Fight Aging!

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.