Fight Aging!

The human body hosts countless viruses in addition to the other forms of microbe such as bacteria and fungi. Most of these viruses are commensal species, most likely harmless throughout much or all of the life span, playing their parts in the microbial ecosystems that exist within and around the body. At the present time there is considerable enthusiasm for the study of the gut microbiome, and this is one avenue of research in which viruses are being cataloged and their activities considered by researchers. Another avenue is the study of persistent infectious viruses, primarily herpesviruses, and their effects of health over the course of aging. Persistent viruses may contribute meaningfully to age-related immune dysfunction and various age-related diseases. Consider what is known of the effects of cytomegalovirus on the immune system, or the evidence for other herpesvirus species to contribute to the onset and progression of Alzheimer's disease.

In today's open access paper, researchers review what is known of the human virome and its impact on health and aging. At the high level, the theme is that much is yet to be mapped and discovered. Despite considerable progress in gathering data, particularly in recent years, the research community's understanding of the role of viruses in human aging still contains large dark areas and many unknowns. We might think that this is in part the case because we lack a good way to clear viral infections. Given tools that can selectively destroy specific viruses, such as the DRACO system still somewhere in the development process, it would become much easier to determine the activities of various species and their effects on health.

The gut and circulating virome: emerging players in aging and longevity

A growing body of evidence indicates that the human virome, comprising both the gut and circulating viral communities, plays a critical role in shaping host physiology across the lifespan. In the context of aging, this complex viral ecosystem is increasingly recognized as a key modulator of immune function, inflammation, and metabolic balance, with direct implications for healthspan and longevity. While much attention has traditionally focused on bacterial components of the microbiota, recent advances in metagenomics have uncovered age-related shifts in the composition and function of the virome, including expansion of specific bacteriophage families, reactivation of latent viruses, and the persistence of commensal viral pathobionts.

These changes are tightly linked to immunosenescence, chronic inflammation, and neurodegeneration, hallmarks of unhealthy aging. Notably, centenarians appear to harbor a unique virome signature marked by increased viral diversity, enhanced lytic activity, and the enrichment of phage-encoded metabolic functions, suggesting a potential protective role in extreme longevity. Despite these insights, significant challenges remain in virome profiling, including technical biases, database limitations, and the vast proportion of taxonomically unassigned sequences known as "viral dark matter". This review highlights emerging data on the aging virome, underscores its relevance within the Geroscience framework, and discusses current barriers and future directions for translating virome research into clinical aging studies.

Research into the biochemistry of longevity does not proceed at a rapid pace, even now that the field has become popular. Much of this research takes the form of first discovering longevity-enhancing mutations in short-lived species and then painstakingly tracing chains of cause and effect from protein to protein and interaction to interaction. Since cellular metabolism is by no means fully understood, even in the extremely well studied nematode worm C. elegans, this takes a long time. For example, we can see that is has taken thirty years or so to move from the first C. elegans longevity-enhancing mutation to the discovery of many more, and now here finding that some of these mutations converge on the activity of the FMO-2 gene. This slow pace of increased understanding is one of the reasons why manipulating the operation of cellular metabolism to slow the pace of aging seems a poor choice of primary goal for research and development, versus the alternative approach of finding specific forms of damage and attempting to repair them.

A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of fmo-2 in the long lifespan of genetic mitochondrial mutants in C. elegans. We found that fmo-2, but not other fmo genes, are specifically upregulated in the long-lived mitochondrial mutants clk-1, isp-1, and nuo-6. Disruption of fmo-2 through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that fmo-2 is required for lifespan extension in these worms.

Moreover, signaling molecules that have been shown to be involved in upregulation of fmo-2 are also required for the long life of clk-1, isp-1, and nuo-6 mutants including HLH-30, NHR-49, and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in clk-1 mutants on the expression of fmo-2. We found that in all cases, genes required for clk-1 longevity are also required for the upregulation of fmo-2 in clk-1 worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.

Link: https://doi.org/10.64898/2026.02.10.705198

That new neurons are generated in the adult brain and integrate into existing neural networks was first established in mice in the 1990s, but considerable debate has taken place since then as to whether this adult neurogenesis also occurs in humans. Working with human brain tissue has always been logistically difficult, and this combined with methological challenges in the quantification of neurogenesis allowed uncertainty to continue. At this point, the balance of evidence and scientific consensus is that adult neurogenesis does occur in our species, and further is necessary to the operation of memory and learning. Here, in addition to providing further confirming data for human adult neurogenesis, researchers suggest that differences in neurogenesis could contribute to sustained cognitive function in older individuals who exhibit relatively little cognitive aging.

The existence of human hippocampal neurogenesis has long been disputed and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD). However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers), adults with preclinical intermediate pathology or adults with AD.

Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons.

Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

Link: https://doi.org/10.1038/s41586-026-10169-4

The composition of the gut microbiome changes with age. Microbial species capable of provoking inflammation, by infiltrating tissues or via production of harmful metabolites, grow in number. This occurs at the expense of populations that produce beneficial metabolites, such as butyrate, known to promote function in a number of different tissues. The reasons for this shift of composition are not fully understood, especially since meaningful change starts to occur relatively early in adult life. Immune dysfunction likely plays a significant role, however, as the immune system is responsible for gardening the gut microbiome, keeping harmful species to a minimum.

Rejuvenation of the aged gut microbiome via fecal microbiota transplantation from a young donor has been shown to improve health and extend life in animal studies. To what degree are these benefits a restoration of youthful microbial metabolite production versus a removal of inflammatory species, however? Today's open access paper provides evidence to suggest that it is mostly a matter of reducing the production of harmful metabolites. The researchers did not rejuvenate the aged microbiome in old mice, but instead used high dose antibiotic treatment to greatly reduce all microbial populations in the gut. This allowed the assessment of health and physiology in an environment in which the production of harmful microbial metabolites was also greatly reduced.

The result reported in the paper is a significant improvement in aspects of brain health. Removing the gut microbiome in this way is not a viable approach to therapy for the population at large, but the results reported here suggest that benefits will arise from any approach that successfully reverses the increase in numbers of harmful microbes that is characteristic of the aged gut microbiome. Restoring the youthful population sizes of helpful microbes is good, but likely less important to the benefits demonstrated in animal studies of gut microbiome rejuvenation via fecal microbiota transplantation.

Microbiome depletion rejuvenates the aging brain

Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain.

Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging.

Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.

Some gene sequences can give rise to circular RNAs when transcribed. As a class, circular RNAs are not as well studied as other classes of molecule in the cell, but it is becoming apparent that, as for just about everything one might find in a cell, some circular RNAs become relevant in the context of aging. Here, researchers discuss findings relating to circular RNAs generated from mitochondrial genes. In particular circular RNAs for MT-RNR2 appear to meaningfully affect mitochondrial function, and lower levels of MT-RNR2 in older individuals may be involved in the age-related decline of mitochondrial function. The best way forward to a greater understanding is to manipulate MT-RNR2 expression and see what happens as a result. In general, improved mitochondrial function should be a good path to the production of therapies that improve health, but the question is always how great an improvement can be achieved, and that remains to be seen in this case.

During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs. Although global profiles of the human transcriptome and epitranscriptome during the aging process are available, the existence and function of mitochondrial circular RNAs originating from the mitochondrial genome are poorly studied. Here, we report profiles of circular RNAs annotated to the mitochondrial chromosome in young and old cohorts.

The most abundant circular RNA junctions are found in MT-RNR2, whose level is depleted in old cohorts and senescent fibroblasts. The mitochondria-localized RNA-binding protein GRSF1 binds various mitochondrial transcripts, including linear and circular MT-RNR2, with a distinct RNA motif. Linear and circular MT-RNR2 bind a subset of TCA cycle enzymes, suggesting their possible function in regulating glucose metabolism in mitochondria to preserve proliferating status in young cohorts. In human fibroblasts, depletion of GRSF1 reduced levels of circMT-RNR2 and fumarate/succinate, concomitantly accelerating cellular senescence and mitochondrial dysfunction.

Taken together, our findings demonstrate the existence and possible function of circular MT-RNR2 during human aging and senescence, implicating its role in promoting the TCA cycle. Future mechanistic studies will reveal how these mitochondrial circular RNAs are produced by trans-splicing, possibly, and how the circular RNAs accelerate the TCA cycle to preserve the proliferation status and suppress senescence as well as aging.

Link: https://doi.org/10.18632/aging.206354

The brain requires a great deal of energy to function. That energy is provided by mitochondria, hundreds of these organelles in every cell producing the chemical energy store molecule adenosine triphosphate (ATP), that activity reliant on the nutrients and oxygen delivered via the vascular system. The brain operates at the limit of its metabolic capacity even in youth, as demonstrated by the fact that exercise and the consequent increased supply of blood to the brain transiently increases cognitive function. Mitochondrial function declines with age, and this has consequences. But as researchers show here, improving the capacity of mitochondria to provide the cell with energy can enhance cognitive function at any age.

Expensive energy usage in neurons must be limited to avoid unnecessary overconsumption of fuels in the brain that could otherwise be useful for survival. During neuronal activity, synapses synthesize the exact levels of energy that are consumed during each firing event, without underproducing or overproducing ATP. While the work of several laboratories has identified how mitochondrial metabolism is upregulated on demand in activated neurons to preserve the metabolic integrity of synapses, the importance and the molecular identity of mechanisms slowing down mitochondrial metabolism after firing have remained elusive.

From insects to mammals, essential brain functions, such as forming long-term memories (LTMs), increase metabolic activity in stimulated neurons to meet the energetic demand associated with brain activation. However, while impairing neuronal metabolism limits brain performance, whether expanding the metabolic capacity of neurons boosts brain function remains poorly understood. Here, we show that LTM formation of flies and mice can be enhanced by increasing mitochondrial metabolism in central memory circuits.

By knocking down the mitochondrial Ca2+ exporter Letm1, we favour Ca2+ retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H+/Ca2+ exchange. The resulting increase in mitochondrial Ca2+ over-activates mitochondrial metabolism in neurons of central memory circuits, leading to improved LTM storage in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in neurons and indicate its involvement in shaping higher brain functions, such as LTM.

Link: https://doi.org/10.1038/s42255-026-01451-w

The longevity industry will at some point diffuse into the broader pharmaceutical and biotech industries. It will cease to be so distinct in culture, technology, and regulation as to merit the drawing of firm lines. Treating aging as a medical condition is no longer looked upon as strange by the powers that be, even though the public at large has yet to catch up entirely to this new viewpoint. This relatively new environment of approval means that sizable funding is available, and indeed deployed in large amounts to advance the cause, both by private and public sources.

One of the US government programs in which program managers have become very sympathetic to the cause of treating aging is ARPA-H, portions of which one might think of as spiritual successors to the attitudes and aims of DARPA, except that the focus is progress in medical technology specifically. That clinical trials are so enormously expensive to prepare for and run is the fault of government regulatory bodies, a mess created over decades. Now another arm of government will feed public funds into that process to enable more groups to make progress in passing the financial hurdle that regulators created. As is usually the case, however, it is largely the already well funded, high-profile initiatives that receive that assistance; if one is connected enough to have a large chance of obtaining major government funding, one is connected enough to be able to raise just as much from private sources, and have probably already done so.

Regardless, medicine is a highly regulated industry, and this is how the game is played in any industry in which government appointees exert such a large degree of control over what does and does not happen. In these years in which the first therapies that might slow aging (or in a few cases selectively reverse aging) are making their way into clinical trials, most groups are indeed trying to play the game as it exists, with all of its flaws, as in the bigger picture it is vital to demonstrate to the world at large that the treatment of aging can be real. An increasing number of companies are looking for alternative paths, however, such as those setting up their initial clinical trials in much less costly locations, and intending to initially prove their worth and provide access via medical tourism. From a very high level perspective, the most important outcome for the next decade or two is that therapies for aging, as many different approaches as possible, are meaningfully tested in humans - however that outcome is achieved. Even a few successes will give rise to a massively larger industry, with enough weight behind it to meaningfully change the way in which medical development takes place.

ARPA-H pours millions into healthspan-focused human trials

The US Government, via its Advanced Research Projects Agency for Health (ARPA-H) initiative, is putting up to $144 million into multiple projects aimed at extending healthspan - the years people live in good health. Through its PROSPR program, ARPA-H is funding seven research teams working to treat aging as a tractable biological process, and proving, in humans, that intervening earlier can help people stay healthier for longer.

Short for "Proactive Solutions for Prolonging Resilience," PROSPR's goal is to overcome one of the key challenges that has limited clinical development in geroscience: aging is slow, and its associated diseases and conditions can take years or decades to emerge, making conventional trials unwieldy and expensive. The initiative aims to use longitudinal human data to identify early, actionable biomarkers that respond before late-stage outcomes appear. Those biomarkers are intended to serve as surrogate endpoints that can show, within one to three years, whether an intervention is plausibly shifting an individual's trajectory toward better function, resilience, and quality of life.

Longevity biotech Cambrian has been awarded up to $30.8 million to support human trials of a daily, oral, next-generation rapamycin analog intended to selectively inhibit mTORC1. The company views dysregulated mTORC1 signaling as a key driver of the metabolic decline that accumulates with age, and it is tying its program to "intrinsic capacity," a composite measure of physical and metabolic resilience that declines over time.

Linnaeus has been awarded up to $22 million to advance a drug targeting the G protein-coupled estrogen receptor (GPER) into human trials for healthspan preservation. Interestingly, the company is building on its work in oncology, where more than 100 cancer patients have been treated with its drug (LNS8801) in early human trials and signals observed in those patients suggested potential translation into aging-related benefits.

TDP-43 is a protein only relatively recently discovered to undergo pathological modification and aggregation in the aging brain. Much like amyloid-β, α-synuclein, and tau, this aggregation is thought important in the progression of specific neurodegenerative conditions. Here, researchers present evidence for TDP-43 aggregation to contribute to lost function in vascular dementia. Vascular dementia arises from a reduced blood supply to the brain, or other issues in the vasculature supplying brain tissue with the oxygen and nutrients it needs. The brain operates at the edge of metabolic capacity at the best of times, and as that supply diminishes with age, function suffers. Can some of the consequent damage done to the brain be prevented? Obviously it would be ideal to maintain a healthy vasculature instead of trying to compensate for vascular aging, but the research community does spend a lot of time looking at possible compensatory approaches, ways to sabotage at least some of the maladaptive reactions to the damage and dysfunction of aging.

Vascular dementia (VaD) ranks as the second most common cause of dementia worldwide and is linked to the highest mortality rate among dementia subtypes. A key driver of VaD pathogenesis is chronic cerebral hypoperfusion (CCH), a state of persistently reduced blood flow to the brain stemming from cerebrovascular compromise. A hallmark of VaD, CCH can diminish cerebral blood flow by as much as 40%, triggering hypoxia-induced cellular stress. This includes oxidative damage, mitochondrial failure, and heightened neuroinflammation, which collectively impair blood-brain barrier integrity and promote white matter lesion (WML) formation.

Recent evidence points to Tar DNA-binding protein 43 (TDP-43) as a potential mediator in this cascade. While TDP-43′s pathological role is well-established in amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and Alzheimer's disease (AD), its involvement in VaD is poorly understood. In healthy neurons, TDP-43 is crucial for synaptic function and stress response. Under pathological conditions, however, it undergoes detrimental modifications, including hyperphosphorylation, nuclear-to-cytoplasmic mislocalization, and aggregation that are common processes across neurodegenerative diseases. These aberrant forms of TDP-43 lose their normal function and can acquire toxic properties, potentially exacerbating neuroinflammation. While TDP-43 pathology is a well-established feature of several neurodegenerative diseases, its potential role in the context of cerebrovascular injury remains largely unexplored.

This study demonstrates that CCH, a key feature of VaD, triggers pathological TDP-43 changes, namely cytoplasmic mislocalisation and hyperphosphorylation, in both in vivo and in vitro models. In a mouse model of VaD, time-dependent cytoplasmic accumulation of TDP-43 and pTDP-43 was observed in cortical and hippocampal neurons, with elevated pTDP-43 despite stable total TDP-43 levels, implicating phosphorylation in its aberrant redistribution. These results mirror hallmark features of TDP-43 proteinopathies in neurodegenerative diseases, such as ALS and AD, and suggest that similar mechanisms may be triggered by vascular insults.

Link: https://doi.org/10.1002/alz.71196

Researchers here report an association between late life survival and levels of specific piwi-interacting RNAs. This subcategory of non-coding RNAs, meaning RNA molecules that are not translated into proteins, has attracted more interest of late in the context of aging and age-related changes to the regulation of gene expression. The understanding of the role of non-coding RNAs in metabolism lags behind the still incomplete understanding of proteins. The life science community is slowly filling in an enormous map of interactions, a map that will contain many large dark areas for a long time yet. There are only so many researchers, and developing a reasonably complete understanding of how even a single protein or RNA contributes to cell metabolism requires years of work in the best of circumstances.

To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs - 687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs) - in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the EPESE study. Our predictive model incorporating small RNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated area under the curve (AUC) values of 0.92 for 2-year survival in Discovery and 0.87 in external Validation.

Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.

Link: https://doi.org/10.1111/acel.70403

The shape and packaging of nuclear DNA is actively controlled by the cell via decoration of the DNA and supporting structures with additional molecular motifs, such as methyl groups. At any given time much of the genome is tightly spooled into regions known as heterochromatin that are inaccessible to the machinery of gene expression that surrounds nuclear DNA, constantly interacting with it. The structure of nuclear DNA determines gene expression, which regions are unspooled and accessible to translation machinery for the production of RNA from gene sequences versus which regions are spooled and the genes there silenced.

Here researchers examine immune cells from centenarian blood samples and note a distinct pattern of structure in their DNA. Further investigation points to one specific transcription factor, ERG, that appears to reduce cellular senescence, and thus might be theorized to improve immune function in the aged tissue environment. There are no doubt many other specific differences in activity that might be investigated more deeply, however. Transcription factors alter DNA structure and other aspects of gene expression for many genes, thousands in some cases. They are thus interesting points of potential intervention in the behavior of the cell, a greater centralization of regulatory control over function than most genes.

ERG phase separation attenuates cellular senescence

Our study defines a distinct chromatin accessibility signature in perihipheral blood mononuclear cells of centenarians, characterized by a global increase in chromatin openness across multiple immune subsets. Notably, this increase does not reflect accelerated senescence as aging usually along with increase chromatin accessibility, but rather suggests a unique chromatin configuration associated with exceptional longevity. In particular, B cells from centenarians display enhanced accessibility at promoter and enhancer regions that typically close with age, while closing peaks are enriched in quiescent loci that generally open during aging. These findings highlight that centenarians maintain an atypical epigenetic state, potentially supporting immune resilience and genomic stability in extreme old age.

Integrative analysis highlighted the E-26 transformation-specific (ETS)-related transcription factor ERG as a longevity-associated regulator. Functional studies in human cells showed that ERG forms nuclear condensates through liquid-liquid phase separation, a property associated with altered chromatin organization and reduced expression of cellular senescence-related genes, including CDKN2A. Consistent with these effects, ERG condensation was associated with attenuation of cellular senescence phenotypes. Together, these findings connect epigenomic features observed in centenarians with transcription factor biophysical properties and cellular aging control, highlighting phase separation as a regulatory layer that may contribute to cellular resilience during aging.

Cells have evolved to detect molecular markers of invading pathogens, such as out of place DNA sequences, and react with inflammatory signaling. One such system is the interaction between the DNA sensor cGAS and the regulatory of inflammation STING. Researchers have focused on this system in recent years, as it becomes maladaptively triggered with advancing age. Age-related dysfunctions in the cell lead to fragments of mitochondrial DNA and nuclear DNA escaping into the cytoplasm, where they are detected by cGAS, which then triggers STING. The result is an environment of inflammatory signaling that is disruptive to tissue structure and function, a further contribution to degenerative aging. Interfering in this process presents the same challenges as interfering in any aspect of inflammation, in that the cGAS-STING interaction serves a necessary purpose in addition to becoming problematic with age. It cannot be straightforwardly suppressed without producing harmful side effects.

The past few years have seen an explosion of interest in and knowledge about the cGAS-STING pathway in aging and neurodegenerative disease. Although this pathway is indispensable for host defense and is tightly regulated under physiological conditions, its aberrant activation emerges as a potent driver of the neuroinflammatory cascade and neuronal dysfunction during aging. The accumulation of both exogenous and endogenous DNA serves as a persistent trigger for cGAS, culminating in a vicious cycle of STING-dependent IFN-I and pro-inflammatory cytokine production. This chronic, low-grade inflammation is a hallmark of aged brain tissue and a key contributor to the progression of conditions like Alzheimer's disease, Parkinson's disease, and ALS. The promising results from preclinical studies utilizing cGAS or STING inhibitors, which have demonstrated efficacy in ameliorating cognitive decline and neuropathology in various models, underscore the therapeutic potential of targeting this pathway.

However, several pivotal questions and challenges must be addressed to translate these foundational discoveries into effective clinical interventions. For example, the characteristics of the DNA that activate the cGAS-STING pathway are crucial. The origins, oxidation extent, amount, manner, and rate of DNA release (e.g., during different forms of cell death) significantly influence the intensity of the downstream immune response. The relative contribution of mitochondrial DNA versus nuclear DNA and viral DNA remains hotly debated.

In conclusion, the cGAS-STING pathway serves as a master regulator of age- related neuroinflammation and a compelling therapeutic target for a range of neurodegenerative conditions. Importantly, the pathological outcome is determined not merely by whether the pathway is activated, but more profoundly by the strength of the signal, the cellular context of activation, and the source and properties of the stimulating DNA, such as whether it is exogenous or endogenous, oxidized, or otherwise modified. Given this complexity, a precise understanding of the cGAS-STING pathway is essential to understanding neuroinflammatory damage. Looking ahead, we should aim to design therapeutic strategies that precisely modulate the cGAS-STING pathway - both in degree of activity and cell-type specificity - to safely unlock its potential for clinical benefit.

Link: https://doi.org/10.1186/s40364-026-00906-2

Aging clocks derived from a database of age-related changes in specific biological data must be validated for any specific use. The construction of the clock grants no insight into how its component measures relate to any specific aspect of aging, or to any specific age-related condition. Even conceptually similar clocks might exhibit quite different relationships with a given age-related condition, a point that is illustrated by the results of this study: some epigenetic clocks show very poor correlation with dementia risk, while others do correlate well enough to provide some insight.

Aging is the strongest risk factor for dementia; however, few studies have examined the association of biological aging with incident dementia. We analyzed 6,069 cognitively unimpaired women (mean age = 70.0 ± 3.8 years) in the Women's Health Initiative Memory Study to examine the association of accelerated biological aging, measured with second and third-generation epigenetic clocks (AgeAccelPheno and AgeAccelGrim2, and DunedinPACE, respectively) with incident mild cognitive impairment (MCI) and probable dementia.

Multivariable Cox proportional hazards models were adjusted for age, education, race, ethnicity, smoking, hormone therapy regimen, physical activity, body mass index, and estimated white blood cell counts. For comparison, we also examined first-generation epigenetic clocks (AgeAccelHorvath; AgeAccelHannum). We evaluated effect modification by age, race/ethnicity, hormone therapy regimen, menopause type (natural vs. surgical), and APOE ε4 carriage.

There were 1,307 incident MCI or probable dementia events over a median follow-up of 9.3 years. The adjusted hazard ratios for incident MCI/probable dementia per one-standard deviation increment were 1.07 for DunedinPACE, 1.11 for AgeAccelGrim2, and 1.01 for AgeAccelPheno. Only AgeAccelGrim2 remained significant under the Bonferroni-corrected threshold for significance. Other epigenetic clocks were not associated with incident MCI/probable dementia. There was no effect modification in most subgroup analyses.

Link: https://doi.org/10.1111/acel.70424

Somatic mosaicism in tissues occurs as a result of random mutational events in stem cell populations. Stem cells accumulate mutations randomly over time, a small fraction of the continual damage to nuclear DNA that slips past the highly efficient DNA repair machinery. Those mutations spread out into tissue via the daughter somatic cells generated by the stem cells. A tissue made up of somatic cells thus exhibits an ever more complex mosaic pattern of overlapping mutations over time. Somatic mosaicism in the immune system is known as clonal hematopoiesis. This is arguably the most studied form of somatic mosaicism, as the immune cells produced by hematopoietic stem cells are readily accessible via a blood sample.

Somatic mosacism sets the stage for cancer by spreading mutations that raise the odds of any specific cancerous combination of mutations occurring in any one somatic cell. But does somatic mosaicism contribute more generally to degenerative aging and loss of function, and is this contribution large enough for us to care about? There is some evidence to suggest that this is the case, but an important role for somatic mosaicism in aspects of aging other than cancer risk is far from conclusively demonstrated at this point in time. Clonal hematopoiesis seems likely to be where that is initially proven, if it is going to be.

Ageing Through the Looking-Glass: The Different Flavours of Clonal Haematopoiesis

Clonal haematopoiesis (CH) is the presence of acquired mutations in blood cells and is a consequence of ageing that is linked to malignancy, cardiovascular disease and other diseases of ageing. CH is a reflection of genomic instability with ageing; however, there is evidence that CH may exacerbate features of normal ageing, including inflammageing and immunosenescence, and more directly contribute to disease causation. CH can manifest as mosaic loss of X or Y chromosomes, autosomal mosaic chromosomal rearrangements, or point mutations or small insertions or deletions. However, differences in CH definitions, detection methods and cohort characteristics have contributed to heterogeneous and sometimes discordant findings across studies.

It has been hypothesised that the different forms of CH may all arise from a 'common soil' of genomic instability, that is, that shared heritable and environmental factors may promote the acquisition and subsequent expansion of mutations. However, it remains largely unknown whether associations between CH and diseases of ageing reflect correlation or whether CH may directly cause disease. Here, we review the relationship between ageing and CH, including how CH develops, and how it interacts with other features of ageing including inflammageing, immunosenescence, epigenetic ageing and telomere shortening. We also review what is known about the overlap between different forms of CH and whether they make independent contributions to risk of disease.

The different forms of CH share common germline and environmental risk factors and have overlapping prevalence and disease associations, suggesting they reflect common underlying processes of ageing. CH is also associated with other biomarkers of ageing, namely accelerated epigenetic age and shorter telomere length. The presence of CH may reflect a biologically older haematopoietic system and exacerbate features of normal ageing, including inflammageing and immunosenescence, which may be important causal mechanisms explaining the association between CH and a variety of diseases of ageing. Additionally, inflammation likely also promotes further expansion of CH. Different forms of CH may work together to promote clonal expansion and synergistically promote disease including through promoting inflammation. CH may also synergise with, or be influenced by, other sources of inflammation outside the haematopoietic system, potentially including somatic mutations in other tissues or epigenetic changes. There is some evidence that different forms of CH may make independent contributions to disease risk.

The balance of microbial species making up the gut microbiome changes with age in ways that promote inflammation and other harms. Researchers can accurately map the composition of the gut microbiome using sequencing approaches, and are steadily identifying specific microbial species and mechanisms that contribute to the dysfunctions of age. A number of approaches exist to restore a more youthful gut microbiome composition, such as fecal microbiota transplantation from a young donor or flagellin immunization, but none are yet very widely used in the context of attempting to improve late life health.

Physiological and pathological changes associated with aging contribute to deteriorating disease prognosis in sepsis. However, the mechanisms by which these disturbances exacerbate inflammation remain underexplored. In this study, fecal samples were collected from aged and young septic patients and mice and subsequently transplanted into young pseudo-germ-free mice via fecal microbiota transplantation. Fecal, colon tissue, and blood samples were collected to be used 16S rDNA sequencing to characterize the gut microbiota, histopathological examination, enzyme-linked immunosorbent assay and FITC-dextran intestinal permeability assay to assess gut injury and gut barrier function.

Additionally, nontargeted and targeted metabolomics were used to identify differential metabolites in the feces of aged and young septic mice. To further validate the roles of specific bacterial strains and their metabolites in sepsis, genetically engineered bacteria were used in both in vivo and in vitro experiments.

The results showed an increased abundance of Klebsiella aerogenes (K. aero) in aged hosts, which led to elevated histamine (HA) production and exacerbated intestinal barrier dysfunction. Importantly, K. aero strains carrying a histidine decarboxylase gene variant were identified as major HA producers. Mechanistically, HA was shown to drive intestinal barrier dysfunction by inhibiting Nlrp6 expression and its subsequent binding to LC3, thereby impairing autophagy. Treatments that modulated HA levels or overexpressed Nlrp6 ameliorated inflammation in septic mice. These findings suggest that targeting the HA-Nlrp6-LC3 axis could offer a novel therapeutic approach for managing sepsis, particularly in aged populations.

Link: https://doi.org/10.1080/19490976.2026.2630475

Atherosclerosis involves the growth of fatty plaques in blood vessel walls that weaken and obstruct those blood vessels. It is a universal condition; all older individuals exhibit some degree of plaque formation. A heart attack or stroke occurs when an unstable, fatty atherosclerotic plaque ruptures and the debris blocks a vessel somewhere downstream. Interestingly, atherosclerosis is quite different in character between the sexes. Until menopause, atherosclerosis proceeds more slowly in women, and as noted here women tend to exhibit lesser degrees of plaque in later life. That does not, unfortunately, translate into a lesser degree of risk of plaque rupture.

This study evaluated health data for more than 4,200 adults (more than half of whom were women) to compare how quantity of plaque influenced the risk of major heart conditions. The study included people with stable chest pain and no prior history of coronary artery disease. Participants were randomized to undergo diagnostic evaluation via coronary computed tomography angiography (X-ray images of the heart and blood vessels) and followed for about two years.

Fewer women had plaque in their coronary arteries than men (55% of women vs. 75% of men). Women also had a lower volume of artery plaque than men (a median of 78 mm^3 among women vs. 156 mm^3 in men). Despite less plaque, women were just as likely as men to die from any cause, have a non-fatal heart attack or be hospitalized for chest pain (2.3% of women vs. 3.4% of men). In addition, women faced increased heart risk at lower levels of plaque compared to men. For total plaque burden, women's risk began to rise at 20% plaque burden, while men's risk started at 28%. With increasing plaque levels, risk rose more sharply for women than for men.

"Because women have smaller coronary arteries, a small amount of plaque can have a bigger impact. Moderate increases in plaque burden appear to have disproportionate risk in women, suggesting that standard definitions of high risk may underestimate risk in women."

Link: https://newsroom.heart.org/news/women-may-face-heart-attack-risk-with-a-lower-plaque-level-than-men