate immunity.

Neuroinflammation is typically characterized by persistent, low-grade inflammatory signaling, underscoring the importance of identifying the precise triggers and sustaining mechanisms of cGAS-STING activation in the CNS. Studies in Alzheimer's disease models have implicated mitochondrial DNA (mtDNA) leakage as a key activator of this pathway. However, whether additional sources of cytosolic DNA, or even non-DNA ligands, contribute to chronic cGAS-STING engagement remains unclear. This issue is particularly relevant in nonimmune cells such as neurons and endothelial cells, where the mechanisms governing cGAS activation, signal amplification, and persistence are still largely undefined.

The growing recognition of cGAS-STING signaling as a driver of chronic neuroinflammation positions this pathway as an attractive, yet complex, therapeutic target for brain disorders. Sustained or inappropriate activation of cGAS-STING in the CNS is increasingly linked to neurodegeneration, cognitive decline, and aging. This highlights the need for therapeutic strategies that selectively attenuate pathological signaling while preserving essential antiviral functions. Pharmacological inhibition of cGAS or STING has shown encouraging results in preclinical models of neurodegenerative disease and brain injury, where suppression of IFN-I and downstream inflammatory cascades reduce neuronal loss and improve functional outcomes. Small-molecule cGAS inhibitors, STING antagonists, and modulators of cyclic dinucleotide metabolism represent the most direct approaches.

While targeting the cGAS-STING pathway is of therapeutic interest, chronic inhibition may carry risks. Given its role in antiviral defense and tumor surveillance, sustained suppression could increase susceptibility to infection or impair immune function. A potential therapeutic strategy is partial and context-dependent modulation, as neurodegenerative conditions are often associated with elevated cGAS-STING activity and IFN-I signaling. To mitigate systemic effects, CNS-selective or temporally restricted approaches may be beneficial. Over time, more refined strategies, including microglia-biased small molecules or glia-targeted degraders, may further improve specificity and safety.

Mitochondria are power plants, hundreds of these organelles working in every cell to manufacture the adenosine triphosphate (ATP) chemical energy store molecule used to power cell operations. The decline of mitochondrial function with age impacts this supply, with negative consequences, but other equally important issues arise from mitochondrial dysfunction. For example, an important realization in aging research was that dysfunctional mitochondria contribute meaningfully to the chronic inflammation of aging, a topic that is a primary focus of this paper.

Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals.

A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline.

Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.

Link: https://doi.org/10.1038/s41514-026-00422-5

Biochemistry is enormously complex. The closer that researchers look, the more that they will find. Details remain incompletely mapped and understood at every level; there are only so many researchers and only so much funding. Much of the ongoing fundamental research into interventions to treat aging remains focused on the ability of mild stress to provoke beneficial changes in cell behavior, such as the way in which calorie restriction or heat produce increased cell maintenance activities. Here, researchers delve into the extremely complex landscape of RNA molecules in the cell to search for specific RNAs that are essential to beneficial stress responses that slow aging.

Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using Caenorhabditis elegans, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5′-tRH-Gln and 5′-tRH-Asp, from tRNAs. Among them, 5′-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction.

Generation of 5′-tRH-Gln reduces translation via ribosomal protein binding and upregulates the SKN-1 transcription factor responsible for lifespan extension. We further show that mammalian DIS3 contributes to tRH generation and delays cellular senescence through translation downregulation by another tRH, 5′-tRH-Cys. Overall, our data demonstrate that DIS-3/DIS3 is an evolutionarily conserved tRH-generating ribonuclease that counteracts organismal and cellular aging.

Link: https://doi.org/10.1038/s41467-026-73295-7

Fecal microbiota transplantation from young donor to old recipient can reset the composition of the aged gut microbiome to produce benefits to health. Animal studies are very positive. Unfortunately fecal microbiota transplantation doesn't mix all that well with the present approach to regulation of medicine in the US and EU. One product, meaning one approach to donor screening and some attempt at standardization, has been approved by the FDA for use in the treatment of C. difficile infection. Following that the FDA has made it hard for other donor screening and connection services such as Human Microbes to operate at all for any purpose in the US, so for most people the situation is now worse than it was.

Regulators want standardization, which is always going to be challenging and expensive to achieve for donor material given the high human to human variability in gut microbiome composition. So the incentive exists to develop the means to create artificial gut microbiomes with a standarized composition. Unfortunately the state of probiotic manufacture is a long way removed from being able to assemble hundreds or thousands of species in defined proportions in a cost-effective manner. Still, inroads are being made; if researchers can produce a 15 species mix today, then working with defined mixes of hundreds and then thousands of species will become viable in time.

Engineered gut bacteria therapy emerges as scalable potential alternative to fecal microbiota transplants following clinical trial

Recurrent C. difficile infection is a serious and often debilitating condition that can occur after antibiotic treatment disrupts the natural balance of bacteria in the gut. Although fecal microbiota transplants (FMT) - a treatment that transfers stool from healthy donors to restore gut bacteria in patients with severe or recurrent infections - have proven effective for many patients, more standardized and scalable therapeutic options are needed.

To address this challenge, the investigators developed a cost-effective production platform capable of manufacturing live biotherapeutic product (LBP), composed of known bacterial strains rather than whole-stool material. The first product generated using the platform was evaluated in patients with recurrent C. difficile infection and compared directly with FMT prepared from the same donor source used to isolate the bacterial strains. The team compared treatments using microbes from the new platform with those using FMT. The study enrolled 18 participants across four groups: low- and high-dose FMT and low- and high-dose LBP, with four to five patients in each arm. "We demonstrated comparable safety and efficacy between undefined stool-based FMT and a defined, in vitro-manufactured LBP. We also found that bacterial strains delivered through both FMT and LBP durably engrafted in recipients."

The new approach uses a defined consortium of bacterial strains isolated from donor stool and grown under controlled manufacturing conditions. Unlike traditional fecal microbiota transplants, which can vary from donor to donor, the platform is designed to produce standardized microbial therapies at scale. The researchers say the findings support the feasibility of manufacturing defined microbiome therapeutics that may one day offer a more standardized alternative to traditional fecal microbiota transplants.

15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial

Fecal microbiota transplant (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI) but has undefined composition and poor scalability. In vitro manufactured live biotherapeutic products (LBPs) enable both scalability and defined strain composition but with higher manufacturing complexity, resulting in few LBP clinical trials. Here we show how an accessible platform to produce human-grade LBPs could accelerate LBP development. We provide regulatory documentation and manufacturing protocols to facilitate translating microbiome advances to human trials.

With this platform, we conducted the first direct comparison of the same bacterial strains from donor-sourced FMT compared to an in vitro manufactured 15-strain LBP drug product, MTC01, for the treatment of rCDI. In a phase 1b randomized controlled trial, 18 of 20 screened patients met eligibility and were randomized equally to one of four arms: low-dose FMT (n = 4), high-dose FMT (n = 5), low-dose MTC01 (n = 4) or high-dose MTC01 (n = 5), with a 5:1 female:male ratio. The primary outcome of safety was met with 10 adverse events across eight patients, evenly spread across MTC01 (five events) and FMT (five events) recipients and no treatment-related adverse events across all four groups. For secondary outcomes of efficacy and engraftment, rCDI was prevented 8 weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients. Strain engraftment was high and durable for both FMT and MTC01 with a dose effect for the LBP.

The concept of antagonistic pleiotropy looms large over present thought on the evolution of aging: that the proteins produced from a given gene can have multiple functions that are beneficial in youth but harmful in later life. Evolution selects for such a gene because the advantage of early life reproductive success near always wins out over the disadvantage of a shorter overall reproductive life span. Thus near all species undergo degenerative aging. More subtly the concept can also apply to systems, protein interactions, or other higher level constructs in cells and tissues. Finding specific, simple, defensible examples of antagonist pleiotropy in cellular biochemistry has proven to be surprisingly hard, suggesting that this is largely a systems-level issue, but here researchers put forward the gene VGLL3 as a candidate.

The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly from causal genetic experiments. Here, combining genetic perturbation with longitudinal phenotyping in the turquoise killifish (Nothobranchius furzeri), we identify vestigial-like 3 (vgll3), previously linked by genome-wide association studies (GWAS) to age at maturity in humans and male Atlantic salmon, as a gene with antagonistically pleiotropic effects.

Selective disruption of vgll3 isoforms accelerates male growth and maturation in a dose-dependent manner. Transcriptomic and cellular analyses indicated increased cell division, corroborated in vivo by elevated germline and intestinal stem-cell proliferation. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit a shortened lifespan. Thus, we identify vgll3 as a key regulator of life-history variation with antagonistic effects across ages, balancing early-life fitness against late-life mortality.

Link: https://doi.org/10.1038/s41467-026-72381-0

Rapamycin is an immunosuppressant long used in transplant medicine at relatively high doses. At lower doses, it slows aging and extends life in animal studies by mimicking some of the beneficial metabolic reactions to calorie restriction, such as increased autophagy. A fair number of people use rapamycin with the hopes of achieving the same outcome, though the human data for this use case and dosage remains sparse. Normally rapamyin is taken once a week, but here researchers mix it in with the diet in a study of immune aging in mice.

Aging is the gradual accumulation of structural and functional changes in an organism over time, including immune remodeling and a progressive increase in basal inflammation, or inflammaging. The mTOR pathway is a central driver of aging-related diseases, such as cancer, chronic inflammation, and neurodegeneration; pharmacological inhibition with rapamycin is associated with reduced aged-related morbidity and increased lifespan across species. Nonetheless, concerns remain about the use of rapamycin, a well-established immunosuppressant in transplant medicine, as an anti-aging intervention.

Here, we evaluated the impact of prolonged low-dose dietary rapamycin on the aging immune system. Treatment did not significantly alter innate or adaptive immune cell populations, including brain resident microglia; however, it attenuated the age-associated accumulation of IL-17-producing γδ T cells, particularly in the peritoneal cavity. After a peripheral inflammatory endotoxin challenge, circulating IL-17 levels were significantly reduced and correlated with an attenuation of microglia inflammatory phenotype. These findings suggest that prolonged low-dose rapamycin exposure exerts minor systemic immune changes, while selectively limiting age-related γδ T cell expansion and neuroinflammation associated with systemic inflammation.

Link: https://doi.org/10.1371/journal.pone.0343183

Nucleic acids such as DNA and RNA should in the normal course of events largely remain localized within the cell nucleus and mitochondria, the locations of the nuclear genome and mitochondrial genomes respectively. Changes that take place with age disrupt everything, however, and this disruption includes the mislocalization of DNA and RNA fragments into the body of the cell. One of the many lines of defense against infectious pathogens such as viruses and bacteria deployed by cells takes the form of sensor proteins that detect inappropriate DNA and RNA in the cytosol of the cell, and then trigger inflammatory signaling and potentially even cell death. Thus a sizable portion of the chronic inflammation characteristic of later life is a maladaptive reaction to some aspects of the poor state of structural organization within aged cells.

Today's open access paper reviews these mechanisms, with a particular emphasis on the connection between age-related chronic inflammation and increased tendency towards an inappropriate coagulation response in the aging vasculature, the cause of thrombosis. An important facet of present research into immune aging is the effort to find ways to interfere in chronic inflammatory signaling without disabling necessary inflammatory responses. This has so far proven to be challenging, as all inflammation runs through much the same triggers and regulatory systems. The only alternative is to remove the underlying damage of aging that causes maladaptive inflammatory responses, but at present that is not the primary focus of the research community.

Misplaced nucleic acids as a trigger of Coagul-Aging

Aging is characterized by a gradual decline in tissue homeostasis and regenerative capacity, accompanied by the emergence of a chronic, low-grade inflammatory state termed inflammaging. This sterile inflammation stems from the accumulation of cellular and molecular damage, defective clearance of self-derived debris, and persistent activation of innate immune pathways. Inflammaging plays a central role in the development of age-related pathologies, including cardiovascular and thrombotic diseases.

One of the major vascular consequences of inflammaging is the establishment of a prothrombotic phenotype, referred here to as coagul-aging. This state results from endothelial dysfunction, platelet hyperreactivity, and altered hemostatic balance. Importantly, inflammation and coagulation are not isolated processes but are functionally intertwined through the concept of thrombo-inflammation, a coordinated response originally evolved to contain infection and repair tissue damage. When chronically activated, however, this crosstalk becomes maladaptive, sustaining vascular injury and thrombotic risk.

Emerging evidence suggests that misplaced nucleic acids, including extracellular or cytosolic DNA, RNA, and RNA:DNA hybrids, act as molecular triggers of both innate immune activation and coagulation. These nucleic acids, often derived from endogenous retroelements or senescence-associated damage, are sensed by pattern recognition receptors such as cGAS-STING, TLR9, and RIG-I-like receptors, promoting type I interferon responses, cytokine release, and tissue factor expression. In parallel, they may directly activate the contact pathway of coagulation via factor XII, providing a non-inflammatory route to thrombin generation.

In this review, we examine the role of nucleic acid accumulation and dysregulation in linking inflammaging to coagul-aging. We propose that extracellular nucleic acids act as central effectors of age-associated thrombo-inflammatory circuits, not only by sustaining chronic immune activation, but also by directly triggering coagulation, potentially bypassing classical inflammatory pathways. These properties position nucleic acids as both mechanistic drivers and potential therapeutic targets in vascular aging.

Individuals are transient vehicles for the immortal lineage of germline cells. Incompletely understood processes firstly ensure that the germline remains relatively untouched by aging, and secondly ensure that new individuals generated from the cells of two aged individuals are born functionally young. In recent years, researchers have discovered some of the regulatory systems that drive rejuvenation in early embryonic development, the conversion of an old oocyte into a mass of young embryonic stem cells. This has given rise to the techniques of cell reprogramming to generate induced pluripotent stem cells, and of much greater interest at the present time, the techniques of partial reprogramming to restore more youthful function to adult tissues. Yet this is just a first step, and the methods used reflect only a very partial understanding of what exactly happens in the oocyte during reproduction. There is work yet to be done.

Aging‌‌ biology has largely focused on the gradual deterioration of somatic tissues. DNA damage accumulates, epigenetic regulation becomes unstable, mitochondria lose efficiency, senescent cells accumulate, and regenerative capacity wanes, together with many other categorized hallmarks of aging. This framework is remarkably successful in explaining many features of tissues and organismal aging, yet it fails to account for one of the most fundamental processes in biology: the generation of offspring that begin life biologically young, even when derived from aged parents. Somewhere during reproduction, aging is not merely slowed but actively and effectively reversed.

The mammalian ovary embodies this paradox. It is among the first organs to exhibit functional decline, with fertility and endocrine function decreasing well before the end of life. Nonetheless, even decades after its formation, the ovary still produces a subset of oocytes capable of generating an "age zero" offspring. No other cell type in adult mammals, besides the oocyte, routinely performs such a comprehensive reset. The oocytes are therefore intrinsically endowed with the capacity for what we define here as rejuvenation. While it is undoubtably true that oocytes' developmental competence declines with age, it is remarkable to consider that whenever natural conception occurs successfully, the chronological and/or biological age of the oocytes (i.e., of the mother) is not vertically transmitted to the following generation.

Historically, reproductive biology and geroscience have developed as largely separate and divergent disciplines. The ovary has been studied primarily in the context of fertility and endocrine regulation, whereas aging research has focused on loss of function in somatic tissues such as the brain, muscle, immune system, and heart, including the ovary. This separation has obscured an essential insight: the ovary is not only a site of age-related decline but also the only mammalian tissue that naturally preserves an intrinsic rejuvenation capacity within its oocytes.

We argue that the ovary, and the oocyte in particular, represent nature's most compelling example of controlled rejuvenation. We examine how epigenetic reprogramming, mitochondrial quality control, and proteostasis operate in oocytes to preserve cellular youth. We also explore how tissue homeostasis mechanisms differ fundamentally within the ovarian niche from aging processes in somatic tissues and discuss how insights from ovarian biology can inform emerging rejuvenation strategies, including partial reprogramming, senescence modulation, and niche engineering. Finally, we discuss how the ovary itself could be a gateway to systemic rejuvenation and extended healthspan.

Link: https://doi.org/10.1371/journal.pbio.3003804

A small number of humans with an inherited PAI-1 loss of function mutation live up to seven years longer than peers. PAI-1 appears involved in cellular senescence, and thus effects on health and life span may reflect a lower burden of harm resulting from the presence of increasing numbers of senescent cells with advancing age. Researchers have been developing small molecule drugs to inhibit PAI-1 activity, and here find a review paper covering these efforts. Recall that inhibition via a small molecule drug tends to have a much smaller effect than a loss of function mutation, as firstly the drug is only used for part of a life span, and secondly the drug does not produce complete inhibition of activity. This is nonetheless how research and development tends to progress.

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state.

In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia.

This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds.

Link: https://doi.org/10.3390/cells15100941

Many bat species are extremely long-lived for their size, rivaling naked mole rats when it comes to a comparison with shorter-lived and similarly sized mammals. One hypothesis is that the very high metabolic demands of flight forced bats to evolve highly efficient defenses against metabolic stress, and particularly stresses generated by mitochondrial activity. Other factors have come to light, however, related to bat resilience to viral infection, triggers of chronic inflammation, and DNA damage. Bats exhibit far greater control over chronic inflammation than other mammals, for example, and researchers have experimented with moving some of the relevant biology into mice to reduce their age-related inflammation.

Today's open access paper grows from the seed of an interesting idea: can we categorize the biology of bat longevity in ways that can then be applied usefully to thinking about variation in human longevity? What does that categorization look like, and what insights emerge from it? Unfortunately the lead author is primarily involved in dietary research, and so this interesting idea, once established and explored, thereafter collapses into dietary recommendations rather than any more useful exploration of the possibilities of drug development and applied biotechnology. Departmental affiliation in academia comes with an intellectual tax that must be paid, in terms of fitting one's interesting ideas into what the department ostensibly does. Still, there something here worthy of greater consideration.

Bat-Inspired Longevity: Immune Damage Management and Nutritional Modulation for Healthy Aging

The exceptional longevity of bats challenges classical theories of inflammaging and suggests an alternative that improved resilience in responding to pathogens and cellular damage can increase longevity. Accordingly, we have developed the Core Longevity State Vector (CLSV-6) to characterize an expanded explanation for inflammaging that can be predictive of successful aging and used to develop potential strategies for successful aging. Despite high metabolic rates and persistent viral exposure, many bat species have much longer lifespans than would be predicted for mammals of their size. The increased longevity of many bat species is achieved through damage tolerance, regulated inflammasome activity, constitutive basal antiviral defenses, enhanced autophagy-mitophagy, and efficient resolution of inflammation, rather than through heightened inflammatory immunity.

The CLSV-6 is introduced as a multidimensional immunotype framework integrating six conserved mechanisms that link bat immunity to bat longevity and to human healthy aging: (1) damage tolerance, (2) autophagy-mitophagy, (3) proteostasis (management of degraded proteins), (4) basal immune readiness without activation, (5) inflammasome regulation, and (6) inflammatory resolution capacity. Together, these mechanisms enable a robust antiviral defense when needed without chronic inflammation. Notably, human centenarians converge toward this bat-like configuration. Studies suggest that centenarians often preserve more functional natural killer cells, better macrophage regulation, and improved anti-inflammatory control, with both bats and humans exhibiting reduced activation of the NLRP3 inflammasome, resulting in greater immune resilience.

Building on this framework, functional foods - including polyphenols, fermented foods, and herbal extracts - are proposed as practical strategies to shift human immunity toward bat-like, CLSV-6 immunotype by enhancing cellular quality control, regulating inflammasome activity, strengthening basal antiviral readiness, and supporting inflammatory resolution, thereby redirecting longevity strategies from immune stimulation toward damage containment and repair. This review reframes longevity as an emergent property of integrated immune damage management and provides a mechanistic roadmap for nutritional interventions to engineer healthier human aging inspired by bat immunity.

One can build a network of genes by function, by interactions between tissues, by association with specific disease, and so forth. Researchers here assemble a gene network considering associations with aging, age-related disease, and function, and attempt to derive some insight into what the shape of the network, its clusters and connectors, might say about processes of aging. They suggest that there are two broad categories of process at work here: firstly, genes that very broadly affect aging throughout the body, such as those regulating immune system or mitochondrial function, and thus tend to be associated with all age-related disease; versus secondly, genes that affect vulnerability to age-related dysfunction in one specific organ or tissue, and thus tend to be associated with a cluster of diseases associated with that organ or tissue.

Ageing-related diseases (ARDs) display diverse phenotypes yet share an age-dependent rise in incidence, suggesting mechanistic links with ageing processes. We examined whether ageing-related genes differ systematically from genes associated with multiple ARD clusters. Across 57 ARDs from UK Biobank, network analyses showed that ageing-related genes, although rarely ARD-associated, lie significantly closer to many ARDs through greater-than-chance proximity in protein-protein interaction and KEGG networks.

Our results demonstrate that the broad disease impact of highly pleiotropic genes does not require network centrality or broad expression. Rather than forming universal ageing-related cores, these genes often act within tissue-specific, weakly connected modules - a pattern consistent with previous reports that pleiotropic disease-related genes span diverse biological processes rather than collapsing onto a single functional axis.

Beyond these structural insights, our machine learning framework successfully predicted novel ageing-related gene candidates based on their connectivity to clusters of ARD-related genes. Many of these top-ranked genes belonged to conserved stress-response and signalling pathways - such as MAPK, TGF-β/SMAD, and phosphorylation cascades - reinforcing their role in systemic adaptation and maintenance during ageing.

Together, these results reveal a dual organization in the genetic architecture of ageing and multimorbidity: ageing-related genes act as cross-system integrators that maintain regulatory balance, whereas pleiotropic genes associated with specific age-related disease clusters operate as localized drivers of age-dependent disease vulnerability. Integrating these complementary perspectives provides a coherent framework for understanding how intrinsic ageing mechanisms and immune-mediated susceptibility jointly shape the landscape of human multimorbidity.

Link: https://doi.org/10.1007/s10522-026-10429-w

If one can develop a single aging clock that works in much the same way in both mice and humans, could it be used to determine which of the interventions to treat aging that have been tested in mice are more likely to work well in humans? It is clearly the case that most of the established approaches to slowing the progression of aging, largely derived from manipulation of stress response mechanisms that clean up damage and improve cell function, produce much larger increases in life span in short-lived species than in long-lived species. How will that difference manifest in an aging clock designed to work similarly in both short-lived and long-lived mammals? That is an interesting question, still awaiting an answer.

Ageing and interventions modulate health and mortality, yet the underlying molecular mechanisms of this modulation remain unclear. Here we integrate more than 11,000 transcriptomes from more than 25 tissues across 4 mammals (mouse, rat, macaque, and human) to develop accurate, interpretable rodent and multi-species biomarkers of chronological age and expected mortality, predicting lifespan-modulating interventions, time to death, chronic diseases, and rejuvenation. Ageing-related changes were conserved across species and cell types, revealing universal transcriptomic signatures of mammalian ageing and mortality, including CDKN1A and LGALS3, whose protein levels were also associated with mortality and multimorbidity in UK Biobank.

Mortality-associated features were recapitulated across in vivo and in vitro damage-accumulation models, including inflammation, replicative senescence, metabolic inhibition, and γ-irradiation, and were attenuated or reversed by cell immortalization, reprogramming, heterochronic parabiosis, and early embryogenesis. Network analysis uncovered a modular architecture of ageing- and mortality-associated hallmarks, encompassing inflammation, interferon signalling, mitochondrial function, chromatin modification, and extracellular matrix organization.

To quantify ageing of individual cellular components, we developed module-specific clocks, which revealed pathway-specific effects of interventions: chronic diseases primarily accelerated inflammatory-module ageing, whereas caloric restriction and Klotho deficiency targeted mitochondrial and metabolic modules. Transcriptomic and DNA methylation clocks showed correlated age acceleration in human blood, which was strongest for the chromatin-associated module clock, highlighting mechanistic links between molecular ageing modalities. This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.

Link: https://doi.org/10.1038/s41586-026-10542-3

The gut microbiome is clearly important to health, and changes in the composition of the gut microbiome influence the progression of degenerative aging to a meaningful degree. Gut microbes of various species generate useful or harmful metabolites that interact with cells in the body. The aging of the gut microbiome is now known to reduce the supply of some useful metabolites, while increasing inflammatory interactions with the immune system. It is possible to restore a more youthful composition to the gut microbiome via a number of different approaches. Flagellin immunization encourages the immune system to more aggressively remove problematic microbial species that have grown in number with age, while fecal microbiota transplantation from a young donor to an old recipient directly resets the composition of the gut microbiome to a more youthful state.

Researchers are continuing to identify specific metabolites relevant to health and aging and the species that produce them. This will ultimately give rise to new strategies to improve health, such as supplementation of beneficial metabolites, selective removal or introduction of specific microbial species, or the tailored creation of entire new synthetic gut microbiomes that can be provided to patients. Today's open access paper is an example of the sort of research presently taking place, in which researchers identify glutamic acid as a metabolite important to oocyte quality in the aging ovaries. While provided by the gut microbiome, short term supplementation of glutamic acid does just as good a job as changes to the microbiome when it comes to restoring lost oocyte quality in old female mice.

Gut microbiota-modulated glutamic acid rejuvenates the quality of oocytes deteriorated by advanced reproductive age

The gut microbiota plays a vital role in maintaining the physiological function of host health and the pathogenesis of various diseases. However, its relationship with maternal age-associated decline in oocyte quality remains elusive. Here, we report that establishment of gut microbiota from young donors in aged mice by fecal microbiota transplantation (FMT) is an effective method to rejuvenate the quality of maternally aged oocytes. Specifically, young gut microbiota promoted the ovulation and maturation of aged oocytes, and inhibited occurrence of cytoplasm fragmentation and spindle/chromosome abnormalities, hence enhancing the oocyte quality and female fertility.

By integrating metagenome and untargeted metabolome of intestinal digesta, as well as targeted metabolome of ovaries and micro-transcriptome of oocytes, we identified that Bacteroides_caecimuris-modulated glutamic acid levels mediated the restorative effects of young gut microbiota on the aged oocytes through strengthening the mitochondria function. In addition, we demonstrated that in vivo supplementation of glutamic acid also enhanced the quality of aged oocytes, and the improvement of oocyte quality by glutamic acid was conserved across species. Altogether, our findings highlight the importance of gut microbiota in the oocyte aging and provide potential improvement strategies for age-related decline in oocyte quality and female fertility.

Once past the early stages, an atherosclerotic plaque in a blood vessel wall grows by drawing in and killing macrophage cells of the innate immune system. These cells are responsible for clearing up damage and excess lipids in blood vessel walls, but the plaque environment has become too toxic for their long term survival. Some macrophages work to resolve the issue, but most are overwhelmed, become inflammatory and eventually die. Researchers are very interested in finding possible ways to alter macrophage behavior to favor greater efforts to repair the plaque environment. One class of possible approaches involves trying to force adoption of particular set of behaviors via altering regulatory systems in the cell to override the normal reaction to the plaque environment. New options on this front arise from efforts to obtain a better understanding of which factors are in fact determining cell behavior.

Over many years, so-called macrophages - scavenger cells of the immune system - accumulate in the vessel wall. They take up fat, store it, and eventually die. What remains are cell debris and deposited fats, from which cholesterol crystals can form. These crystals destabilize plaques, promote blood clot formation, and thereby increase the risk of an acute vascular blockage. Researchers have now taken a closer look at the role played by different macrophages in atherosclerotic plaques. Not only lipid-laden macrophages but also lipid-free macrophages play a decisive role in shaping the disease process.

These lipid-free macrophages perform a dual function: on the one hand, they clear cellular debris, including DNA from dead cells, thereby limiting the formation of cholesterol crystals. On the other hand, they also attack the endothelium - the thin cell layer that lines and protects the inside of blood vessels. Inflammation, therefore, acts not only as a damaging force but also, in part, as a limiting one.

At the center of this balance is a small RNA molecule: miR-147. This microRNA is produced mainly in lipid-free macrophages. There, it helps the cells remove dead cell debris while also limiting damage to the endothelium. When miR-147 is absent, plaque formation, DNA deposits from dead cells, and cholesterol crystals all increase markedly. According to the research team, this effect is due to miR-147 suppressing the production of the protein Galectin-3 in lipid-free macrophages. When Galectin-3 is released, it not only damages endothelial cells but also disrupts the macrophages' energy supply. Without that energy, the cells clear away debris more slowly - a process that can further drive plaque formation.

Link: https://www.lmu.de/en/newsroom/news-overview/news/cardiovascular-disease-inflammation-drives-atherosclerosis-and-may-also-help-limit-it-b9e10042.html

Sepsis is a state of runaway inflammation resulting from infection, in which inflammatory signaling becomes so intense that organs fail under the stress. Crudely, one might think of initiation of sepsis as a tipping point between the normal balance of initiation and suppression of inflammation versus a runaway positive feedback loop of inflammatory signaling. Here, researchers show that the composition of the gut microbiome contributes to the risk of sepsis, and one microbial species in particular is involved in pushing individuals past the tipping point. This is one of many studies identifying specific undesirable microbial species for a near future in which highly targeted therapies can eliminate the unwanted components of the gut microbiome as needed.

Host survival during sepsis depends not only on pathogen burden but also on inflammatory thresholds calibrated by the gut microbiota. Here, we show that different survival outcomes were observed in genetically equivalent female C57BL/6 mouse populations depending on their specific gut microbiota configuration. A Muribaculaceae-enriched gut microbiota, characterized by the dominance of Sangeribacter muris KT1-3, predisposed mice to fatal sepsis caused by Acinetobacter baumannii via TLR4-dependent hyperinflammation. This lethal phenotype, reproduced by colonization with S. muris strain KT1-3, was transferable by fecal microbiota transplantation and co-housing. Notably, fixed-dose lipopolysaccharide challenge and ex vivo stimulation assays demonstrated that this configuration induces a heightened TLR4-dependent inflammatory responsiveness independent of bacterial replication.

Single-cell transcriptomics revealed that these microbiota-derived factors establish a transcriptionally pre-activated macrophage state, resulting in production of excessive pro-inflammatory cytokines upon challenge. Mechanistically, S. muris strain KT1-3 releases heat-stable and low-molecular-weight metabolites that are sufficient to potentiate systemic cytokine surges under a fixed-dose endotoxin challenge in vivo, effectively lowering the host's activation threshold for TLR4-driven signaling. Tlr4-deficient mice harboring the KT1-3-enriched susceptible microbiota survived despite persistent bacterial dissemination, demonstrating that the microbiota-TLR4 axis dictates hyperinflammatory A. baumannii-induced sepsis outcomes by modulating inflammatory magnitude rather than pathogen clearance.

Link: https://doi.org/10.1038/s41467-026-72435-3

Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that have by now evolved into components of the cell. Much of their original bacterial genome has migrated into the cell nucleus to become incorporated into nuclear DNA, leaving behind only a small remnant mitochondrial genome. The primary role of mitochondria is to supply the cell with adenosine triphosphate (ATP), a chemical energy store molecule used to power cell operations. Mitochondria interact with a range of important cellular processes beyond this, however. They continue to act much like bacteria in many other ways: they replicate, fuse together, swap component parts between one another.

The behavior of mitochondria is complex and incompletely understood, as are the contributing causes and fine details of the changes that take place in mitochondria with age. In aged cells, mitochondria exhibit reduced ATP production, greater production of oxidative molecules, altered structure, leakage of DNA fragments into the cell body where they can provoke inflammation, impaired responsiveness to quality control processes that work to remove damaged mitochondria, and so forth. Their dynamics of fusion and fission change. That all of this is important to the progression of degenerative aging is well demonstrated; numerous approaches to slowing aging in short-lived species involve improvement in mitochondrial function in aged individuals.

Still, the fact that mitochondria are so complicated has hindered efforts to produce simple therapies that can dramatically improve mitochondrial function in old humans. As things stand the best approaches remain arguably less impressive than the results of undertaking more exercise. The most plausible near future approach at this time is to transplant replacement mitochondria into old people, where the challenge is reduced to being able to harvest mitochondria from cell cultures at the enormous scale required for a medical industry based on this approach. Several companies are working on this. Meanwhile, research community efforts to better understand mitochondrial function and identify points of intervention continue. Today's open access paper is an example of the type.

FAM162A Is a Key Regulator of Mitochondrial Structure, Dynamics, and Bioenergetics, Driving Cellular Protection and Longevity

FAM162A is an inner mitochondrial protein known for its role in hypoxia-induced apoptosis. However, it is often overexpressed in cancer, where its pro-apoptotic function appears to be overridden, suggesting novel unknown roles in mitochondrial function and cell survival. Furthermore, its precise localization, topology, and orientation remain controversial. In this study, we aimed to assess the role of FAM162A in mitochondrial structure, dynamics, and bioenergetics and its impact on cellular and organismal stress resistance, while also establishing its localization, topology, and orientation.

To this end, localization, topology, and orientation were determined by protease-protection assays in COS7 cells. In vitro loss- and gain-of-function experiments assessed mitochondrial structure and function by confocal microscopy, immunoblotting, and Seahorse analysis, while a transgenic Drosophila model overexpressing human FAM162A was generated to evaluate organismal survival under normal and heat stress conditions.

We found that FAM162A localized to the inner mitochondrial membrane, predominantly within the cristae, and supported cristae ultrastructure, bioenergetics, and mitochondrial turnover, thereby enhancing oxidative metabolism, cell viability, and stress resistance. FAM162A expression was positively associated with the fusion protein OPA1 and interacted with OPA1 to regulate the proportion of long- and short-OPA1 isoforms. Transgenic Drosophila overexpressing human FAM162A exhibited increased lifespan and locomotor activity under both normal and heat stress conditions. Overall, FAM162A emerges as a key regulator of mitochondrial integrity and bioenergetics through its association with OPA1, confirming a novel role in cellular health and stress resistance.

No part of the body is truly isolated; all organs, systems, and cell populations interact with all of the others in various ways. Cells secrete and take up countless varieties of molecules and vesicles, carried throughout the body by the circulatory system to cause reactions elsewhere. Given the strong impact of reproductive success on the evolution of a species, including the characteristics of aging in that species, it perhaps shouldn't be surprising to find that germline cells get an outsized vote in the behavior of other bodily systems. In some senses, the individuals of a species are just temporary vehicles that exist to ensure the continuation of the germline, and they are shaped by the requirements of that task.

Aging is a complex biological process whose regulatory mechanisms remain incompletely understood. Accumulating evidence indicates that germ cells play pivotal roles in the systemic regulation of aging. The link between germ cells and somatic aging was first established in invertebrate models, where germ cells positively regulate the rate of organismal aging. However, whether and how this relationship operates in vertebrates has remained unresolved for nearly a quarter of a century. Recently, using the short-lived vertebrate model Nothobranchius furzeri, we demonstrated that germ cells exert sex-dependent effects on somatic aging.

In males, germ cell ablation improved healthspan and extended lifespan, accompanied by enhanced vitamin D signaling. In contrast, germ cell removal in females shortened lifespan, associated with increased IGF-1 signaling and reduced estrogen signaling. These findings suggest a vertebrate-specific mechanistic link between germ cells and somatic tissues mediated by sex-specific endocrine signaling. Such a mechanism may contribute to sexual dimorphism in reproductive strategies and potentially underlie the female longevity advantage observed across many species.

Link: https://doi.org/10.1262/jrd.2026-044

It is not surprising to find aspects of aging correlated with one another; some people have a greater burden of cell and tissue damage than others, and thus tend to be more greatly impacted in all organs and systems as a result. Equally, the failing capacity of any one organ or system can accelerate the decline of all the others. The immune system is a good example, given its importance to tissue function, and the kidney is another. Kidney function is absolutely vital for health, and impairment drags down the rest of the body. As an example of this, researchers here report on a correlation between degree of kidney aging and degree of frailty in older people.

This study aimed to investigate the association between baseline kidney function and frailty trajectories in middle-aged and older adults. Data were derived from the China Health and Retirement Longitudinal Study (2011-2018), including 5,364 participants aged ≥45 years at baseline with up to four assessment waves over approximately 7 years. Kidney function was evaluated using estimated glomerular filtration rate based on serum creatinine and cystatin C (eGFRscr-cysc). Frailty was assessed using a 30-item frailty index (0-100 scale).

At baseline, the mean frailty index was higher in participants with mildly (β=2.28) and moderately-to-severely (β=3.70) reduced kidney function compared to normal kidney function, where β represents the adjusted difference in frailty index relative to the reference group. Frailty index increased over time in all groups; in participants with normal kidney function, it rose by 0.83 points per year. The annual increase was 0.26 points greater in the mildly reduced and 0.70 points greater in the moderately-to-severely reduced group. Over approximately 7 years, predicted mean frailty index increased from 15.1 to 20.9, 17.4 to 25.0, and 18.8 to 29.5 in the normal, mildly reduced and moderately-to-severely reduced groups, respectively.

Thus middle-aged and older adults with lower kidney function exhibited higher frailty index levels at baseline and faster frailty progression over time.

Link: https://doi.org/10.1016/j.tjfa.2026.100151

You might recall that gene therapy to overexpress caveolin-1 in the brain was recently shown to reduce pathology in a mouse model of Alzheimer's disease. In today's open access paper, researchers apply the same gene therapy to a mouse model of TDP-43 pathology in the aging brain. In this model, the mice express higher than normal levels of TDP-43, and thus as they age, the animals exhibit greater levels of altered forms of TDP-43 that form aggregates and disrupt cell biochemistry in the brain as a consequence. This pathological aggregation and its consequences are particularly important in amyotrophic lateral sclerosis (ALS) and the recently named limbic-predominant age-related TDP-43 encephalopathy (LATE), but it seems likely that TDP-43 aggregation contributes in some way to all of the major named age-related neurodegenerative conditions.

Of note, the viral vector used in these studies, AAV-PHP.eB, is a relatively recently developed AAV serotype that allows for both intravenous injection and efficient transduction of cells in the brain. From a logistics and cost perspective, this is a large improvement over the need for stereotactic approaches to direct injection of the brain and intrathecal injections, and is spurring more interest in the development brain targeted gene therapies.

The mechanism by which increased caveolin-1 expression improves function in a brain undergoing neurodegenerative issues is quite interesting; it seems more suited to TDP-43 pathology than Alzheimer's pathology, as one might argue that it is actually doing something to mitigate much of the core problem of TDP-43 alteration and mislocalization, rather than only compensating for root causes by enabling greater synaptic plasticity, as seems more the case in the Alzheimer's disease models.

Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43-induced cognitive decline and neurodegenerative changes

Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer's disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy. AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.

Systemic AAV-PhP.eB-SynCav1 gene therapy efficiently crossed the blood-brain barrier and achieved central nervous system-wide neuroprotection. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43-induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling.

These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a "neuron-centric" candidate for treating TDP-43-related neurodegeneration.

Macular degeneration involves the death of vital cells in the retina, leading to progressive blindness. The less common neovascular (or "wet") form of the condition involves the inappropriate growth of leaky blood vessels in the retina and underlying choroid. Existing treatments focus on trying to prevent this blood vessel growth or remove the vessels, rather than addressing underlying causes. Here, researchers make a step in the direction of those underlying causes by identifying a problem immune cell population that appears to contribute to the dysfunction and leakage of blood vessels in the eye.

Age-related macular degeneration (AMD) is the leading cause of irreversible central blindness and can result in pathological neovascularization. Using a "human-first" approach, we identify immunotherapy as a disease modifier in models of neovascular AMD. Plasma cytokine analysis in a large population cohort reveals an imbalance of lymphocytic cytokines associated with severity of AMD, leading to discovery of a skewed peripheral natural killer (NK) cell phenotype in individuals with AMD.

Peripheral NK cells are rapidly activated in neovascular AMD models, and single-cell RNA sequencing demonstrates expansion of activated cytolytic NK cells within neovascular lesions during resolution. NK cells localize to neovessels in human AMD donor eyes; however, they exhibit markers of terminal differentiation and quiescence. Adoptive transfer of pre-activated NK cells reduces neovascularization and restores barrier integrity. Our data identify a distinct, functionally altered NK cell phenotype in neovascular AMD and suggests harnessing NK cells represents an immunotherapeutic alternative for the treatment of neovascular AMD.

Link: https://doi.org/10.1016/j.xcrm.2026.102792

Researchers continue to produce new aging clocks at a fair pace. Any sufficiently complex set of biological data obtained from people of various ages can yield a clock given the use of various forms of machine learning. It is straightforward to make a new clock. Most of these will vanish into obscurity, as they will demonstrate no advantages over existing, more well studied clocks. The need is not for new clocks, but to solve the challenges inherent in the use of any clock, which is to say that it is entirely unclear as to whether a clock provides a reasonable representation of biological aging, and whether it can be trusted as an assessment of any given intervention to slow or reverse aspects of aging. The research community struggles to connect clock parameters to aging in any meaningful way that yields confidence in the ability of a clock to assess novel forms of therapy.

Amino acids are fundamental to human physiology, yet their impact on growth, development, and aging remains elusive. Here, we introduce AmiAge, a biological age predictor constructed using a Random Forest model trained on the concentrations of 18 amino acids across individuals aged 1 to 89 years. Leveraging data from 9 studies encompassing over 11,000 in-house and more than 270,000 publicly available samples with diverse demographic and genetic backgrounds,

AmiAge demonstrates robust accuracy. The deviation between AmiAge and chronological age (AmiAge Gap) correlates strongly with established aging biomarkers, disease risk, and clinical outcomes. Individuals with higher gaps exhibit increased frailty, telomere attrition, and elevated incidence of age-related diseases. To enhance clinical utility, we distilled AmiAge into an 8-amino acid model (including alanine, glutamine, glycine, histidine, leucine, phenylalanine, tyrosine, and valine). Our findings suggest that this simple, scalable amino acid clock offers a valuable complement to existing biological aging metrics, with potential applications in personalized health management and aging research.

Link: https://doi.org/10.1038/s41467-026-73371-y

In a sense, exercise is damaging. It places stress on cells, but we have evolved to react to that stress and damage with greater maintenance, repair, and a shift of cell metabolism into a more beneficial state. That a mild or short term stress results in a long term benefit is called hormesis, and it is the case for near all forms of stress. There is a point at which any form of cellular stress or metabolic disarray tips over from net benefit to net harm, a dose-response curve that looks quite similar at the high level for cold, toxins, heat, lack of nutrients, exercise, and so forth. This remains the case once you move past the source of the stress and start picking apart the biochemical changes in cell activity and cell signaling generated in reaction to that stress.

Today's open access paper looks at HMGB1 in this context of stress and hormesis relating to exercise. HMGB1 is variously regarded as devil or angel in different scientific papers, and this does tend to be the case for many of the components of a stress response. HMGB1 can produce both benefits and harms, and the dose is everything when it comes to how the balance of outcomes affects health. So HMGB1 promotes cellular senescence in bystander cells when secreted by senescent cells as a part of the senescence-associated secretory phenotype, for example. But HMGB1 also reverses some losses of DNA structure in aged cells and increases stem cell activity to accelerate regeneration. This sort of characteristic can make stress response emulation a difficult class of therapy to bring to the clinic, as optimal doses (or even whether more versus less HMGB1 is beneficial!) might vary widely from species to species and from individual to individual within a species.

High mobility group box 1: DAMPening the danger molecule in cardiovascular disease with exercise

High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP). During cellular stress, it leaves the nucleus and moves into the extracellular space, where it modulates the development of cardiovascular diseases (CVDs), a leading global cause of age-related mortality. In preclinical models, administration of HMGB1-neutralizing antibodies increased the survival rates of lipopolysaccharide-treated mice by up to 30%, whereas treatment with recombinant HMGB1 was lethal. Furthermore, chronological aging is accompanied by a gradual increase in systemic HMGB1. Compared with young adults (18-30 years), older adults (≥70 years) have ∼ 25% higher serum HMGB1 concentrations. A longitudinal study also revealed an age-related increase in plasma HMGB1 from 3.5 ± 1.8 to 4.7 ± 1.5 ng/mL as participants aged from 24.6 ± 3.3 to 30.4 ± 3.4 years,4 suggesting that HMGB1 may reflect age-related inflammatory burden and contribute to the increased cardiovascular risk seen in older populations.

While evidence indicates that HMGB1 is associated with both the progression and severity of CVDs, it also has a paradoxically beneficial role in mitigating tissue repair. HMGB1 appears to have an important role in promoting stem cell recruitment and tissue regeneration. A role for HMGB1 in stem cell mobilization has been reported, wherein HMGB1 knockout mice exhibited impaired skeletal muscle regeneration following toxin-induced injury. In the same study, leukocyte-derived HMGB1 was required for the activation of satellite cells and vascularization in murine skeletal muscle.

Exercise training improves cardiovascular function and modulates systemic concentrations of HMGB1. Acute exercise induces the release of HMGB1 into systemic concentration, whereas long-term exercise training appears to reduce its systemic levels. This paradoxical response of HMGB1 to either short-term or chronic exercise, alongside its complex role in the pathogenesis of age-associated CVDs, makes it an intriguing subject for research. A potential explanation for this paradox may lie in HMGB1's capacity in regulating stem cell recruitment and tissue regeneration.

One of the outcomes of the past few decades of focus on the development of tissue engineering and cell therapies is an increased understanding of what can be achieved with nanomaterials, meaning any manufactured substance or structure with nanoscale features that can engage with cells in a defined way. The use of nanoscale scaffolding to emulate aspects of the extracellular matrix in order to support transplanted cells is a going concern, for example. Another line of research and development is the use of nanoparticles that are engineered to steer tissue penetration in specific directions, release cargo in response to specific stimuli, and interact with cells to alter their behavior. Here, researchers review the state of the art in the context of developing therapies for osteoarthritis, the age-related degeneration of joint tissues.

Osteoarthritis (OA) is no longer viewed as a mere "wear-and-tear" disease, but rather as a multifactorial joint failure syndrome driven by cellular senescence, metabolic dysregulation, and low-grade chronic inflammation. These pathological pillars synergistically disrupt cartilage homeostasis, subchondral bone remodeling, and synovial inflammation, collectively fueling disease progression. While conventional therapies offer only symptomatic relief, they fail to reverse or reprogram the underlying pathological microenvironment. Consequently, there is an urgent need to develop disease-modifying interventions that can simultaneously target these pathological pillars.

Here, we critically examine how nanomaterial-based platforms - leveraging tailorable surface chemistry, cartilage-penetrating dimensions, and stimuli-responsive cargo release - enable precision targeting of these interconnected mechanisms. We highlight advances in senolytic delivery for senescent cell clearance, redox-modulating nanozymes for metabolic reprogramming, and immunoregulatory strategies for macrophage repolarization, emphasizing designs that transcend passive drug delivery to actively remodel the joint microenvironment. By integrating mechanistic insights with engineering innovation, this review outlines a roadmap for next-generation disease-modifying nanomedicines that promise not merely to slow OA progression, but to restore the biological clock of the joint. We also discuss current translational barriers and propose future directions for personalized OA therapy.

Link: https://doi.org/10.2147/IJN.S584027

Allostatic load is a fairly fuzzy concept, meaning the degree of wear and tear on the body that acts degrades its ability to resist stress and function correctly. Debates over exactly how to measure allostatic load are a microcosm of the debates over exactly how to measure biological age: various scientists all using the same conceptual term to describe what turn out to be a wide range of proposed approaches to the concrete assessment of that term. The measurement is the definition at the end of the day, and so one researcher's allostatic load is not the same as that of another researcher. It remains to be seen as to whether consensus will be achieved at any point in the near future, for either biological age or allostatic load.

Chronic stress contributes to the development of cardiometabolic, malignant, and other chronic diseases through cumulative multisystem physiological dysregulation, conceptualized as allostatic load (AL). However, traditional AL relies on heterogeneous clinical biomarkers that limit reproducibility and translational utility. Here, we develop and validate ProAL50, a proteomics-based measure of AL derived from 50 circulating proteins. Using high-dimensional plasma proteomic data from the UK Biobank, we constructed ProAL50 via penalized regression and stability selection and externally validated it in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

ProAL50 closely mirrored traditional AL in its associations with sociodemographic characteristics, lifestyle behaviors, physical and mental health, inflammation, and biological aging, supporting strong construct validity. Beyond replication, ProAL50 consistently demonstrated stronger associations with incident chronic diseases, including all cancers, type 2 diabetes, ischemic heart disease, chronic lung disease, and chronic kidney disease, and with all-cause and cause-specific mortality. Functional enrichment analyses revealed that ProAL50 proteins cluster within lipid metabolic and immune-inflammatory pathways. These findings establish ProAL50 as a scalable, biologically grounded measure of cumulative stress that not only replaces traditional AL but surpasses it in predicting disease risk and mortality, offering a novel tool for population health and translational research.

Link: https://doi.org/10.21203/rs.3.rs-8881432/v1