Fight Aging!

Lysosomes are structures within cells packed full of enzymes capable of breaking down proteins and structures into raw materials; they serve as recycling centers. Lysosomes are the final destination of damaged or unwanted proteins and structures flagged for destruction by the cellular maintenance processes of autophagy. Lysosomes are known to become dysfunctional with age, for reasons that are not fully explored. Some of it is a matter of changes in the expression of relevant genes, some of it is a matter of the accumulation of persistent metabolic waste that lysosomes cannot effectively break down. Given enough of that waste, lysosomes become bloated and inefficient. If a cell cannot effectively recycle, it becomes dysfunctional, inflammatory, and eventually dies. The more that this happens, the more that it contributes to degenerative aging.

Lysosomal dysfunction didn't make it into the Hallmarks of Aging as a headline category of its own. Arguably it should have. The earlier Strategies for Engineered Negligible Senescence (SENS) proposals included lysosomal dysfunction as a part of the problem of the aggregation of persistent metabolic waste inside cells, and did not focus all that much on harmful epigenetic change, save as it exists as a maladaptive reaction to other forms of molecular damage.

In today's open access paper, researchers report on novel findings in lysosomal aging, and show that it is possible to build a sufficiently complex signature of lysosomal aging from these findings to enable the creation of an aging clock. That one can build a decent aging clock from this data doesn't definitively indicate that this is an important cause of degenerative aging, however. That has to be separately determined the old-fashioned way. As is usually the case, the fastest path to demonstrating relevance as a contributing cause of aging is to find a way to reverse the specific observed changes in isolation, and then observe the outcome. Unfortunately one has to establish a path to therapy, then see whether or not it is viable, and not the other way around.

The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic, and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Researchers now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine, and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis.

The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine, and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders, and vulnerability to late-onset neurodegeneration.

Researchers here propose that greater efforts should be devoted to considering the variety of G-protein coupled receptors (GPCRs) as a regulatory network in the matter of aging and age-related disease. Aging produces sweeping changes in protein levels, gene expression, protein function and interactions, and one can thus make similar arguments for many different classes of molecule found in cells. The question is always whether one can justify intervention in a given mechanism on the basis of its importance to aging: where does it sit in the interacting network of cause and consequence? Is it causing a great deal of downstream harm, or is it more of an end stage consequence? How close is it to root causes of aging? This is a lot harder to answer than whether or not a mechanism has a role at all, but it is the crux of the matter, determining whether targeting that mechanism is a good choice or not.

G protein-coupled receptors (GPCRs) are arguably the most important class of signal transducers discovered to date. GPCRs are heptahelical transmembrane proteins that mediate responses to, among others, hormones, neurotransmitters, steroids, and immune modulators, many of which undergo dysregulation with age. GPCRs efficiently modulate a wide variety of signaling processes that underpin nearly all the mechanisms responsible for chronic age-related disease. Given their vital physiological role, dysfunction of GPCR signaling networks may represent a potential driver of aging pathophysiology. For example, age-related alterations in GPCR signaling contribute to chronic, low-grade inflammation (inflammaging), as seen in the increased activity of chemokine and cytokine receptors that results in immune system dysfunction. Additionally, GPCRs involved in metabolic regulation, such as adrenergic and insulin-sensitizing receptors, become less responsive with age, exacerbating metabolic disorders and insulin resistance. Mitochondrial dysfunction, another profound hallmark of aging, is also influenced by GPCR signaling through pathways that regulate oxidative stress and cellular energy homeostasis.

Therefore, GPCRs represent promising new therapeutic targets for mitigating - at both tissue-specific and systemic levels - age-associated diseases, which could work toward extending a person's healthspan. We posit that, while many diseases possess a specific genomic basis in their later stages, they may share a common feature in their genesis: the loss of cellular homeostasis. In this article, we evaluate the "GPCR-ome" as a central, "mega-trophic" regulator of human healthspan. We begin by examining the structural and functional vulnerabilities across major GPCR classes that render them susceptible to age-dependent decline. We then detail how these receptors functionally integrate with the fundamental hallmarks of aging (e.g., inflammaging, mitochondrial failure, and cellular senescence) to drive multisystemic disease. Finally, we propose a transformative therapeutic framework to transition from treating individual symptoms to targeting aging itself as a manageable, tunable process.

Link: https://doi.org/10.3389/fsci.2026.1891819

Researchers here provide a demonstration that a form of liver cancer can emerge from change in the epigenetic control over gene expression in the absence of mutation of nuclear DNA, rather than from mutation of nuclear DNA. It is an interesting open question as to the degree to which aging predisposes to cancer via a growing burden of mutation versus a growing burden of epigenetic change that alters expression of oncogenes. The answer will likely be very different on a tissue by tissue and cancer by cancer basis; biology is complex at every level.

Large-scale genome sequencing analyses have identified driver gene mutations (DGMs) in most cancers as well as their associated tumorigenic mechanisms. However, a small fraction of cancers are not positive for these canonical DGMs, leaving the mechanisms underpinning their formation a mystery. We hypothesized that canonical DGM-negative cancers might be driven by activation of the transcriptional coactivator YAP1 that led to the induction of epigenetic changes.

To test this theory, we established a mouse mosaic model of hepatocellular carcinoma (HCC) in which we induced YAP1-TEAD activation in a few hepatocytes. Whole-exome sequencing did not identify canonical DGMs in HCCs, but bisulfite sequencing revealed widespread DNA demethylation leading to the transcriptional activation of multiple oncogenes. Knockdown of the DNA demethylation-promoting gene, Tet1, attenuated HCC formation in these mice. Single-cell spatial transcriptomics identified a Tet1-high subpopulation of HCC cells that interacted with other hepatic cell types.

Our mechanistic mouse data align with the observation that YAP1-TEAD-TET1-associated signatures were also elevated in hepatocytes from patients with Fontan-associated liver disease (FALD), a condition associated with the development of HCCs with lower frequencies of canonical DGMs. Our study suggests that the YAP1-TEAD-TET1 axis promotes canonical DGM-negative HCC development, and provides new insights into the molecular processes involved.

Link: https://doi.org/10.1038/s42003-026-10882-w

Stem cell therapies involve a stage of expansion of cells in culture prior to injecting them into the patient. The research community has realized that both the state of the original source cells and small variations in the subsequent cell culture environment can result in large differences in the quality of the transplanted cells. For example, how many of the cells in the culture have become senescent, and are thus now generating pro-inflammatory signals. There are other possible variations in cell state that could contribute negatively to outcomes, diminishing any benefits resulting from the therapy, however. Differences in cell state and behavior may be the cause of much of the well-known and undesirable variability of outcomes in stem cell therapy.

Some clinics may have started to at least attempt to use senolytic treatments to reduce the number of senescent cells in stem cell cultures, but this is by no means yet a standard. Today's open access paper discusses this issue, expanding the consideration from senescent cells to other problematic changes in cell state that may negatively impact outcomes for patients. They present this as a quality issue, discoveries to be added to the consensus on what constitutes Good Manufacturing Practice (GMP) for stem cell therapies provided within more regulated regions of the world. Medical tourism of course remains a black box in this as in many other matters.

Proteotoxic stress in stem cell therapies: The overlooked roles of senescence, EV cargo, and SOD1

The rapid clinical expansion of therapies based on stem cells and cell-free extracellular vesicles (EVs) has outpaced the development of rigorous quality control standards. Current Good Manufacturing Practice (GMP) standards evaluate identity, viability, sterility, and genetic stability, but do not routinely assess protein homeostasis in donor cells. Cellular senescence, which frequently emerges during ex vivo expansion, impairs protein quality control and yields an EV secretome enriched with proteotoxic cargo. In neural stem cells (NSCs), oxidized superoxide dismutase 1 (SOD1) accumulates during senescence and is packaged into EVs that propagate neuronal toxicity and secondary senescence in recipient cells.

While established primarily in NSCs, analogous proteostatic decline across other stem cell types warrants targeted validation in mesenchymal stromal cell (MSC) and induced pluripotent stem cell (iPSC)-derived products. Donor cell proteostatic fitness is a plausible determinant of therapeutic outcome. Evaluating senescence burden and EV proteomic integrity should therefore become a standard critical quality attribute within cell and EV manufacturing pipelines. Practical steps toward this goal include the careful selection of cell sources, the establishment of quantitative senescence thresholds, and proteomic profiling of EV cargo. Targeted cargo sanitization strategies, such as selective clearance of misfolded SOD1, shows promise for pre-transplant conditioning, although clinical feasibility, scalability, and off-target effects require further study.

Peripheral nerves are capable of regeneration to restore connections across gaps caused by injury, but the larger the gap the less likelihood of a successful outcome. The medical community has developed approaches that help by laying guides along the path that regrowth must take, often composed of donor nerve tissue, which may be taken from elsewhere in the patient, but these are far from optimal. There is considerable research interest in the development of entirely artificial nerve regrowth guides that have a low cost and high rate of success in stimulating the necessary regeneration for a complete restoration of function. The paper here is an example of this sort of research and development, focused on bioprinting an implantable path for nerve regrowth.

Conventional cell-laden electro-direct writing (CEDW) technology faces challenges in terms of balancing printability, mechanical integrity, and biocompatibility. As a result, its application in neural tissue engineering remains limited. To overcome this challenge, this study develops a temperature-regulated cell-laden electro-direct writing (TCEDW) technology that achieves stage-specific rheological modulation through precise cylinder temperature control, thereby decoupling printability from biocompatibility and enabling high-resolution (36.05 µm) cell printing.

Using Schwann cell-laden alginate/gelatin methacryloyl/polyethylene oxide (alginate/GelMA/PEO) bioinks, TCEDW constructs were fabricated with both improved structural fidelity and preserved cell viability. In vitro co-culture of Schwann cells and PC12 cells demonstrated that TCEDW microfilaments significantly promoted neurite alignment and maturation by providing synergistic topographical and biochemical cues.

Gene expression analysis revealed that TCEDW scaffolds activated axon guidance and cGMP-PKG signaling pathways while suppressing proliferation programs to promote PC12 neuronal differentiation. Furthermore, a hybrid electro-assisted bioprinting approach integrating melt electro-writing, electro-spinning, and TCEDW was employed to fabricate three-layer composite nerve guidance conduits (NGCs). In vivo investigations demonstrated that the composite NGC platform promoted nerve fiber regrowth, Schwann cell migration, myelination, and functional recovery.

Link: https://doi.org/10.1088/2631-7990/aea8a3

Many forms of cell stress provoke much the same response of increased maintenance and damage repair activities, such as increased autophagy. A mild level or intermittent stress can result in overall benefit to cell and tissue function, and when applied over time to an organism this can modestly slow aging. How the cell regulates this response to stress and the fine details of the response to stress vary between different forms of stress, however. Thus developing a therapy to mimic, for example, the response to the low nutrient stress of calorie restriction, may be quite a different exercise to mimicking the response to cold, or heat, or toxin exposure. For illustration, researchers here dig into some of the regulatory mechanisms involved in the beneficial response to cold stress in nematode worms, and one can see the differences from what is known of calorie restriction in the same species.

Moderately cold temperatures extend lifespan and promote health across species, yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4).

BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures.

In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.

Link: https://doi.org/10.1038/s41586-026-11152-9

One of the many factors impeding the pace of research into age-related neurodegeneration is that it is relatively challenging to obtain human brain tissue from any sizable living population for study. Post-mortem tissue is more accessible, albeit burdened by the usual regulation, but this represents only a slice of the population, largely those with the most advanced burden of damage and dysfunction. By necessity, researchers wanting to investigate earlier stages of degeneration, or healthy brains, are steered towards patients who must undergo forms of brain surgery, and there are always questions as to the degree to which those patients are reflective of the broader population.

In today's open access paper, researchers work with brain tissue derived from epilepsy patients who underwent brain surgery in an attempt to reduce the severity of their condition. Their argument is that this population can provide insight into features of cognitive aging, even though that cognitive aging is accelerated in epileptic patients versus non-epileptic individuals. The study is of interest for the reported correlation between a population of supporting cells in the brain and the severity of cognitive decline. The paper has little to say about the exact mechanisms involved: that is for others to follow up on given the direction provided here.

An age-related decline in human fluid intelligence corresponds with immature astroglia prevalence

Therapeutic development for cognitive decline has been steered by the interpretation that it predominantly results from compromised neuronal function, yet neuron-focused strategies have so far yielded only modest benefits. With the advent of cell type-directed combination therapies targeting both neurons and glia identifying specific cellular drivers of discrete cognitive deficits can guide the design of more effective treatment strategies. Rodent studies have recognized that astroglial cells, traditionally viewed as mere supportive cells to neurons, are active regulators of learning and memory. Meanwhile, various studies indicate that dysfunctional astrocytes contribute to the decline of rodent cognitive functions.

Cognitive decline is a comorbidity that occurs progressively in epilepsy patients. People with epilepsy demonstrate accelerated brain aging and cognitive decline is especially pronounced in older individuals. Mesial Temporal Lobe Epilepsy (MTLE) is the most common form of adult epilepsy, and patients who do not respond to medications undergo surgical removal of epileptic hippocampal tissue as treatment. Since these patients have detailed presurgical cognitive assessment, this platform provides a unique ante-mortem window into understanding the altered cellular features that are associated with human cognitive decline.

Our previous research in MTLE patients revealed the persistent presence of a pathological Dcx+ immature astroglial cell in the epileptic hippocampus that was undetectable in control postmortem tissue. The number of Dcx+ immature astroglial cells in MTLE hippocampus trended toward an increase with age; however, the significance of this phenotype and its association with cognitive decline was not investigated. In this study, we first identified cognitive functions that strongly undergo an age-associated decline in epilepsy patients. We then assessed the significance of an age-associated increase in Dcx+ immature astroglia and how it is associated with various cognitive functions. Our study identified an association between aging, a decline in fluid intelligence and an increase of immature astroglia in epilepsy patients. These findings highlight immature astroglia as an epilepsy-associated cellular feature corresponding to age-related cognitive decline and provides a basis for future mechanistic and translational studies.

Researchers are engaged in finding alternative ways to induce the desirable epigenetic rejuvenation produced by exposing cells to the Yamanaka factors, without the risk of losing cell state to dedifferentiation and the creation of induced pluripotent stem cells that could give rise to tumors. Yamanaka factors are a challenging basis for many forms of therapy because it would be somewhere between difficult and impossible to reconcile the different requirements for dose and timing for different cell populations in a tissue. Here, screening leads researchers to a splicing factor that is capable of producing some degree of epigenetic rejuvenation in cells and extended healthy life in mice. Splicing factors are of interest because each influences the expression of many different genes, potentially thousands of genes, and thus represent centralized points of control over cell state and behavior. This result will likely encourage a range of existing programs aimed at better understanding what can be achieved by manipulation of splicing factor activity.

The therapeutic use of Yamanaka factors is causing concern for some researchers because their overexpression also raises the risk of cancer formation. Researchers have therefore been hunting other factors for rejuvenating aging tissues in safer and more controllable ways. However, "in reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line."

In this study, researchers designed a machine learning algorithm trained on gene expression (transcriptomic) profiles across multiple aging processes in human skin fibroblast cells spanning a wide age range. This predictor accurately pinpointed the "transcriptomic age" of skin cells obtained from several donors. Leveraging this age predictor as a scorable readout then enabled the team to screen a focused collection of genes that were predicted to affect aging processes in one way or another. The goal was to identify candidates that, when over-expressed, could shift the originally assigned aging score of old fibroblast cell lines to a more youthful score.

The top-scoring gene, encoding an RNA processing factor known as SRSF1, was indeed able to reduce features that corresponded to several hallmarks of aging, such as a biological process where damaged cells stop dividing but do not die (cellular senescence), disruptions in the normal balance and turnover of proteins (proteostatic stress), and chronic low-grade inflammation (also dubbed "inflammaging"). Importantly, the rejuvenated fibroblasts maintained their identity: they kept their specific spindle-shaped morphology, continued the expression of genes that encode typical fibroblast functions and didn't induce the pluripotency programs that Yamanaka factors turn on. Importantly, when delivered to aged mice, where it primarily accumulated in the liver, SRSF1 reduced the animals' rate of aging and extended their lifespan by 14%, highlighting SRSF1 as a "geroprotective" target.

Link: https://wyss.harvard.edu/news/reversing-age-by-reprogramming-gene-expression-networks/

Extracellular vesicles secreted by cells are divided into types by size, in the absence of greater knowledge that would allow functional classification. Exosomes are one of these size classes, and a popular choice as a basis for therapies intended to replace the transplantation of stem cells. Stem cell therapies produce benefits via the signaling generated by transplanted cells, a sizeable fraction of that signaling is carried in extracellular vesicles, and it is logistically much easier to harvest, store, and use exosomes than it is to use cells in therapy. As researchers here note, exosomes are not universally beneficial. Like all cell communications, context matters, and stem cell derived exosomes can produce potential harms, such as promotion of cancerous growth or undesirable immunomodulation that dampens the response to infection.

Exosomes are nanosized extracellular vesicles (30-150 nm) with a bilayer lipid membrane that encapsulates proteins, lipids, and nucleic acids, first identified in the 1960s and expanded in application from disease diagnostics to targeted therapeutics. They are intercellular communicators with roles in physiological regulation and pathological progression, which have a large applications in gene therapy, drug delivery, tissue regeneration, and disease diagnostics. Their unique biological properties have attracted considerable attention for applications in regenerative medicine, targeted drug delivery, gene therapy, and disease diagnosis.

This review highlights the dual biological nature of exosomes by discussing their beneficial 'Elixir' and detrimental 'Trojan Horse' functions. Exosomes activate signaling pathways such as Wnt/β-catenin and PI3K/Akt, deliver anti-aging molecules, and promote angiogenesis, owing to their properties such as biocompatibility, ability to cross the blood-brain barrier, and use as vectors for selective cargo delivery. Conversely, the same mechanisms that promote regeneration can also lead to undesired outcomes like tumor progression, drug resistance, immune responses suppression, and pathogenic factors spread underscore their "Trojan horse" potential. The exosome's dual nature can presents challenges.

Link: https://doi.org/10.1016/j.biopha.2026.119957

The gut microbiome is made up of thousands of distinct microbial species, interacting with one another to process food and generate a broad range of metabolite molecules that are varying degrees of necessary, helpful, and harmful to the tissues of the body. The balance of these microbial populations changes with age in detrimental ways; microbes that provoke chronic inflammation grow in number at the expense of microbes that manufacture beneficial metabolites. In recent years, researchers have mapped the microbiome in human populations, finding correlations with age-related diseases and specific microbial metabolites that contribute to specific forms of age-related dysfunction. We might expect near every common age-related disease to have many different meaningful connections to aspects of the composition of the gut microbiome and how that composition changes with age.

In today's open access paper, researchers discuss what is known of the ways in which the aging of the gut microbiome contributes to the characteristic age-related loss of bone mineral density, leading to osteoporosis. The extracellular matrix of bone is continually remodeled throughout life, created by osteoblast cells and broken down by osteoclast cells. The proximate cause of osteoporosis is a growing imbalance between these two cell populations that favors osteoclasts. Why this imbalance happens, which of the many known contributing mechanisms are more versus less important than the others, and whether all of the important mechanisms are in fact known, is a topic of ongoing debate and research. Here, researchers focus on inflammatory effects resulting from the influence of the aging gut microbiome upon the immune system, which in turn disrupts the balance to favor destruction of bone extracellular matrix.

Research progress on the mechanisms by which gut microbiota dysbiosis remodels the bone marrow neuroimmune microenvironment to drive age-related osteoporosis

Age-related osteoporosis has traditionally been attributed to impaired bone formation, excessive bone resorption, senescence of bone marrow mesenchymal stem/stromal cells (BMSCs), and deterioration of the bone marrow microenvironment. However, these local alterations do not fully explain the progressive, systemic, and heterogeneous nature of age-related bone loss. The bone marrow is not only a site of bone remodeling but also a critical niche for hematopoietic stem cell maintenance and for the generation, differentiation, and functional regulation of immune cells. Aging is accompanied by profound remodeling of the immune system. T cells, B cells, macrophages, and dendritic cells undergo age-related changes in phenotype and function. Together, immunosenescence and inflammaging disrupt the RANKL/OPG axis, increase exposure to pro-inflammatory cytokines, and enhance osteoclastogenic signaling. Consequently, bone homeostasis gradually shifts from protective immunoregulation toward a resorption-dominant state.

Gut microbiota dysbiosis has recently emerged as an important upstream regulator of bone homeostasis. During aging, alterations in microbial composition and metabolism, together with impaired intestinal barrier integrity, may promote the systemic dissemination of gut-derived inflammatory signals. These signals may reach the bone marrow and contribute to remodeling of its immune microenvironment. In addition, gut microbiota and their metabolites may influence autonomic nervous system activity through vagal and sympathetic pathways. Through these routes, intestinal signals may modulate the activation state of bone marrow immune cells and the immune networks that regulate bone remodeling. Although gut microbiota dysbiosis, inflammaging, and neural regulation have each been implicated in disordered bone metabolism, their interactions in age-related osteoporosis remain incompletely understood. In particular, the mechanistic links among gut microbiota dysbiosis, neuroimmune dysregulation, remodeling of the bone marrow immune microenvironment, and impaired bone remodeling have not been systematically clarified.

Therefore, this review summarizes the pathological basis of age-related osteoporosis, focusing on how aging-associated gut microbiota dysbiosis, intestinal barrier dysfunction, and gut-derived inflammatory signals reshape the bone marrow immune microenvironment. We also discuss the potential roles of impaired vagal anti-inflammatory signaling and abnormal sympathetic outflow in promoting osteoimmune imbalance within the bone marrow. By positioning the bone marrow neuroimmune microenvironment as a key intersection between gut-derived signals, neural regulation, and osteoimmune remodeling, this review provides an immunological framework for understanding disease mechanisms and for developing risk-stratification strategies and precision interventions in age-related osteoporosis.

Senescent cells accumulate with age to drive the onset and progression of age-related disease and loss of function. Over the past decade, a broad range of research and development efforts have emerged to attempt to address this cause of aging. Senostatic therapies reduce the pace at which senescent cells are created. Senolytic therapies selectively destroy senescent cells. Senomorphic therapies suppress aspects of the harmful behavior of senescent cells, principally the pro-inflammatory signaling that contributes to the chronic inflammation of aging and is disruptive to tissue structure and function. Researchers here describe the discovery of a senomorphic microRNA in the context of an attempt to reduce the burden of senescent cells generated by cancer therapy. Many forms of cancer treatment leave the patient with increased numbers of senescent cells, and this greater burden of dysfunction is thought to be an important contributing cause of increased mortality and disease risk in cancer survivors.

Senomorphic microRNAs (miRNAs) are a class of small regulatory RNAs that selectively suppress the senescence-associated secretory phenotype (SASP) without eliminating senescent cells, thereby offering a targeted approach to counteract the pro-tumorigenic consequences of therapy-induced senescence (TIS). Despite their therapeutic potential, senomorphic miRNAs in luminal breast cancer remain poorly characterized. Here, we performed small RNA sequencing to profile miRNA expression changes in a doxorubicin-induced TIS model using the luminal breast cancer line MCF7. We identified miR-3155b as a previously uncharacterized miRNA significantly downregulated during TIS.

Functional studies revealed that miR-3155b overexpression suppressed the mRNA and protein levels of multiple SASP factors, including IL6, IL8 (CXCL8), MMP13, TNF, IL1B, and IFNB1, whereas its knockdown enhanced their expression. Critically, these effects occurred without affecting core senescence phenotypes such as proliferation arrest, SA-β-gal activity, or DNA damage foci formation. This senomorphic function was further confirmed in an ionizing radiation (IR)-induced TIS model and in T47D luminal breast cancer cells. miR-3155b was confirmed to target the CXCL8 mRNA by luciferase reporter assays, and RNA pull-down assays indicated that miR-3155b physically associates with IFNB1, IL6, TNF, and MMP13 mRNAs.

Collectively, our findings identify miR-3155b as a senomorphic miRNA in Luminal A breast cancer TIS and provide a potential target for optimizing chemoradiotherapy strategies aimed at mitigating SASP-driven adverse effects.

Link: https://doi.org/10.3389/fcell.2026.1868137

Researchers here relate an interesting story: they designed and synthesized a small peptide that is intended to interfere with an interaction between amyloid-β and zinc ions, with the aim of suppressing a necessary part of the process of amyloid-β aggregation. This amyloid-β aggregation, proceeding slowly over years, is thought to be the causative mechanism in Alzheimer's disease. The researchers then discovered that this peptide already exists in the body, and is in fact reduced in level in Alzheimer's patients.

A hallmark of Alzheimer's disease (AD) is extra-neuronal protein aggregates formed mainly by the amyloid-β peptide (Aβ), that are deposited inside the brain as amyloid plaques. The formation of amyloid plaques requires participation of zinc ions. The 11-Glu-Val-His-His-14 region of Aβ is critical for interaction between Aβ and zinc ions. The engineered peptide Ac-His-Ala-Glu-Glu-NH2 (HAEE) acts as competitive inhibitor of such interactions and suppresses formation of Aβ aggregates in animal models of AD.

We sought to develop a reliable method for studying the behavior of the synthetic HAEE peptide in the human blood in preparation for clinical trials of this peptide as a potential anti-amyloid drug for AD. The analytical method to monitor HAEE concentration in blood plasma combines separation by high-performance liquid chromatography and registration on a mass detector of the parent quasi-molecular ion and fragment ions. We discover that HAEE peptide represents a normal endogenous component of human blood plasma. Moreover, the HAEE level has been significantly reduced in patients with a clinical diagnosis of AD (n = 200) as compared with the control participants with no clinical diagnosis of cognitive impairment (n = 150). Deficiency of endogenous HAEE may be considered as a potential blood-based biomarker in the diagnosis of AD, while exogenous synthetic HAEE may serve as a drug in AD-modifying therapy.

Link: https://doi.org/10.1093/pnasnexus/pgag320

Microglia are innate immune cells of the brain, similar in behavior to tissue resident macrophages elsewhere in the body, but with an additional portfolio of duties relating to maintenance of neural networks. Like macrophages, microglia can adopt packages of behavior, and switch between them depending on environment cues; pro-inflammatory M1 focused on defense against pathogens versus anti-inflammatory M2 focused on tissue maintenance, for example. With age, the microglial population becomes more inflammatory, contributing to chronic inflammation of brain tissue and consequent disruption of normal function that contributes to the onset and progression of neurodegenerative conditions. Some of this inflammatory behavior is a consequence of an increased burden of cellular senescence in microglia and other supporting cells of the brain, but not all of it. Regardless, microglial dysfunction is a topic of increasing interest for researchers aiming to produce novel therapies to address the aging of the brain.

An active area of exploration is the contribution of lipid metabolism dysfunction to the inflammatory behavior of microglia in the aging brain. Of particular interest is the point that variants of APOE are well demonstrated to alter the risk of Alzheimer's disease, this protein is deeply involved in lipid metabolism, and evidence suggests it contributes to microglial inflammation. A further point is that excess cholesterol in cells can cause mitochondrial dysfunction, and the aging brain (and particularly in neurodegenerative conditions) exhibits both of these features. Finding specific dysfunctions in lipid metabolism and then attempting to address them with novel therapies seems a promising area of exploration in neurodegenerative research. Today's open access paper discusses evidence for the involvement of lysosomal aging in dysfunctional lipid metabolism in microglia, another possible starting point for a search for novel treatments.

Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?

The metabolism of lipids is emerging as an essential regulator of microglial homeostatic activity and the ability to adapt their functional state to environmental changes across the lifespan. Microglial lipids serve structural roles in membrane maintenance and remodeling and act as signaling mediators in key regulatory pathways, including energy production and inflammatory mediator release. Beyond their intrinsic lipid needs, microglia phagocytose lipid-rich substrates (i.e., myelin fragments, cell debris, and synaptic elements) and generate intracellular lipid cargo through housekeeping autophagic processes. Intracellular lipid droplets (LD), which store excess lipids, are emerging as essential regulators of microglial metabolic programming and functional capacity. To maintain lipid balance and prevent lipotoxicity, microglia possess a complex feedback-regulated system for lipid uptake, processing, recycling, storage and export of excess lipids. Lysosomes, the cellular degradative and signaling hubs, lie at the center of these key lipid-handling pathways, both organizing lipid turnover and being modulated by the lipid status. This bi-directional interplay underlying microglial metabolic programming is coordinated by a variety of lipid- and nutrient-sensing molecular players, notably involving mechanistic target of rapamycin complex 1 (mTORC1) or triggering receptor expressed on myeloid cells 2 (TREM2).

Aging drives maladaptive microglial functions contributing to inflammation and neurotoxicity in age-associated disorders. Dysfunctional lipid handling and lysosomal processing have been connected to this detrimental polarization, highlighting the relevance of this pathway for therapeutic targeting. While significant advances have been made in the study of microglial lipid metabolism in contexts of aging-related diseases, our understanding of its changes over the course of physiological aging remains lacking, which creates a critical knowledge gap. Several single-cell analyses further indicate that microglial aging occurs in a central nervous system region-dependent manner, raising fundamental questions: (1) is this regional heterogeneity associated with distinct microglial lipid signatures and/or lysosomal capacities; (2) do these putative baseline differences play a role in susceptibility to and extent of aging-related microglial dysfunction; and (3) is microglial lipid shift inherent and/or driven by environmental challenges? On a broader level, how these metabolic and functional aging microglial changes are translated into higher cognitive processes, and what role they play in their aging-associated decline and disease susceptibility, represents a crucial area for investigation.

Despite the only small benefits shown to Alzheimer's patients following clearance of amyloid-β aggregates in the aging brain, the consensus remains that a slow accumulation of amyloid-β aggregates over years is the inciting form of dysfunction that gives rise to the later tau aggregation, neuroinflammation, and cell death in Alzheimer's disease. Removal of amyloid-β may be preventative in the earliest stages of the condition, but this is a hypothesis still undergoing assessment. Amyloid-β in the brain has been shown to be in dynamic equilibrium with amyloid-β outside the brain, and this has led to clinical trials in which amyloid-β is removed from blood, causing a greater amount of amyloid-β to exit the brain. Here, researchers discuss this holistic view of amyloid-β distribution throughout body and brain, and whether current efforts are too focused on only the burden of amyloid-β aggregates in the brain.

Alzheimer's disease (AD) represents one of the most prevalent neurodegenerative disorders without approved disease-modifying therapies. A major contributing factor is that, for decades, drug development has focused almost exclusively on repairing or removing lesions within the brain itself. Yet a growing body of work now points to AD as a systemic disorder, rooted in a breakdown of whole-body Aβ homeostasis. Nevertheless cerebral Aβ transport and peripheral Aβ clearance are commonly investigated as independent processes, and the coordinated interplay remains insufficiently characterized. This review bridges the current research gap by systematically elaborating the full trafficking cascade of brain-derived Aβ from intracerebral drainage to peripheral elimination.

Four major intracranial clearance pathways are comprehensively summarized, including the blood-brain barrier, blood-cerebrospinal fluid barrier, arachnoid granulation venous outflow, and meningeal lymphatic/glymphatic system. The peripheral clearance processes of circulating Aβ in the blood, liver, kidney, and gastrointestinal tract are further illustrated. A broad spectrum of emerging therapeutic strategies targeting Aβ transport and clearance is also reviewed, including specific pathway modulators, microglia regulators, Aβ aggregation inhibitors, natural multi-target compounds, ultrasound-mediated blood-brain barrier opening, and exosome-based intervention approaches.

When we compare the relative contributions of central versus peripheral clearance, comparative analysis of central and peripheral Aβ clearance indicates that the liver appears to dominate the peripheral elimination of Aβ, yet the real driver of cerebral Aβ deposition is not the failure of any single route, but rather the loss of synergy among multiple pathways. This mechanistic framework explains why purely brain-centric therapeutics are unlikely to correct a systemic Aβ imbalance. Instead, future translational efforts should give higher priority to combination regimens that simultaneously facilitate intracerebral drainage and bolster peripheral organ clearance. This review further discusses current hurdles and emerging opportunities in systemic AD drug discovery, with the aim of offering a unified conceptual framework-one that providing a unified conceptual framework for understanding AD pathogenesis and facilitating the exploration of novel therapeutic paradigms.

Link: https://doi.org/10.3389/fragi.2026.1921485

Recovery and transplantation of organs following vitrification using cryoprotectant is an important step along the road to the future technological capability of whole body vitrification and recovery - and recovery of those individuals already preserved at low temperature by the cryonics industry. It is particularly important because it is a highly desirable capability for the organ transplant industry, and thus a way to bring significant funding and credibility to the endeavor of cryonics, the preservation of people for future revival. Scaling up vitrification and rewarming to human sized organs has been a major challenge on several fronts, such as effective perfusion of cryoprotectant in large tissues, performance of the cryoprotectant, consistent warming of deeper tissue in a large vitrified mass, and so forth. It is much easier to vitrify and reward small tissue samples than large ones. Here researchers report success in pig kidneys, albeit using an approach to rewarming that requires preparation of the organs prior to vitrification, and thus cannot be applied to tissues and people preserved prior to its introduction. Nonetheless, it is an important step forward.

Vitrification and nanowarming have enabled long-term preservation and transplantation of rodent kidneys but have not been demonstrated at the scale of clinically relevant organs. Here we show that vitrification and electromagnetic nanowarming enable long-term cryogenic storage and functional recovery of human-scale porcine kidneys. Kidneys 100-fold larger than previously nanowarmed kidneys were successfully recovered after storage at -150 °C for up to one year. A new cryoprotectant formulation and multithermic perfusion strategy enabled ice-free vitrification at cooling rates achievable in large kidneys, while controlled cooling with annealing and staged volumetric nanowarming limited thermal stress and enabled rapid rewarming without cracking.

Nanowarming was developed to overcome the limitations of surface-based rewarming. Silica-coated iron oxide nanoparticles distributed through the vasculature before vitrification generate heat when exposed to an alternating electromagnetic field, enabling rapid volumetric rewarming throughout the organ.

Rewarmed kidneys demonstrated vascular, metabolic, and excretory function during normothermic perfusion, with limited histological injury, and reperfused homogeneously and produced urine immediately after transplantation. Functional recovery approached static cold storage outcomes across several measures and was similar to that of kidneys exposed to cryoprotectant alone, suggesting minimal additional functional injury from vitrification, cryogenic storage, and nanowarming. These findings overcome major scale and storage-duration barriers to organ cryopreservation and establish a path toward organ banking on timescales far beyond those of conventional preservation.

Link: https://doi.org/10.64898/2026.10.07.756990

The vascular system is prone to calcification with advancing age. Cells in the vasculature inappropriately take on the features and behavior of the osteoblast cells responsible for building bone extracellular matrix. These errant vascular cells deposit calcium phosphate structures into vascular tissue, stiffening it. Calcification proceeds in parallel with atherosclerosis, the thickening of artery walls and generation of fatty plaques that obstruct vessels and ultimately rupture to cause a heart attack or stroke, but is an independent process that would cause dysfunction and mortality even if the causative mechanisms of atherosclerosis were eliminated.

Stiffening of vascular walls, however it occurs, whether by this process, other forms of damage and change in the extracellular matrix, or loss of responsiveness to cues for contraction and dilation in vascular smooth muscle, induces hypertension, among other issues. Perhaps more importantly, calcification of structures in the heart, such as the aortic valves, is ultimately fatal.

Present therapeutic options for calcification are limited. For example, a form of chelation using EDTA has been assessed in clinical trials, is readily available in clinics, but produces only modest benefits at best. Thus it is interesting to keep an eye on developments in this space. Today's open access paper describes a micropeptide therapy that can inhibit calcification processes, slowing vascular calcification meaningful in animal models. Slowing is a start, but effective reversal of age-related tissue calcification remains a unfulfilled goal.

PKM2 AP: a micropeptide inhibits vascular calcification via molecular glue-mediated ubiquitination of PKM2

Vascular calcification (VC) is not merely a passive mineralization process, rather, it is an active pathological event that is propelled by the osteogenic phenotypic transition of vascular smooth muscle cells (VSMCs). This transition is characterized by aberrant deposition of hydroxyapatite crystals within the vascular wall, leading to loss of vascular elasticity and increased risk of cardiovascular events. Despite advancements in clinical management strategies for VC, such as intensified dialysis regimens and phosphate binder therapies, current treatments remain insufficient to halt calcification progression, resulting in limited long-term prognostic improvement.

VSMCs undergo phenotypic switching from contractile to synthetic or inflammatory states under pathological stimulation, a critical initiating event in VC. Notably, this phenotypic transition is accompanied by marked metabolic reprogramming, characterized by a shift from oxidative phosphorylation to aerobic glycolysis, leading to lactate accumulation. Emerging evidence suggests that lactate not only induces synthetic phenotypic switching in VSMCs but also promotes vascular calcification through dual mechanisms: activating NR4A1-mediated mitochondrial fission and BNIP3-dependent mitophagy. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, catalyzes the irreversible conversion of phosphoenolpyruvate to pyruvate, directly regulating lactate biosynthesis. Strikingly, recent studies demonstrate that PKM2 inhibition preserves VSMC contractile phenotype and improves vascular homeostasis, suggesting its pivotal role in calcification-associated metabolic regulation.

In this study, we identified a 40-amino acid micropeptide, termed PKM2-associated micropeptide (PKM2 AP), which was highly expressed in patients with chronic kidney disease-related vascular calcification. PKM2 AP localized to both mitochondrial and cytoplasmic compartments and exhibited functional interactions with PKM2. Functional experiments demonstrated that overexpression of PKM2 AP both in vitro and in vivo attenuated the progression of vascular calcification. Mechanistically, PKM2 AP functioned as a molecular glue-like factor that facilitated the recruitment of the E3 ubiquitin ligase STUB1 to PKM2, thereby promoting PKM2 ubiquitination and degradation, ultimately suppressing aerobic glycolysis and lactate production in human aortic vascular smooth muscle cells (HAVSMCs). In vivo administration of PKM2 AP alleviates vascular calcification phenotypes in mouse models.

Researchers here identify the gene PLA2G2F as a regulator of compensatory responses to some of the damage and dysfunction of aging. The researchers were primarily investigating a population of neurons found in the hippocampus, involved in memory function, but find that the gene is relevant in supporting cells of the brain also, such as microglia. Expression of PLA2G2F increases with age, and artificially increasing expression over natural levels produces greater protection. PLA2G2F appears to be involved in maintenance of normal lipid metabolism. Evidence suggests that dysfunctions in lipid metabolism occur in the aging brain, and cause harm via provoking greater inflammatory behavior in a number of supporting cell populations.

Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation, and hippocampal-dependent memory loss.

Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory, and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.

Link: https://doi.org/10.1038/s41593-026-02465-z

Of the common variants of the APOE gene, APOEε4 presents the greatest risk of Alzheimer's disease. APOE is involved in lipid metabolism, and APOEε4 is associated with lipid-related contributions to inflammation in microglia, suggesting a primarily inflammatory mechanism for the increased risk of neurodegeneration. Here, researchers find that APOEε4 also interferes in the ability of oligodendrocyte cells to maintain the myelin structures that sheath the axons that connect neurons into neural networks, again via lipid-related mechanisms. This myelin sheathing is required for effective communication between neurons. Myelin maintenance does falter to some degree in normal aging, and the consequent loss of myelin is thought to contribute to dysfunction in the aging brain. It is reasonable to hypothesize that greater myelin loss driven by APOEε4 is a factor in accelerated neurodegeneration.

A new study shows that APOE4 leads to a suppression of Wnt signaling in the oligodendrocyte cells that provide neurons with a fatty insulation, called myelin. When Wnt signaling is deficient, the cells accumulate droplets of lipids rather than deploying fats to properly myelinate the neurons' axon branches. When the researchers restored Wnt signaling in APOE4-carrying oligodendrocytes, myelination rebounded, both in human cell cultures and in mice modeling Alzheimer's.

Researchers discovered Wnt's key role via multiple methods including a screen in which they used CRISPR gene editing to systematically knock out each protein-coding gene in the genome, one by one, in cultures of human APOE4-carrying oligodendrocytes. The screen showed that when genes promoting Wnt activity in oligodendrocytes were lacking, lipid droplets accumulated, and that when genes suppressing Wnt were lacking, lipid droplets were, too. Further analysis revealed how Wnt signaling became depressed in cultured APOE4 oligodendrocytes. Two proteins, beta-catenin and GSK3b, each compete to regulate Wnt-beta-catenin promotes it and GSK3b suppresses it. The team found that in APOE4 oligodendrocytes compared to APOE3 ones, there was reduced beta-catenin expression and excessive GSK3b expression.

The team then tested interventions that manipulate GSK3b activity. In human APOE3 oligodendrocyte cultures, they showed that increasing GSK3b with a chemical called Dif3 increased lipid droplets. In APOE4 oligodendrocytes, they showed that inhibiting GSK3b with a chemical called CHIR99021 reduced droplets. In more complex "organoid" cultures combining APOE4 oligodendrocytes with neurons, they found that inhibiting GSK3b increased myelination and promoted the growth of neural axons. The tests suggested that GSK3b inhibition could be a proof-of-concept therapeutic strategy for restoring Wnt signaling and myelination.

Link: https://picower.mit.edu/news/how-biggest-alzheimers-risk-gene-disrupts-process-insulating-neurons

Mitochondria are the power plants of the cell, creating the chemical energy store molecule adenosine triphosphate used to power cellular processes. Mitochondrial function declines with age, and the research community is engaged in a variety of approaches that might at least modestly reduce this loss. The supplement urolithin A is known to improve mitochondrial function, though, and as is the case for other approaches, how exactly urolithin A accomplishes this outcome is not fully understood. Most of the ways to modestly improve mitochondrial function, ranging from exercise and calorie restriction through to NAD+ upregulation via vitamin B3 derivatives and MitoQ, may primarily function through improvements to autophagy targeted at mitochondria, improving overall mitochondrial function via improved clearance of damaged and dysfunctional mitochondria. This is by no means a definitive answer, but the supporting evidence is suggestive.

In today's open access paper, researchers show that topical application of urolithin A improves the function of aged skin. It is interesting to compare this with a small study of topical application of low dose rapamycin, another approach to improve autophagy. Increased autophagy (and accompanied improvement in mitochondrial function) has in the past been shown to reduce the pace at which cells become senescent in aged tissues. This allows the immune system to catch up in its task of clearing senescent cells, and thus reduce the harmful burden of senescent cells that contributes to dysfunction in aged tissues. Cellular senescence is known to be important in the aging of skin, and increased autophagy over time is an approach to reducing this contribution to degenerative aging.

Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity

The most common visual signs of aging skin are the appearance of wrinkles, skin thinning, hyperpigmentation, sagginess, and dryness. This derives from a combination of biological changes, including a decline in the quantity and quality of structural components of the skin, such as collagen and elastin, as well as dysfunctions in cellular bioenergetics. Indeed, most of the energy to support skin cell health is derived from mitochondria, making mitochondrial dysfunction a key hallmark of skin aging. The aging process impacts immune cells in the skin. This reduces the ability of the skin to cope with excessive inflammation and significantly contributes to the emergence of photoaging. Finally, cellular senescence is emerging as a key additional hallmark that affects skin health as we age, which can be counteracted by removal of the senescent cells (i.e., senolytic effect) or blunting of their detrimental secretome (i.e., senomorphic effect).

Urolithin A (UA) is a promising molecule to explore for its impact on skin longevity, considering its origins as a postbiotic of the gut microbiome that has been shown to both improve mitochondrial health and reduce age-associated inflammation, i.e., inflammaging, when administered orally. UA increases mitophagy, the process of recycling faulty mitochondria, and enhances biomarkers associated with improved mitochondrial function in several models of aging and age-associated conditions. In humans, oral supplementation of UA was shown to be safe, improve mitochondrial function, and increase muscle strength, endurance, and immune decline in clinical studies in middle-aged and elderly subjects. Topical application of UA represents a compelling approach to support skin health and extend skin longevity through its combined effect on multiple hallmarks of cellular aging.

UA was evaluated for its effects on skin health in human skin models and when applied topically to healthy subjects in randomized clinical studies. UA tested in 2D and 3D reconstructed human skin and ex vivo human skin explants showed enhanced mitochondrial respiration, activated mitophagy markers, reduced inflammatory mediators and senescence-associated markers, and increased proteins involved in extracellular matrix structure and epidermal differentiation. In randomized, placebo-controlled clinical studies, UA reduced periorbital wrinkle depth after 8 weeks and attenuated UVB-induced erythema. Skin transcriptomics supported increased extracellular matrix and epidermal development programs together with decreased inflammatory and senescence-associated signaling.

Why, mechanistically, is female reproductive aging so accelerated in relation to the rest of the aging process? Researchers here point to a role for a progressive loss of ribosomes in oocytes. Cells contain many ribosomes, vital components of the cell where messenger RNA is translated into protein, and usually synthesize more as needed. Oocytes do not tend to synthesize new ribosomes, however, one of many differences in behavior intended to retain a much higher standard of cell quality during the reproductive lifespan. Female germline cells are among the most protected of all cell types, and have to be in order to maintain a sufficiently low level of reproductive failure for evolutionary success. Here, it is suggested that this ribosomal approach to increased cell quality produces the trade-off of a shorter cell life span and an earlier end to reproductive life span, as ribosomes are not replaced as they fail, and new oocytes are not created in adult life. In support of this view, researchers find that artificially reducing ribosome count in oocytes recapitulates the features of reproductive aging.

Protein synthesis declines with age across many tissues, but whether this decline actively contributes to physiological aging remains unclear. Oocytes may be particularly vulnerable because they rely on ribosomes synthesized during growth and maintained for prolonged periods without continual replacement. Here we show that declining translational capacity is a causal component of oocyte aging. An unbiased genetic screen identified ribosome dosage as a major determinant of oocyte longevity, and experimentally reducing ribosome abundance was sufficient to accelerate the loss of developmental competence and prematurely recapitulate meiotic defects that arise during natural aging, while also producing defects in early embryonic development.

Ribosomes isolated from aged Drosophila oocytes exhibit ∼50% lower translational activity despite only a modest reduction in ribosome abundance and preserved gross structure and composition, with both ribosomal subunits contributing to this functional decline. Protein synthesis also declines markedly in aged metaphase-I mouse oocytes. Together, these findings identify long-lived translational machinery as an intrinsic vulnerability of the oocyte and establish declining ribosome function as a mechanistic contributor to reproductive aging.

Link: https://doi.org/10.64898/2026.09.29.755503

Aging clocks can be produced from large databases of near any form of biological data that changes with age via the use of machine learning techniques that identify weighted combinations of measures that correlate strongly with chronological age, remaining life expectancy, mortality risk, and so forth. The true goal of developing clock technology is to find a way to rapidly assess the quality of any new potential therapy to slow or reverse aspects of aging, and thus greatly accelerate research and development, focusing attention on the best possible approaches. Unfortunately no clock can be trusted to perform accurately in the face of a new approach to treat aging. A clock could underestimate, overestimate, or be unaffected by biological changes that do have meaningful effects on aging. It is unknowable in advance how this will play out, and the only way to determine what will happen is to first calibrate the clock against the therapy using lengthy studies, which defeats the point of the exercise. Nonetheless, researchers are engaged in producing as much data as possible on the way in which clocks behave, in an attempt to at least try to predict the degree of trust one should have in a giving clock assessing a given therapy.

Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock intervention studies to include additional clock models, no additional clocks reach statistical significance.

We then analyze clock behavior across positive control datasets (age-accelerating events) to propose three criteria that increase confidence in a result: (1) reliable principle component based clocks respond, (2) mortality-trained or pace-of-aging clocks respond, and (3) multiple clocks respond in the same direction. To explain why genuine effects would appear across multiple clocks, we perform a simulation study to demonstrate how reliable clocks are more sensitive to true effects, and use longitudinal control datasets to show that reliable clock changes are correlated with each other. We then show examples of interventions that do satisfy these criteria.

These findings provide a framework for interpreting epigenetic clock results in anti-aging intervention studies, and suggest that some previously published single-clock findings may warrant reexamination.

Link: https://doi.org/10.1111/acel.70756

Naked mole rats are very long-lived in comparison to similarly sized rodents, undergo little to no age-related loss of function for much of their later life, and exhibit a near complete resistance to cancer. A sizable fraction of research into the comparative biology of aging is focused on this species, in an attempt to better understand which mechanisms of aging are more versus less important, and whether any of the unusual biochemistry of naked mole rats can be used as a basis for therapies to treat aging or cancer. Science moves slowly, and so only recently has the research community started to import a few naked mole rat genes into other species, a first step to validating whether or not therapies are possible. Early results are promising.

Today's open access paper is a little along the lines of naked mole rat researchers calling for more naked mole rat research, but the argument is justified based on what has been learned to date. Gene transfer showing benefits may give way to a search for gene therapies or small molecules, but the first step on the long road towards therapies derived from the advantageous aging biology of another species has been taken. The authors of the paper are largely focused on reviewing what is known of the way in which naked mole rat biochemistry interacts with the hallmarks of aging. Some quite interesting discoveries have been made in recent years, such as naked mole rat senescent cells exhibiting only a muted senescence-associated secretory phenotype, and thus being much less disruptive to tissue function. There is no doubt much more of interest yet to be uncovered.

Unlocking the secrets of naked mole-rat longevity

Fourteen hallmarks have been proposed to describe the core features of biological aging; however, whether their direct enhancement contributes to longevity remains unclear. Here, we summarize current knowledge on the differential regulation of these aging hallmarks in the naked mole-rat and their potential roles in its exceptional lifespan. We also discuss current research limitations and suggest future directions to better elucidate the basis of naked mole-rat longevity, ultimately enabling the development of strategies to promote healthy aging in humans.

The exploration of extreme longevity mechanisms in the naked mole-rat ultimately points to an evolutionary biology question: Is this anti-aging phenotype a "free lunch" shaped by natural selection, or a "trade-off" incurring corresponding costs? Classic trade-off theory posits that, due to limited resources, allocating energy to somatic maintenance and repair necessarily comes at the expense of other functions, such as reproduction. Based on this, it is reasonable to speculate that naked mole-rat longevity is likely not an isolated advantage but rather the result of sacrificing certain conventional physiological functions. However, female naked mole-rats demonstrate no decline in fertility for the vast majority of their long lifespan, attributed to an exceptionally large ovarian reserve and postnatal oogenesis. Interestingly, their reproductive strategy is fundamentally reshaped, as the vast majority of colony members remain in a state of reproductive suppression throughout their lives. A study found higher plasma oxidative stress in breeders than non-breeders, indicating a potential trade-off.

Although enhanced function in multiple organs has been identified, some "degenerations" exist, including visual function and thermoregulation. Understanding these potential trade-offs is not only an intriguing evolutionary biology question but also crucial for evaluating the risks of translating these mechanisms into humans. However, current experimental evidence regarding this trade-off is lacking. Establishing techniques such as genetic manipulation in the naked mole-rat is an important step towards systematically evaluating this phenotypic trade-off in vivo. If a trade-off does exist, whether these mechanisms can be separated from their associated costs is another intriguing question. If the answer is yes, then anti-aging strategies translated from naked mole-rats to humans might circumvent the corresponding negative effects.

Can longevity mechanisms discovered in naked mole-rats finally translate into human anti-aging clinics? As a proof-of-concept, researchers successfully introduced the nmrHAS2 gene into mice, demonstrating that it significantly reduced tumor incidence, extended both median and maximum lifespan, and improved multiple health span parameters, thereby laying a solid foundation for HMM-HA-based anti-aging interventions. Another example involves the four specific amino acid mutations at the C-terminus of the naked mole-rat cGAS protein. Introducing these four mutations into human cGAS reverses its inhibitory effect on homologous recombination repair of DNA. Furthermore, transgenic expression of naked mole-rat cGAS in fruit flies extends lifespan, and its overexpression in aged mice mitigates multi-organ aging phenotypes. However, naked mole-rat longevity is attributed to multiple mechanisms. Identifying additional translatable mechanisms and exploring combinatory intervention strategies are among the key future directions.

The presently available data and understanding of aging might be thought of as a jigsaw with more missing pieces than there are pieces in hand. There is a great deal of latitude to assemble what is known into a wide variety of views of the whole without being strongly contradicted in any of them. Thus theories of aging proliferate; it is always easier to theorize about existing puzzle pieces than to run a research program that will meaningfully add to the collection of puzzle pieces. Here, researchers present a framework for the relationship of the mechanisms of aging that places epigenetic change as the dominant (but not only) important process that drives loss of function, disease, and mortality.

Age-related dysfunction is unlikely to arise from a single universal mechanism. This review develops the Polycentric Aging Framework (PAF) by integrating evidence from somatic cell nuclear transfer (SCNT), DNA methylation (DNAm) clocks, nutrient-sensing pathways, cellular senescence, systemic signaling, and human intervention studies. PAF organizes aging into partially independent, interacting centers that differ in timing, causal status, resettability, reversibility, systemic influence, regenerative impact, interventional accessibility, and lifespan-limiting potential.

SCNT is interpreted not as rejuvenation of an existing organism but as a reset-hierarchy model: selected epigenetic and developmental states can be extensively reconfigured; telomere dynamics, mitochondrial state, proteostasis, stem-cell and stem cell niche capacity, and senescence and senescence-associated secretory phenotype (SASP) phenotypes show context-dependent reset, redevelopment, or recurrence; and nuclear DNA sequence and structural damage remain least resettable. In humans, PAF proposes epigenetic regulation as a dominant, but not exclusive, lifespan-limiting center because it coordinates cell identity, developmental-program persistence, nutrient sensing, inflammatory and endocrine signaling, repair, and tissue regeneration.

DNAm clocks are useful but incomplete biomarkers and may conflate pathological or causal Type 1 changes with adaptive or compensatory Type 2 responses. Clock shifts should therefore be interpreted against tissue-specific function, healthspan, morbidity, and mortality rather than as stand-alone evidence of rejuvenation. PAF predicts that intervention efficacy will depend on whether the targeted center is functionally limiting for a given tissue, disease context, and life stage, and whether another center subsequently becomes limiting. This provides a testable basis for center-specific geroprotective interventions combining controlled epigenetic reprogramming, metabolic modulation, senescence or SASP targeting, and systemic signaling modulation, with rigorous safety monitoring and tissue-context stratification.

Link: https://doi.org/10.18632/aging.206426

The manifestations of aging, such as age-related diseases and mortality, all arise from the same underlying root cause mechanisms of damage and dysfunction. If an individual exhibits evident consequences of aging in one part of the body, in the form of a specific age-related condition, it is likely that the burden of damage and dysfunction throughout the body is high enough to cause other specific age-related conditions to arise as well. It doesn't necessarily mean that the conditions are linked in any way other than being consequences of the same processes. That said, aging is complex, everything in the body and brain is connected to at least some degree, and dysfunction in one system often does add to the dysfunction of other systems in ways that are distinct from the core mechanisms of aging. One might not think that to be the case for hearing loss, except for the fact that use of hearing aids reduces risk of mortality via cardiovascular disease, as demonstrated here. Possible explanations are that (a) hearing aid users tend to take better care of their health and function in other ways as well, or (b) there is some functional path linking the accelerated neurodegeneration that is known to take place without functional hearing and cardiovascular mortality.

Hearing loss affects more than 1.5 billion people or nearly 20% of the global population. Prevalence is increased particularly among the ageing population, and is linked to various adverse outcomes, including poorer health, diminished quality of life, depression, and cognitive decline. Emerging evidence suggests that hearing loss could also be linked to higher mortality risk. Most existing studies have relied on smaller sample sizes based on cohorts of older adults (aged between 50 years and 80 years or more), overlooking younger (aged 20-49 years) populations. Most studies have been observational and have not assessed the long-term effect of hearing-aid use among those with hearing loss.

Results of previous studies of association between hearing-aid use and mortality have been mixed. To address these limitations, our study conducted an individual participant data (IPD) meta-analysis using large datasets from Australia, Iceland, and the USA, followed by a replication study using data from Norway, to examine the relationship between hearing-loss severity, hearing-aid use, and mortality. These studies provided extensive audiometric and mortality data, enabling a robust examination of the relationship between hearing loss and mortality across different populations and settings while adjusting for key confounding variables.

The IPD meta-analysis included 13,851 participants, with a mean age of 61.8. Mild (1.19), moderate (1.55), and moderately severe or worse (1.56) hearing loss were associated with increasing all-cause mortality risk. Mild (1.18), moderate (1.43), and moderately severe or worse (1.30) hearing loss were also associated with increased cardiovascular-related mortality risk. Current use of hearing aids was associated with reduced all-cause mortality risk [0.91] and reduced cardiovascular-related mortality [0.85]. The replication study of 50,277 adults corroborated these findings.

Link: https://doi.org/10.1016/j.lanhl.2026.100903

Messenger RNA (mRNA) can be delivered into tissues and cells by encapsulating it into lipid nanoparticles (LNPs), and then injecting the nanoparticles. A target cell engulfs a LNP, and the cargo of mRNA is released into the cytoplasm where it is translated into protein. Typically a protein is manufactured in cells exposed to a LNP-mRNA therapy for a few days only before the last of the delivered mRNA is broken down and recycled, so the end result might be considered a half-way point between the characteristics of a gene therapy and the characteristics of a small molecule drug: a treatment that produces a protein of interest to cause specific desired outcomes in cell behavior, but that only lasts a little while.

The lipid nanoparticle industry looks today much like the viral vector industry did a decade ago. A great deal of research and early stage development of therapeutics is taking place, a great deal of invention, but much of the intellectual property remains locked down and either impossible or very expensive to use in a commercial product. To date only a small number of specific lipid nanoparticle formulations with a small number of different delivery characteristics have made it into clinical trials or become approved drugs. Many very interesting technology demonstrations in animal studies are taking place, however.

Today's open access paper is an example of one of the areas in which LNP-mRNA therapies may really shine, which is to take the concept of chimeric antigen receptor (CAR) cell therapies, and make them affordable. Delivery of a CAR T cell therapy involves taking a patient's cells, engineering them to express the desired CAR, growing their numbers in culture, and then returning the cells to the patient. The artificial receptor steers the T cells towards desired targets, such as cancer cells, and has proven quite effective in treating a number of different forms of cancer. Sadly it is enormously expensive as a mode of therapy, due to the time and complexity required to manufacture each patient-specific batch. LNP-mRNA that can turn native cells into CAR T cells (or in this case CAR natural killer cells) for a short while will be both much less costly and more controllable.

Reprogrammed NK immune cells target cancer and autoimmune disorders

Over the past decade, the U.S. Food and Drug Administration has approved seven new cancer treatments based on engineered T cells called chimeric antigen receptor (CAR) T cells. Chimeric antigen receptors are proteins that can be embedded into T cells, allowing them to detect a target antigen, such as a cancer protein. When the target is detected, the T cell becomes activated and destroys the target cell. In recent years, scientists have begun using a similar strategy to create CAR natural killer (NK) cells. One potential advantage of CAR NK cells over CAR T cells is that they could be used to kill diseased T cells. Using CAR T cells to treat T cell diseases often doesn't work well because T cells that are engineered to target T cell proteins may end up killing each other, in addition to the diseased T cells. That issue doesn't arise when using NK cells to target T cells.

However, manufacturing large quantities of CAR NK cells poses many of the same difficulties as generating CAR T cells. To simplify the process, researchers wanted to come up with a way to generate CAR NK cells in the patient's own body, without having to remove any cells. To generate these cells, the team designed lipid nanoparticles (LNPs) that can deliver an mRNA payload. These strands of mRNA encode a CAR that can be targeted to specific cell types. For example, they could deliver a CAR that targets CD19, a protein found on B cells, or CD3, a protein found on autoreactive T cells. The particles are coated with antibody fragments that bind to receptors found on the surface of NK cells, to ensure they reach the correct targets.

After these particles were infused into mice, the researchers found that they could successfully reprogram about 80% of the targeted NK cells. The researchers then tested the particles' potential to treat cancer and autoimmune hepatitis, which is caused by autoreactive T cells. In a mouse model of an aggressive form of melanoma, three of the five mice that received LNPs that reprogrammed their NK cells to target the cancer cells went into complete remission. The researchers also saw significant tumor destruction when they used the LNPs to treat T cell lymphoma in a humanized mouse model. In these mice, tumors were eradicated after five injections of the reprogramming LNPs. This result was similar to what the researchers saw when they treated mice with CAR NK cells that were generated using the conventional approach.

Lastly, the researchers demonstrated that their LNPs could generate CAR NK cells that target autoreactive T cells. For this application, they studied mice with autoimmune hepatitis, in which T cells attack hepatocytes in the liver. They found that in the treated mice, the autoreactive T cells were destroyed, and liver damage healed. These effects were seen after just one injection of the LNPs.

In vivo engineering of CAR natural killer cells for immunotherapy using ligand-directed lipid nanoparticles

Targeted lipid nanoparticles (LNPs) offer a nonviral approach for in vivo cell engineering but efficient programming of natural killer (NK) cells remains underexplored. Here we develop NK cell-targeted LNPs (NtLNPs) using engineered biparatopic NK cell ligands to drive receptor-specific uptake and mRNA delivery. Lead NtLNPs achieve up to ~80% NK cell transfection with minimal off-target effects in mice. Systemic delivery of chimeric antigen receptor (CAR) mRNA using NtLNPs generates CAR NK cells in vivo.

CD19-targeted CAR NKs completely deplete circulating B cells in healthy mice and CD3-targeted CAR NKs eliminate nearly all autoreactive T cells in an autoimmune hepatitis model, highlighting a potential advantage over CAR T therapies for T cell-driven disease. In solid tumors, NtLNPs targeting the inhibitory checkpoint NKG2A enhance antitumor efficacy by relieving Qa-1b-mediated immunosuppression. Lastly, we optimized NtLNPs for in vivo engineering of human CAR NK cells, enabling regression of two humanized hematologic malignancy models and establishing NtLNPs as a modular immunotherapy system.

Peroxisomes in cells are responsible for helping to maintain oxidative metabolism via making and removing hydrogen peroxide, but are also involved in numerous aspects of lipid metabolism, breaking down or converting various lipids necessary to cell function. They have other, less well mapped functions relating to defense against pathogens. There is some evidence for peroxisome loss to occur with age, for this to be a meaningful cause of further cellular dysfunction. As researchers note here, however, the evidence for forms of peroxisome dysfunction to contribute meaningfully to Alzheimer's disease is suggestive but far from conclusive. As is often the case, the fastest path to clarity would be an approach to restore a more youthful peroxisome function to cells in the brain and elsewhere, and see what happens as a result.

Peroxisomes are dynamic, single-membrane-bound organelles ubiquitously distributed throughout eukaryotic cells, containing abundant oxidases, catalase, and lipid-metabolizing enzymes. Their functions encompass the β-oxidation of very-long-chain fatty acids (VLCFAs), the degradation of branched-chain fatty acids, bile acid synthesis, and the biosynthesis of ether phospholipids - notably plasmalogens. Moreover, via catalase (CAT) and related enzymes, peroxisomes are instrumental in sustaining local reactive oxygen species (ROS) homeostasis.

These functions are of particular relevance to the nervous system, where membrane lipid composition, myelin integrity, synaptic plasticity, and redox homeostasis are intimately interconnected. Consequently, peroxisomal dysfunction may simultaneously impair multiple facets of neural cell physiology. Within the central nervous system, peroxisomes establish an integrated metabolic network with the endoplasmic reticulum, mitochondria, lipid droplets, and lysosomes. Thus, peroxisomal abnormalities can concurrently disrupt membrane architecture, energy metabolism, reactive oxygen species (ROS) signaling, and inflammatory responses.

Reduced plasmalogen levels, diminished peroxisomal enzyme activities, enhanced lipid peroxidation, and elevated oxidative stress have been consistently documented in both Alzheimer's disease (AD) brain tissue and animal models. Furthermore, peroxisome-regulated nuclear receptors - particularly the peroxisome proliferator-activated receptors (PPARs) - are closely intertwined with lipid metabolism, insulin sensitivity, inflammatory suppression, and mitochondrial function, rendering them promising targets for drug repurposing and novel therapeutic discovery.

Current evidence does not establish peroxisomal dysfunction as a necessary, sufficient, or universal cause of AD; it is more defensibly viewed as a context-dependent vulnerability, amplifier, or response within reciprocal metabolic-proteinopathy networks. PPAR agonism, lipid modulation, pexophagy regulation, and restoration of peroxisome-mitochondria communication remain investigational. Translation requires longitudinal human evidence, validated target-engagement biomarkers, and adequately powered trials in biologically defined populations. Peroxisomal biology therefore provides a testable framework for studying lipid-redox-organelle interactions in AD, while substantial uncertainty remains regarding temporal precedence, causal magnitude, and therapeutic tractability.

Link: https://doi.org/10.3389/fnagi.2026.1960320

Senescent cells accumulate with age, perhaps primarily because the aged immune system becomes less able to efficiently destroy senescent cells as it does in youth. When a cell becomes senescent it ceases to replicate, grows in size, and secretes a potent mix of pro-inflammatory, pro-growth signals that contribute to the chronic inflammation of aging and are disruptive to tissue structure and function. Here, researchers investigate some of the specific outcomes of an increased burden of cellular senescence in the aged liver.

The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages.

We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation.

Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

Link: https://doi.org/10.64898/2026.08.08.743614

Partial epigenetic reprogramming involves exposing cells to some or all of the Yamanaka factors for a long enough period of time to reset epigenetic decorations on nuclear DNA and its supporting structures to a youthful state, but not so long as to risk dedifferentiation, and thus loss of cell state and formation of induced pluripotent stem cells that can give rise to teratomas. It is a fine balance, and different cell types need different exposure times. Thus the first practical applications of reprogramming therapy under development are limited to one cell type, or small regions of tissue where greater control over delivery can be exerted. The limited options for delivery of gene therapies further restrict the options on which tissues can be targeted.

Life Biosciences sponsors the first clinical trial of a partial epigenetic reprogramming therapy, targeting degeneration of the retina and optic nerve in glaucoma patients. In animal models, reprogramming has shown itself capable of restoring function to a damaged optic nerve. Life Biosciences is using adeno-associated virus (AAV) as a vector, well proven in delivery to the retina and optic nerve via direct injection into the eye, to introduce an inducible package of Yamanaka factors into cells. Expression only occurs in the presence of doxycycline, which allows dosing of the Yamanaka factors to be tightly controlled and repeated over time as needed. AAV is effectively a permanent therapy in these tissues.

Life Biosciences Announces First-in-Human Data from Ongoing Phase 1 Trial Evaluating ER-100 in Optic Neuropathies

This first-in-human, Phase 1, open-label clinical trial (NCT07290244) is evaluating the safety and tolerability of ER-100 in adults with optic neuropathies. ER-100 uses controlled expression of three transcription factors, OSK (OCT4, SOX2, KLF4), delivered via a single intravitreal injection, with OSK expression induced by systemic doxycycline administered for 8 weeks (56 days). An oral prednisolone taper is administered to minimize risk of inflammation due to AAV-2 immune response. Multiple study visits assessing tolerability and visual endpoints were included in this first 56 day evaluation.

Optic neuropathies are a group of disorders characterized by damage to retinal ganglion cells (RGCs), the primary neurons connecting the eye to the brain. Because RGCs do not naturally regenerate, damage results in permanent vision impairment. One such optic neuropathy, open-angle glaucoma (OAG) is a chronic neurodegenerative disease and a leading cause of blindness in older adults. While often associated with elevated intraocular pressure, disease progression frequently continues despite treatment, and some patients suffer from OAG despite normal intraocular pressure. Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in adults over fifty. It involves sudden, painless vision loss due to insufficient blood flow, for which there are currently no approved treatments.

Interim data demonstrated that a single intravitreal administration along with daily oral doxycycline was well-tolerated through Day 56 in all three participants and showed preliminary signals of improvement in visual field testing in two participants. There were no reported dose-limiting toxicities, adverse events of special interest or serious adverse events. Improvements in Humphrey Visual Fields measurements, a standard eye exam that measures a participant's ability to detect light across many points in their field of vision, scored in decibels (dB), were observed in 2 of 3 OAG participants at Day 56. In each of these 2 participants, ≥ 28% of points in the visual fields showed a > 4 dB improvement.

The gut microbiome changes with age, and evidence suggests that this provides a meaningful contribution to degeneration and disease. Microbial populations that provoke chronic inflammation grow in size at the expense of populations that produce beneficial metabolites. Researchers here show that gut microbiome composition is a better predictor of the burden of inflammation and risk of disease than chronological age, much as one might expect given what is known of age-related changes in gut microbiome composition, and also given that researchers have built aging clocks from gut microbiome data. It is one more argument for a greater focus on the development and availability of therapeutic approaches capable of lasting rejuvenation of the gut microbiome, such as fecal microbiota transplantation and flagellin immunization.

Low-grade systemic inflammation increases with age and accompanies many age-associated lifestyle-related diseases, yet substantial inter-individual variability exists beyond chronological age. Given the gut microbiota's role in immune regulation, we analyzed paired fecal microbiota profiles, 30 plasma cytokines, and 19 biochemical and physiological measures in 1,199 adults (aged 20-72) from the population-based DanFunD cohort to assess the relative associations of microbiota composition and age with systemic inflammation and subsequent disease risk.

Here we show that despite an association between age and 40% of inflammatory cytokines and most physiological variables, gut microbiota composition explained more variance than age for 97% of cytokines and 84% of physiological variables. Individuals with the Bacteroides 2 enterotype exhibited elevated pro-inflammatory cytokines and adverse metabolic profiles already in early adulthood, displaying an inflammaging-like phenotype up to 37 years earlier than other enterotypes. This enterotype was associated with increased risk of future incident disease across multiple organ systems (hazard ratio 1.21), with mediation analyses suggesting that inflammatory cytokines accounted for part of this association. Conversely, a high-diversity enterotype was linked to lower inflammation and reduced disease risk.

These findings position gut microbiota composition as a stronger correlate of systemic inflammatory tone than chronological age and a potentially modifiable determinant of inflammation-related disease trajectories across adulthood.

Link: https://doi.org/10.1038/s41467-026-77499-9

The oldest land animal with an established age is an Aldabra giant tortoise, at 194 years. Researchers have sequenced the genomes of an old and young Aldabra giant tortoise to compare with other long-lived species and with less long-lived giant tortoises, part of a continuing effort to better understand aging via comparative biology. There is that hope that the comparative biology of aging can identify which mechanisms of aging are most important, as well as identify specific biochemical differences in long-lived species that may one day form the basis for therapies to slow aging in humans. We stand some way removed from that goal; only very recently have the first experiments taken place that move specific genes from long-lived species into short-lived species, and it will be years yet before those first studies could give rise to new medicine.

Recent studies on longevity have used comparative genomic analysis, focusing on long-lived animals like the naked mole rat, bowhead whale, Brandt's bat, immortal jellyfish, and long-lived variants of the African turquoise killifish. These investigations have deepened our understanding of gene markers that potentially slow aging and inhibit cancer in these species. To further explore longevity pathways, we evaluated the genome of Jonathan, an Aldabra giant tortoise (Aldabrachelys gigantea) with an estimated age of 194 years, considered the world's oldest known land animal. Giant tortoises are known for their long life spans, and some species harbor longevity-associated genetic features. Prior genomic analyses of two Aldabra giant tortoises and a Galapagos giant tortoise, Lonesome George (Chelonoidis abingdonii), identified longevity-associated nonsynonymous single-nucleotide variations (nsSNVs) in genes like IGF1R, DCLRE1B, and XRCC6. However, no existing study has assessed whether giant tortoises delay or avoid the epigenetic changes that typically accrue with aging in other vertebrate lineages or whether exceptionally long-lived individuals like Jonathan have unique epigenetic features.

Relative to other giant tortoises (A. gigantea and Chelonoidis abingdonii), Jonathan has unique gene variants in most aging pathways. Moreover, Jonathan has substantial DNA methylation and methylation entropy changes compared to four other Aldabras ranging in age from a 5-year-old juvenile to older adults. Notably, we found that lower-entropy regions in Jonathan's methylome were enriched for the promoters of genes involved in the mitochondrial electron transport chain, and RNA metabolism. This suggests that high-fidelity transcription of the genes in these pathways may be crucial for long-lived species. Our findings support a model for aging wherein the maintenance of low methylation entropy in gene promoters is coupled to efficient mitochondrial energy production, efficient RNA processing, and efficient genomic repair.

Link: https://doi.org/10.1126/sciadv.adw8887

Mediation analysis is a statistical technique can be used in an attempt to shed some light on why a correlation between two variables might exist, by involving a third variable that might be causative. In today's open access paper, the correlation of interest is between socioeconomic status and life expectancy, or socioeconomic status and the state of late life health. Socioeconomic status is one of a number of linked traits well established to correlate with longevity, such as wealth, education, and intelligence. How exactly these traits interact with one another and where the various arrows of causation are located, are the subjects of many hypotheses. Unfortunately concrete proof of any sort of causation is challenging to conjure forth from epidemiological databases.

Today's open access paper reports on an effort to seek insight into the degree that the greater life expectancy and lesser burden of age-related disease exhibited by high socioeconomic status study populations is a matter of these individuals tending to make better lifestyle choices, such as in the matter of smoking, diet, weight, exercise, and so forth. The result is interesting in that it suggests only a modest fraction of the differences between socioeconomic groups are caused by lifestyle choice. Other prominent potential causative factors that might differ between socioeconomic groups include exposure to air pollution, exposure to persistent infectious agents, and access to medical resources, all well studied in addition. Again, however, firm conclusions do not tend to emerge from studies of this nature.

How a healthy lifestyle mediates socioeconomic inequities in healthy ageing and life expectancies: A 20-year cohort of older adults

Lower socioeconomic status (SES) is associated with various adverse health outcomes, but its association with healthy ageing is less known, and whether adherence to a healthy lifestyle at late-life years can reduce socioeconomic disparities in health requires further investigation. In a 20-year cohort of 33,541 older adults aged ≥65 years across 23 provinces in China, we investigated socioeconomic disparities in mortality and unhealthy ageing considering physical, cognitive, mental, visual, and hearing functions, and evaluated whether adherence to a healthy lifestyle at late-life years can reduce these health disparities.

We categorized SES into low, medium, or high using latent class analysis based on education level, financial status, and occupation, and established the healthy lifestyle score by never smoking, no heavy alcohol consumption, regular physical and leisure activity, and a healthy diet. Compared with older adults of high SES, those of low SES had increased risks of all-cause mortality and unhealthy ageing, with adjusted hazard ratios (HR) of 1.25 and 1.46, respectively. Overall, a healthy lifestyle mediated 20.5% and 16.4% of socioeconomic inequity in all-cause mortality and unhealthy ageing, respectively. In low, medium, and high SES subpopulations, the healthiest lifestyle group had 3.18, 3.76, and 5.65 more years of total life expectancy, and 1.40, 2.73, and 3.90 more years of healthy life expectancy at age 65, respectively, compared to the least healthy group.

The aging of the immune system arises from the underlying causes of aging, but in and of itself causes significant further pathology. Here, for example, researchers discuss immune aging as a shared underlying cause of degenerative conditions of bone and joint tissues, and how this relates to the more traditional view of the cause of these conditions. In general, aging is not a neat straight line of cause and consequence, but rather a network of interacting processes of damage and dysfunction. In many cases the consequence can accelerate the cause. Consider senescent cells, for example, implicated in degenerative bone and joint conditions: the accumulation of senescent cells contributes to immune aging, which is a matter of both cellular senescence in immune cell populations and inflammatory signaling generated by senescent cells of all types, but immune aging is also one of the factors that allows senescent cells to accumulate, as the immune system is responsible for clearing senescent cells.

Traditional views often attribute osteoporosis to an imbalance in bone remodeling, estrogen deficiency, and increased bone resorption, while osteoarthritis is considered the result of abnormal mechanical loading, cartilage degeneration, and abnormal subchondral bone remodelin. However, osteoporosis (OP) and osteoarthritis (OA) are not simple manifestations within the same disease spectrum but are disease entities with different pathological scales and tissue characteristics: OP reflects systemic bone metabolic abnormalities and decreased bone strength, whereas OA primarily manifests as local joint structural degeneration and dysfunction.

Despite their significant differences, traditional mechanisms are still insufficient to fully explain their frequent co-occurrence and mutual influence in the elderly population. In recent years, an increasing number of studies have suggested that inflammaging, immune imbalance, oxidative stress, mitochondrial dysfunction, and metabolic abnormalities may constitute an important pathological background for their common progression. Among these, inflammaging, as a key biological feature of aging, can provide a new perspective for understanding the pathological link between the two by affecting bone remodeling, cartilage homeostasis, and the local immune microenvironment.

The osteochondral unit, composed of articular cartilage, calcified cartilage, and subchondral bone, is an important structural basis for maintaining joint mechanical transmission and tissue homeostasis. Recent studies have found that bone and joint tissues are not independent pathological units but form a dynamic interaction network through cell communication, immune regulation, and changes in metabolic status. Therefore, bone loss and joint degeneration may not occur completely independently but influence each other against the background of common microenvironmental changes and cellular functional imbalances.

Immune metabolic reprogramming provides a new theoretical framework for understanding OP-OA comorbidity. The metabolic status of immune cells and osteochondral-related cells can affect their functional phenotypes and participate in bone remodeling, inflammatory regulation, and tissue repair processes. In recent years, alterations in glycolysis, oxidative phosphorylation, lipid metabolism, and NAD+-related metabolic regulation have been implicated in bone metabolic imbalance in OP and in cartilage and synovial pathology in OA, respectively. However, current evidence mainly comes from studies focusing on OP or OA in isolation, and there is still insufficient evidence to establish that these form a common causal regulatory network in human OP-OA comorbidity. Therefore, immune metabolic reprogramming is more suitable as a candidate integrative framework for explaining the links among inflammaging, bone metabolic abnormalities, and osteochondral unit imbalance, rather than an established comorbidity-driving mechanism.

Link: https://doi.org/10.3389/fimmu.2026.1941310

Smaller dog breeds live for longer than larger dog breeds, which perhaps allows some insight into mechanisms of aging. Researchers here find that age-related change in the epigenetic regulation of nuclear DNA structure and gene expression proceeds more rapidly in larger dogs, particularly in regions containing transposable elements. Transposable elements are the remnants of ancient viral infections, capable of copying themselves across the genome when active, a form of damage that can break gene sequences. The virus-like particles created by expression of transposable elements provoke inflammatory responses, and thus loss of transposable element suppression contributes the disruptive chronic inflammation of aging. This study adds to the existing body of evidence suggesting that transposable element activation resulting from epigenetic change provides a meaningful contribution to mammalian aging.

Comparative studies across species have identified mechanisms associated with exceptional longevity, but they are less well suited to identifying the molecular drivers of aging variation among individuals within a species. Domestic dogs provide a model for addressing this challenge because body size strongly predicts lifespan, with larger breeds living substantially shorter lives than smaller breeds despite sharing many physiological and environmental conditions.

We generated 1640 methylomes from 894 companion dogs enrolled in the Dog Aging Project and paired these data with detailed demographic and genetic information. Using these data, we developed highly accurate DNA methylation (DNAm) age predictors with a median average error of 0.82 years. We found that dogs with epigenetic ages older than expected exhibited elevated mortality risk, demonstrating that DNAm captures biologically meaningful variation in aging. Larger dogs, males, and younger individuals showed molecular profiles consistent with accelerated epigenetic aging.

Age-associated differential methylation was highly structured by genomic context. Promoters generally gained methylation with age, whereas introns and transposable elements (TEs) predominantly lost methylation with age. Sex differences in age effects were most pronounced on the X chromosome, whereas size-associated differences were greatest in TEs: larger dogs had 31% stronger age-associated TE demethylation than smaller dogs. This amplification was widespread across TE classes and evolutionary lineages, including long interspersed nuclear elements (LINEs), short interspersed nuclear elements, LINE2s, and DNA transposons, but was most pronounced in evolutionarily young LINE1s.

Link: https://doi.org/10.1126/science.aeb2986

Animal studies suggest that the composition and activities of the gut microbiome are as influential on long-term health and the progression of degenerative aging as is the case for lifestyle choices such as degree of physical fitness and level of physical activity. The gut microbiome changes with age: microbial populations delivering harmful metabolites or that otherwise provoke the immune system into a state of chronic inflammation grow in number, while microbial populations delivering beneficial metabolites necessary for tissue function are reduced in number. Rejuvenation of the gut microbiome, which can be achieved via fecal microbiota transplantation from a young donor to old recipient, has been shown to improve health and extend life in aged animals.

In the matters of health and aging, untangling the contribution of the gut microbiome from the contributions of diet and exercise is a challenge. The function of diverse tissues, the composition and activities of the gut microbiome, and lifestyle choices are all components of a single system, linked together and influencing one another. Today's open access paper is a discussion along these lines, focused on what is known of the ways in which exercise and the gut microbiome interact with one another to affect the aging of muscle tissue. Muscle mass and strength declines with age, and in this age of comfort and engines of transport there is a widespread lack of the physical fitness that is needed to slow muscle aging. But even the fittest people become frail eventually. A better understanding of the mechanisms involved in muscle aging may lead to therapies better able to do something about that.

The exercise-gut-muscle axis in physical frailty: A narrative review

Frailty is characterized by a decline in physiological reserve across multiple organ systems. Individuals with frailty are vulnerable to stressors, leading to an increased risk of falls, functional impairment, and death. A key biological factor underlying frailty is sarcopenia, which involves the progressive deterioration of skeletal muscle mass and function during aging. Sarcopenia involves a gradual loss of muscle mass, strength, and physical performance over time. Given the central role of skeletal muscle in physical function and metabolic health, muscle health must be maintained to sustain a healthy life.

Regular exercise is considered a highly effective non-pharmacological strategy for preserving skeletal muscle function during aging. In older adults, both aerobic and resistance exercise have been shown to enhance muscle strength, physical performance, and metabolic health. Regular physical activity is also associated with improved mitochondrial function, enhanced insulin sensitivity, increased muscle protein metabolism, and reduced chronic inflammation. Accordingly, exercise plays a central role in reducing frailty risk and preserving physical independence among older adults.

Despite abundant clinical evidence of the benefits of exercise, the biological mechanisms through which physical activity promotes health in older adults remain unclear. Recent evidence suggests that the gut microbiome may serve as an important link between lifestyle factors and host physiological function. The gut microbiome consists of trillions of microorganisms, including bacteria, viruses, and fungi. These microorganisms influence host physiology through complex metabolic and signaling pathways; they play crucial roles in nutrient metabolism, immune regulation, and energy homeostasis.

Human cohort studies have linked age-related alterations in the gut microbiome to frailty, reduced physical function, and poorer overall health in older populations. Large cohort studies have demonstrated that variations in gut microbiota composition are closely linked to dietary patterns and overall health status in older adults, and further reported microbial signatures associated with early frailty. Among community-dwelling older adults, physical fitness has been associated with dietary patterns, gut microbial composition, and metabolomic profiles. These observations suggest that the gut microbiome may be associated with physical function and frailty during aging, although causal relationships remain unclear.

One plausible mechanism involves microbial metabolites. Gut bacteria produce numerous biologically active metabolites, such as short-chain fatty acids (SCFAs), bile acid metabolites, indole-derived compounds, and products of amino acid metabolism. SCFAs such as acetate, propionate, and butyrate have considerable effects on inflammation, mitochondrial metabolism, glucose homeostasis, and insulin sensitivity. Importantly, exercise has been shown to influence the microbial composition of the gut as well as its metabolic function. Animal and human studies indicates that habitual physical activity may enhance microbial diversity in certain settings and enriches bacterial taxa associated with beneficial metabolic functions, including SCFA production.

Researchers here assess the present animal study evidence for first generation stem cell therapies to produce benefits in the most common neurodegenerative conditions, and also the consequences of stroke. The results are promising. While these therapies have been fairly widely deployed in patients via medical tourism, that data will never be available for analysis in any useful way. A few formal clinical trials have taken place, with unfortunately mixed results, which suggests that the details of manufacturing process, source of cells, and other logistical factors are important to outcomes. In general, these stem cell therapies appear to reliably modulate chronic inflammation, but all other desired outcomes are quite unreliable where they have been assessed rigorously in human patients. This is one of the reasons why factions within the research community are interested in identifying the most influential signals secreted by transplanted stem cells and using those signal molecules instead of cells as a basis for therapy.

Parkinson's disease (PD) and Alzheimer's disease (AD) are the two most prevalent neurodegenerative disorders. Neurodegenerative diseases are conditions characterized by the progressive dysfunction of nerve cells. This process is primarily associated with cellular aging, which advances with the patient's age. In turn, stroke is caused by vascular factors. Although it is not classified as a neurodegenerative disease, it leads to the degeneration of brain cells. These are severe disorders that frequently impair independent functioning.

As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke.

A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models.

Link: https://doi.org/10.1007/s12035-026-06247-3

Transposable elements are DNA sequences that can copy themselves. The remnants of ancient viral infections, they encode viral-like particles that act to insert DNA into the genome. Transposable elements are suppressed in youth, but with age the epigenetic control over DNA structure and gene expression is altered, and one of the consequences is that transposable elements are exposed to translation machinery and begin to copy themselves. This produces a form of DNA damage where that haphazard insertion of new sequences breaks existing genes, but perhaps more importantly generates an inflammatory response to the viral-like particles that innate immune sensors recognize as foreign. Some fraction of the harmful chronic inflammation results from transposable element activity, and thus suppression may form a useful basis for therapy.

The reactivation of transposable elements (TEs) is a recurrent molecular event across cancer, neurodegeneration, autoimmune disease, and aging, yet its therapeutic implications remain largely unexplored. Normally repressed under strict epigenetic surveillance, reactivated transposable elements can generate immunostimulatory nucleic acids that engage cytosolic pattern-recognition receptors, converging on type I interferon signaling and driving chronic sterile inflammation. Yet this inflammatory potential is inherently dual: the same reactivation that drives pathology in some contexts can be harnessed to prime immunity in others.

Here, we review two complementary strategies that exploit this duality. Suppressive approaches, including nucleoside reverse transcriptase inhibitors, antisense oligonucleotides, and epigenetic silencing agents, aim to quench pathological TE-driven inflammation in diseases and restore other adaptive mechanisms governing homeostasis. Conversely, controlled TE reactivation through epigenetic priming can induce a viral mimicry state in tumor cells, sensitizing them to immune checkpoint blockade. In parallel, TE-derived peptides presented on MHC class I molecules are emerging as a largely unexploited reservoir of shared tumor antigens for next-generation vaccines and engineered T cell therapies.

Together, these observations reframe transposable elements not as mere viral relics to be tolerated, but as a tunable immunological switch whose therapeutic modulation holds promise across some of the most challenging diseases of our time.

Link: https://doi.org/10.1038/s44321-026-00528-z

Humanity is poorly supported by its vasculature. Vascular aging is the primary cause of human mortality, giving rise to atherosclerosis, the formation of fatty plaques that narrow vessels and eventually rupture to produce a fatal blockage and thus a heart attack or stroke. The quality of the vasculature suffers in other ways along the road to old age: vessels become leaky where they should not be, allowing the passage of disruptive cells and molecules into tissues; the network of capillaries becomes less dense, reducing delivery of necessary nutrients into tissues; the smooth muscle surrounding vessels becomes less capable of constriction and relaxation, leading to a range of issues relating to blood pressure and pulsatile flow; and so forth. One can find dozens of scientific papers in which Thomas Sydenham's most famous maxim is quoted, that "a man is as old as his arteries." There is of course more to aging that the decline of one important system, but the vasculture is an important system, and its dysfunction does include the single largest cause of mortality, atherosclerosis.

The authors of today's open access paper cast a summary view over the aging of the vasculature, taking the Hallmarks of Aging as their theme, and discussing each hallmark as it aligns with what is known of age-related dysfunction in vascular tissues. Of the hallmarks, study of the age-related accumulation of senescent cells is perhaps the most well advanced when it comes to the construction of therapies and preclinical evidence for rejuvenation following treatment. The parts of this review covering the role of senescent cells and the potential application of senotherapeutics to the treatment of vascular aging are thus the least speculative. Nonetheless, there remains a way to go yet if the goal is the widespread availability of senotherapies in old people; much of the system of medical regulation has yet to be convinced, and large, slow, and expensive clinical trials remain the only practical way to carry out that process of persuasion. This is unfortunately, given that many of the first, readily available senotherapeutics cost very little, but must sit on the sidelines until the regulators and physicians are more engaged on this topic.

Decoding Vascular Senescence: Cellular Insights and Therapeutic Strategies

The vascular system, an intricate network spanning the entire human body, serves as the primary conduit for nutrient delivery, gas exchange, and metabolic waste removal. With advancing age, the vascular wall undergoes a series of degenerative transitions that compromise these vital functions, laying the pathological groundwork for systemic organ decay. The arterial wall is composed of three anatomical layers: the tunica intima, a single layer of endothelial cells (ECs); the tunica media, composed of multiple layers of vascular smooth muscle cells (VSMCs) interspersed with elastic fibers; and the tunica adventitia, containing adipocytes, fibrous connective tissue, and extracellular matrix (ECM). Although each layer has distinct physiological properties, their collective integrity relies on a delicate balance between cellular homeostasis and microenvironmental stability. During aging, this homeostasis is disrupted as the specialized cells within these layers-including ECs, VSMCs, and pericytes-undergo profound phenotypic and functional shifts. Furthermore, exhaustion of the endothelial progenitor cells (EPCs) reservoir and the progressive remodeling of the ECM redefine the vascular niche, shifting it from a regenerative environment toward one characterized by chronic inflammation and structural decay.

In the process of aging in humans, senescent cells tend to accumulate at divergent rates in numerous tissues. Cellular senescence is defined as a terminal state of cell cycle arrest characterized by the irreversible loss of proliferative capacity. This program is primarily executed through the p53/p21WAF1/Cip1 and p16INK4A/pRB axes, which inhibit cyclin-dependent kinases to prevent E2F-mediated DNA replication. While initially a tumor-suppressive mechanism, the excessive accumulation of senescent cells drives vascular aging. In elderly individuals, p53, p21, and p16 levels are significantly elevated in the endothelium, an effect that is attenuated by regular physical activity. Mechanistically, p53 hyperactivation drives capillary rarefaction, whereas its downstream effector p21 (encoded by Cdkn1a) functions as a complicated regulator of vascular homeostasis. Moderate p21 expression is essential for maintaining the quiescence of EPCs and supporting angiogenesis. Furthermore, p16-INK4A (encoded by Cdkn2a) serves as a definitive marker of the senescent state. Although the clearance of p16-positive cells has been shown to delay age-associated disorders, subsequent studies have revealed that age-induced p16 accumulation is a gradual process and that the majority of p16-high cells are vascular ECs. Ultimately, the progressive accumulation of these senescent populations results in a systemic decay in vascular compliance and the functional collapse of capillary networks.

Senolytics represent a specialized class of pharmacological agents that selectively eliminate senescent cells. Intermittent oral administration of the representative senolytic cocktails, dasatinib and quercetin, significantly decreases the burden of senescent cells within the aortic inner layer of aged mice, thereby remarkably improving vasodilatory function. Mechanistically, these agents achieve selectivity by disabling distinct nodes of senescent cell anti-apoptotic pathways (SCAPs). Dasatinib predominantly inhibits ephrin receptors and tyrosine kinases, whereas quercetin targets the PI3K/AKT, p21, and BCL-2 protein families. This targeted elimination holds pivotal therapeutic potential to diminish macrovascular and microvascular morbidity.

Since stem cell therapies produce beneficial effects via a short burst of signaling from the transplanted cells rather than via any long-lasting survival and engraftment of those cells, researchers are attempting to build therapies that deliver the signals instead of the cells. Manufacture involves culturing stem cells and harvesting the culture medium in order to obtain the molecules or extracellular vesicles secreted by the stem cells, and then introducing that material into patients. The signaling produced by different stem cell populations will likely prove to be more versus less useful in different contexts, and so some experimentation is needed. Here, researchers show that the secreted signals generated by dental pulp stem cells help to improve the outcome following stroke in mice.

Ischemic stroke induces oxidative stress, neuroinflammation, neuronal death, and synaptic dysfunction, leading to persistent motor and cognitive deficits. The human dental pulp stem cell (hDPSC) secretome is a promising cell-free therapeutic candidate containing neurotrophic, antioxidant, and immunomodulatory factors. Here, we investigated its therapeutic effects in a photothrombotic mouse model of ischemic stroke and CoCl2-induced hypoxic BV2 microglial cells.

Proteomic profiling identified antioxidant-associated proteins, including SOD2, GSR, and GSTP1, and microglial phenotype-related candidates, including GRN, CSF1, and LRP1. hDPSC secretome treatment reduced stroke-induced infarct volume and attenuated stroke-increased neuronal apoptosis, neuronal reactive oxygen species (ROS) accumulation, and NF-κB-associated inflammatory signaling in the cortex and hippocampus. It also shifted microglial marker expression toward an M2-associated profile and improved stroke-impaired hippocampal neurogenesis, vascular remodeling, and synaptic organization. Proteomic analyses further identified coordinated changes in pathways related to oxidative phosphorylation, inflammatory responses, calcium signaling, SNARE-associated vesicular transport, and ROBO-Rho-associated cytoskeletal remodeling. These molecular and cellular changes were associated with improved motor coordination, spatial learning and memory, contextual memory, and anxiety-like behavior.

These findings support the hDPSC secretome as a cell-free therapeutic candidate for post-stroke functional recovery linked to redox, inflammatory, neurovascular, and synaptic remodeling.

Link: https://doi.org/10.1002/advs.76717

That the calorie restriction imposed by GLP-1 receptor agonists induces loss of muscle mass has proved a boon for research into ways to address the loss of muscle mass that occurs with age, contributing to frailty. Suddenly a relatively large amount of funding and industry attention is available for programs that might result in a drug to prevent muscle loss in GLP-1 receptor agonist patients, and most of those options can at least in principle be used to treat age-related muscle loss. Here, researchers demonstrate a novel approach to inducing muscle growth in aged mice, by inhibiting a relevant microRNA; the technology is developed by Elenae Therapeutics which, as is usual, targets more severe and less common indications at the outset, such as improving outcomes for heart muscle following a heart attack. Given an approved drug at some point in the future, then it becomes possible to discuss other applications.

Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy.

Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.

Link: https://doi.org/10.64898/2026.09.03.749250

The gut microbiome changes with age in ways that are not favorable to health. Microbes that provoke inflammation and tissue dysfunction grow in number, replacing those microbes that generate beneficial metabolites. There are many plausible contributions to this process of change, and as is usually the case for anything to do with aging, it is hard to determine which are more or less important than the others. This is particularly the case here, as studies suggest that meaningful change in the composition of the gut microbiome begins as early as the mid-30s, a point in adult life at which very little is concretely known regarding which mechanisms of aging are dominant.

The authors of today's open access paper surveyed the literature to identify human studies that report specific differences in gut microbiome composition between various groups at different ages. Some of the studies specifically included long-lived populations such as centenarians. If interested in the results, skip ahead to table 2, which lists microbial taxons found to be increased or decreased with age, or in long-lived populations. A fair number of studies are listed, and some commonalities emerge.

This sort of data, taken in the aggregate, will form the basis for later efforts to favorably adjust the composition of the gut microbiome in specific ways in order to slow or reverse aspects of aging and age-related disease. Altering the composition of the gut microbiome can at present be achieved temporarily via probiotics, with some degree of control over the outcome, or permanently via approaches such as fecal microbiota transplantation, but with little control over the specifics of the outcome. It is to be hoped that future approaches can combine permanence of the changes following a single treatment with good control over the resulting mix of populations.

Gut microbiome and healthy ageing: a systematic review of literature

The gut microbiota comprises a diverse community of micro-organisms, including bacteria, archaea, viruses, parasites, and fungi, which inhabit the large intestine. These microbes play a crucial role in various physiological processes, including facilitating digestion, modulating immune responses, protecting against pathogens and synthesizing neurotransmitters and essential metabolites, such as vitamins, amino acids, secondary bile acids and short-chain fatty acids (SCFAs).

In 2023, researchers expanded the hallmarks of ageing framework by introducing three additional hallmarks, one of which is gut microbiome dysbiosis. This condition is characterized by reduced microbial diversity and an increased abundance of pro-inflammatory species. However, in the context of healthy ageing, the gut microbiome tends to maintain relative stability and contributes to systemic homeostasis. Studies have shown that the gut microbiome undergoes physiological changes throughout the ageing process. However, the direction and magnitude of these changes, including shifts in microbial diversity, are highly variable. These changes depend on several factors such as health status, diet, lifestyle, medication use, and population cohort. Microbial alterations often reflect a transition from a diverse and stable adult microbiome to a less balanced state in later life, marked by increased inflammation, reduced production of beneficial metabolites and disrupted immune function, changes that may contribute to the progression of age-related diseases

This systematic review aimed to identify compositional and functional features of the gut microbiome associated with healthy ageing. A total of 41 studies met the eligibility criteria and were included in this review. The included studies represented several regions, including recognized longevity hotspots, although geographic representation remained limited. Most studies used 16S rRNA gene sequencing (n=24; 58.5%), followed by shotgun metagenomics (n=13; 31.7%), both (n=3; 7.4%) or metaproteomics (n=1; 2.4%). Enrichment of specific taxa such as Akkermansia, Alistipes, and Parabacteroides was consistently reported in centenarians, alongside distinct patterns in older adults and long-lived individuals. Functional profiling suggested differences in pathways related to amino acid catabolism, vitamin biosynthesis, and pathways potentially linked to immune modulation, inflammatory processes, and gut barrier support.

It is always good to see a diversification in non-profit efforts to advance the state of research and development in the matter of treating aging as a medical condition. Given the vast costs imposed by aging, humanitarian and fiscal, we stand a long way removed from the deployment of an adequate amount of funding for aging research. New advocates and new organizations are very welcome, to add to existing efforts to induce more funding for necessary research, and more capital into the longevity industry.

We started Second Century Foundation to fulfill our childhood dream of a world where no one has to suffer or die from aging. Second Century Foundation is a 501(c)(3) private operating foundation focused on accelerating breakthroughs in human longevity. Much of the work needed to achieve these breakthroughs isn't fundable today. If it doesn't lead to a publication, the NIH won't fund it. If it doesn't enable an exit in ten years, venture capital can't fund it. We exist to fill those gaps.

Among present projects, we're writing a memo targeting for-profit investors and operators laying out the financial case for longevity biotech: the path to a successful IPO or M&A exit; top funding sources and messaging to Wall Street; a rigorous framework to project the expected NPV (net present value) of a therapeutic product; areas that we believe are overfunded relative to their financial (and lifespan) return; areas where we believe the potential return is highest. Additionally, We're creating a comprehensive map on the flow of capital in the longevity space, across academia, industry, and the government. Our goals are to: quantify and catalogue spending by organization and approach; spotlight research areas that we believe to be underfunded relative to their promise; identify top talent in the field and connect them with funding opportunities.

Which will give you a longer, healthier life: curing cancer, or slowing aging by 20%? (It's the second one, by a huge margin.) The longevity simulator is a free, open-source, browser-based tool that shows how the medicine of the future could change healthspan and lifespan. The tool is meant to demonstrate the enormous benefit of targeting aging itself, rather than playing whack-a-mole with individual diseases of aging.

Have an idea, want to collaborate, or want to help solve aging? We'd love to hear from you, especially students looking to start something: a longevity club, a research project, or a startup.

Link: https://www.secondcentury.org/

Cells become senescent in response to various forms of damage and stress, including the stress induced by reaching the Hayflick limit on replication. This was first described in the context of replicative senescence in cell cultures, and from there cellular senescence became a topic of interest in cancer research. In more recent years, the accumulation of senescent cells in aged tissues was demonstrated to be an important contribution to degenerative aging, and a small industry of biotech companies has emerged to develop a variety of therapies to either selectively destroy or modulate the behavior of senescent cells.

The history of cellular senescence is, in many ways, a history of expanding biological complexity. What began as an observation of finite proliferative capacity in cultured cells has progressively evolved through a series of conceptual transitions that have fundamentally reshaped the field. Senescence was first understood as a consequence of replicative exhaustion, then as a potent tumor-suppressive mechanism, later as a regulator of tissue remodeling through the senescence-associated secretory phenotype, and ultimately as a causal contributor to aging and age-related disease. More recently, the emergence of senotherapeutics has transformed senescence from a biological phenomenon into a clinically actionable target.

A major contemporary shift is the recognition that senescence is not a single cellular state. Advances in single-cell transcriptomics, spatial profiling, and lineage-specific genetic models have revealed extensive heterogeneity among senescent cells across different tissues, stimuli, and biological contexts. This emerging view is reshaping experimental design, biomarker discovery, and therapeutic development, while challenging many of the assumptions that historically treated senescence as a uniform biological process.

More than six decades after the original observations made by Hayflick, one of the most important lessons from the field is that senescence is neither inherently beneficial nor inherently detrimental. Rather, its biological consequences are determined by context. Senescent cells can promote tissue repair, regeneration, and tumor suppression, yet can also drive chronic inflammation, fibrosis, functional decline, and disease progression. Understanding this duality has become central to modern senescence biology.

Link: https://doi.org/10.1038/s44318-026-00922-w

Cells become senescent in response to stress and damage, in response to tissue injury, but most commonly upon reaching the Hayflick limit to replication. A senescent cell ceases to replicate, grows in size, and generates a potent mix of pro-growth, pro-inflammatory signals. Senescent cells are created throughout life in tissues throughout the body, but an established population of lingering senescent cells only begins to accumulate in later life. In youth, the immune system efficiently clears senescent cells, allowing senescence to be a beneficial state in the coordination of regeneration and in drawing the attention of the immune system to potentially cancerous cells. In later life, the immune system falters in this task. An established population of senescent cells that generates signaling constantly, even in relatively small numbers compared to the overall count of cells in a tissue, is highly disruptive to tissue structure and function.

To what degree is the age-related failure of immune clearance of senescent cells a consequence of harmful changes in the immune system versus harmful changes in the senescent cells themselves? This is an interesting and unresolved question, though there is at least some degree of evidence for contributions from both sides. Today's open access paper from a research group with a long history of work on the cellular maintenance processes of autophagy provides evidence for a loss of capacity in chaperone-mediated autophagy in aged senescent cells to induce a loss of chaperone-mediated autophagy in aged innate immune cells, which contributes to the inability of the immune system to efficiently clear senescent cells. In chaperone-mediated autophagy, an target unwanted or damaged protein is bound by a chaperone protein, and that chaperone protein facilitates the entry of the target into a lysosome for disassembly. It is a complex business, and so it seems likely there will be many possible targets for future drug candidates intended to improve this form of autophagy in senescent cells or immune cells.

Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells

Here we focus on the role of chaperone-mediated autophagy (CMA) during establishment, maintenance, and immune resolution of senescence in the aging context. CMA selectively degrades in lysosomes proteins containing a KFERQ-like motif, recognized by the cytosolic chaperone heat shock cognate protein of 71 kDa (HSC70). Substrate delivery to the CMA receptor, the lysosome-associated membrane protein 2A (LAMP2A), triggers its multimerization into a translocation complex for substrate entry into the lysosomal lumen. CMA declines with age in most tissues, and its malfunction is linked to neurodegenerative conditions, metabolic syndrome of aging, and atherosclerosis.

Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic, and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells.

Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.

Functional connectivity is a measure of neuronal activity over time in different parts of the brain, assessed using MRI to detect the increased blood flow that accompanies increased neuronal activity. Researchers here demonstrate that changes in functional connectivity observed in Alzheimer's disease patients differ from age-related changes observed in individuals without dementia. As is the case for many measures of aging, there is some debate within the scientific community with regard to whether any specific change is dysfunction or an adaptive, compensatory reaction to dysfunction. This will likely remain the case until effective rejuvenation therapies or effective treatments for specific neurodegenerative conditions such as Alzheimer's exist, can be used in sizable patient populations, and the results measured.

Aging and Alzheimer's disease (AD) are both associated with changes in functional brain networks - groups of regions that typically communicate with one another and support cognition. However, the precise nature of these changes - their spatio-temporal dynamics and whether they reflect compensatory adaptations, pathological disruptions, or both - remains a topic of active debate. Functional connectivity (FC), the temporal synchrony of activity between brain regions, may be a mechanism facilitating the spread of pathology, a system affected by pathology, or an interplay of both.

Here, in two independent cohorts (BioFINDER-2, N = 973; Alzheimer's Disease Neuroimaging Initiative, N = 129), we show that functional connectivity changes associated with aging and AD are strongly aligned with separate fundamental axes of hierarchical brain communication. Early accumulation of AD pathology and subsequent cognitive decline are both linked to functional change along the sensory-association axis. Meanwhile, age-related functional changes occur along the representation-executive axis consistently throughout the adult lifespan. These findings together suggest that both AD and aging alter major but orthogonal functional pathways in the brain.

Link: https://doi.org/10.1038/s41593-026-02402-0

A great deal of drug discovery starts by screening compounds from the vast libraries of molecules that exist. The libraries are too large to screen everything (and even then the scope of the libraries is only a sampling of the space of the possible). Thus even unbiased screening starts with some hypothesis to cut down the number of molecules being screened to a tractable number for the time and budget at hand. Here, researchers discuss the use of existing transcriptomic data to guide drug screening approaches intended to uncover geroprotective compounds that adjust metabolism to modestly slow aging. Based on results to date, this side of aging research seems unlikely to produce exciting outcomes, as near all of what has been discovered in this way triggers the same array of known beneficial stress responses, and thus doesn't improve on the present state of the art.

To date, invertebrate-based screens have identified hundreds of life span-extending compounds. However, relatively few have been validated across multiple species, and most of the geroprotectors belong to extensively studied classes like mechanistic target of rapamycin (mTOR) inhibitors, AMPK activators, or histone deacetylase (HDAC) inhibitors. Because these pathways regulate broad cellular processes, direct pharmacological modulation of their core components may produce pleiotropic effects. This reliance on a limited set of well-studied targets and drug classes underscores the need for unbiased tools that can prioritize diverse candidate geroprotectors.

Currently, several strategies have been developed to identify small-molecule geroprotectors, ranging from unbiased screening to transcriptomic-based drug prediction. The latter, which infers the geroprotective effects of drugs based on drug-induced transcriptomic changes, is an emerging method and has gained traction thanks to availability of large-scale transcriptomic resources. Several methodologies have been developed within this framework. One widely used strategy is the "reversal approach," which identifies drugs that counteract aging-associated gene expression changes. This approach has led to discoveries such as oridonin, an AKT inhibitor extending life span in yeast and mice. However, the reversal approach assumes that all age-related changes are detrimental despite evidence that some may be adaptive.

Another strategy, the "mimic approach," matches drug-induced transcriptomic profiles to those of known antiaging interventions. This method has been applied to identify compounds like allantoin and rilmenidine, which extend life span in Caenorhabditis elegans. However, this method tends to rediscover drugs similar to known interventions, limiting its capacity to reveal novel mechanisms.

Here, we used C. elegans and mice to explore transcriptomic strategies for geroprotector discovery. Applying transcriptomic clocks and coexpression network analysis, we found that many aging-associated changes in C. elegans are adaptive - some transcriptomic changes that resemble aging may contribute to longevity. We identified conserved coexpression modules associated with life span: "aging modules" enriched in translation and mitochondrial genes and "longevity modules" enriched in stress response genes, including daf-16 targets. Several of these longevity-associated modules are preserved in specific mouse tissues and are associated with mouse health span. Last, we conducted a small-scale screen and identify seven novel geroprotectors using the module gene expressions as our transcriptomic signatures. Our findings demonstrate that expression profiles of conserved aging-related processes can serve as predictive signatures for finding effective geroprotective compounds.

Link: https://doi.org/10.1126/sciadv.aee3657

A reduced intake of calories triggers protective responses to low nutrient availability, dramatically altering the operation of cellular metabolism. For so long as adequate levels micronutrients are still ingested, this response to calorie restriction is beneficial. The cell maintenance processes of autophagy operate more efficiently, for example, and this improved autophagy is thought to be the primary mechanism by which calorie restriction improves health and slows aging. This response to calorie restriction is triggered by a variety of independent sensors that assess the availability of various components of the diet, where essential amino acids are one of the more important components in this respect. Researchers have assessed the metabolic response to diets low in the essential amino acid methionine, and found it to produce broadly similar effects to overall calorie restriction in laboratory animals.

The authors of today's open access paper argue that methionine restriction is likely misnamed, as: (a) low methionine diets are also low in the non-essential amino acid cysteine; (b) in a low cysteine environment, methionine is consumed to produce cysteine, meaning one can't really distinguish between the effects of low methionine and low cysteine easily; (c) given a suitably engineered animal, with the methionine to cysteine pathway disabled, one can show that in fact the important metabolic response occurs as a result of low cysteine levels and not as a result of low methionine levels.

Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging

Cysteine is a dietary non-essential yet biochemically irreplaceable amino acid. Methionine, the other sole proteinogenic sulfur amino acid (SAA), lacks a thiol group and hence cannot form complexes with metals, including disulfide bond formation, nucleophilic catalysis, and redox signaling. Typically, cysteine and methionine contents are high in animal-based diets, while plant-based vegetarian foods are lower in SAA. It is now recognized that cysteine is essential for organismal metabolism through pleiotropic effects, including regulation of coenzyme A (CoA) and glutathione (GSH)-mediated redox balance. Creation of forced cysteine depletion by deletion of cystathionine γ-lyase (CTH) and feeding a cysteine-free diet causes rapid, progressive 30% weight loss. In addition, cysteine depletion induces activation of central nervous system nuclei that control sympathetic nervous system (SNS)-derived norepinephrine, which causes rapid adipose tissue browning and thermogenesis through β3-adrenergic receptors.

However, an important underappreciated issue is that methionine restriction (MR) is erroneously called MR because this diet also lacks cystine. Interestingly, it has been well established that an 80% reduction of methionine content (in a diet with 0% cystine) in adult rats resulted in robust 40% increases in median and maximum lifespan. Additional independent studies confirmed that MR, which in fact lacks both methionine and cysteine, robustly enhances lifespan in mice despite an increase in food intake, without restriction of calories. Moreover, using methionine-and cysteine-titrated diets in wild-type mice, the anti-adiposity effects of SAA restriction have been linked to cysteine restriction.

When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via CTH in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged CTH knockout mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.

Dental follicle stem cells can be used as a basis for regenerative cell therapy in the treatment of periodontitis, the prevalent form of gum disease, and a condition that becomes more common with age. Researchers here note that IGFBP5 expression is reduced in senescent dental follicle stem cells, and find that increased expression of IGFBP5 reduces the pace at which these cells become senescent. Cellular senescence in the cultured cells used in cell therapy is a problem that the regenerative medicine community is becoming increasingly aware of, and various efforts have been made in various contexts to try to mitigate the issue. Here, researchers employ this new knowledge regarding the role of IGFBP5 to design a better cell therapy to promote periodontal regeneration, and carry out a proof of principle study in a rat model of periodontitis.

The improvement of health and the delay of aging represent pivotal goals in medical research. Bone aging contributes to various age-related disorders, including periodontitis. Dental follicle stem cells (DFSCs) serve as ideal seed cells for periodontal regenerative therapy. Insulin-like growth factor binding protein 5 (IGFBP5) has been reported to exert complex and context-dependent effects. However, its role in DFSC senescence remains undefined. In this study, we observed a significant decrease in IGFBP5 expression in DFSCs undergoing replicative or H2O2-induced senescence.

Functional experiments demonstrated that IGFBP5 overexpression alleviated cellular senescence and enhanced osteogenic potential, a process linked to the modulation of non-canonical Wnt signaling. WNT5B was then identified as a potential downstream regulator involved in mediating the pro-osteogenic effects of IGFBP5. To translate these findings clinically, we developed Gel-vHA@oe-DFSC, a nanoparticle-embedded hydrogel system for cell delivery, which enhanced the therapeutic efficacy of DFSCs and promoted periodontal regeneration in a rat model. Collectively, our study reveals a novel function of IGFBP5 in mitigating DFSC senescence and presents a promising strategy for combating periodontal bone loss.

Link: https://doi.org/10.1038/s41368-026-00463-2

Cancers are primarily age-related conditions for a range of reasons, such as the decline of the immune system's ability to find and destroy cancerous cells, a rising burden of senescent cells providing a more hospitable environment for cancerous growth, and the fact that the cells of older people have a greater burden of somatic mutations than younger people. The interesting part of this paper is that normal cells in cancer patients exhibit a higher burden of somatic mutations than normal cells in healthy individuals, thus suggesting that random mutational damage, and particularly that occurring in stem cells that can spread out into tissues over time to form the patterned outcome over overlapping mutations known as somatic mosaicism, raises the odds of a cancerous combination of mutations occurring.

Self-renewing normal tissues generate several somatic mutations at each division. Previous studies have reported that cancer cells have more mutations than their normal counterparts. It is not obvious why dramatic differences in mutational burdens between normal tissues and cancers should exist. To fully understand human tumorigenesis, the increase in mutational burden across cancers will have to be understood. In this study, we provided a systematic comparison of mutational burdens in normal and cancer cells from 5 different organs, revealing a 4-fold increase in mutational burden in cancerous versus noncancerous cells.

Three proposed hypotheses could account for the increased mutational burdens in cancer: the classical hypothesis, in which driver gene mutations explain the higher mutational burden; the catastrophic hypothesis, in which extreme mutational events lead to large-scale genomic alterations; and the tail hypothesis, in which differences in baseline mutation rates among individuals account for the differences. Testing through orthogonal observations showed that the observed medians and distributions of mutational burdens in cancers could be explained by the hypotheses to various degrees of significance, and only the tail hypothesis could easily explain the increase in median mutational burdens in the normal tissues of patients with cancer compared with the normal tissues of noncancer patients.

Overall, this study characterizes an increased mutational burden across multiple types of cancer compared with normal tissue and provides insights into the contributing factors. A tenable hypothesis proposed in this study involving fundamental differences in baseline mutation rates among individuals could have implications for cancer prevention strategies.

Link: https://doi.org/10.1158/0008-5472.CAN-26-0117

The tissues of the mammalian body span a broad range of regenerative capacity, from the highly regenerative liver to the minimal regenerative capabilities of the brain and the heart. We might speculate that the evolutionary road to a reduced capability of regeneration in the central nervous system results need to retain structure that stores memory. The heart incorporates a complex electrical system, and the need to retain the structure of this system may also place constraints on the level of regeneration that can take place following injury. Heart damage, such as that resulting from a heart attack and consequent transient loss of blood supply to regions of the heart, heals poorly, and is typically characterized by fibrosis that is disruptive to heart tissue structure and function. It sets the patient on a downward course towards mortality.

Here, researchers investigate one small part of the regulatory system that determines heart cell activities following injury. They uncover a possible way to improve mitochondrial function and reduce the formation of fibrotic structures in injured heart tissue. Notably, they also demonstrate that it is insufficient to enhance the replication of heart muscle cells if the goal is improved function. More than only this is needed. Regeneration is a complex time and space dependent interplay between multiple cell types in injured tissue; it should not be surprising to find a lack of very straightforward single protein interventions that can improve matters.

A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition

The adult mammalian heart exhibits only a negligible capacity for regeneration following injury. Metabolic reprogramming has emerged as a promising strategy to enhance regenerative capacity in the adult heart. Succinate dehydrogenase (SDH), a protein complex which links the tricarboxylic acid (TCA) cycle and electron transport chain, has been extensively studied in ischemia-reperfusion injury, where malonate reduces succinate accumulation, mitochondrial reactive oxygen species and tissue injury following reperfusion across multiple mammalian models. Moreover, mutations in SDH drive profound metabolic reprogramming in multiple cancers characterized by enhanced glycolysis and Warburg-like metabolic states. Therefore, we hypothesized that transient SDH inhibition could metabolically reprogram the adult heart toward a more regenerative state.

We previously demonstrated that transient pharmacological inhibition of SDH with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific deletion of the Sdhb subunit of SDH dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function.

SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked and H3K27me3-marked chromatin states in cardiomyocytes and fibroblasts. Integration of CUT&RUN, chromatin accessibility and transcriptional profiling identified regulatory targets linking metabolic and epigenetic remodeling to regenerative responses. Together, these findings establish SDH as a multicellular regulator of cardiac regeneration and define distinct cell-specific mechanisms contributing to the regenerative effects of transient pharmacological SDH inhibition.

Any sufficiently complex set of biological data that changes with age can be used as the basis for an aging clock. Well established machine learning techniques can identify patterns and find optimal correlations between algorithmic combinations of measurements taken from the data and outcomes of interest, such as age, mortality risk, risk of age-related disease, and so forth. For all that we are now many years into the development of aging clocks as a technology, it still remains to determine how best to use them to accelerate research and development of therapies to treat aging. In principle, a rapid measure of the state of aging should allow better progress towards rejuvenation therapies. In practice, it is impossible to trust that any given clock will react in the right way to efforts to treat aging, and the only sure way to find out is to run long and expensive life span studies. Until this core challenge is solved, clocks cannot add much to the pace of development.

Biological aging clocks offer estimations of aging and dementia, yet scalability is limited. We introduce a large-scale, cross-national speech clock derived from 2928 individuals across five Latin American countries, spanning healthy controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-language/language-dominant frontotemporal dementia (nldFTD/ldFTD). Multimodal acoustic and linguistic features were trained with supervised models to estimate chronological age, generating speech age gaps (SAGs) as cross-sectional markers of deviations from chronological age, with positive values interpreted as relatively older-appearing speech profiles.

SAGs differentiated diagnostic groups (HCs < patient groups, with AD < nldFTD < ldFTD). This pattern was associated with clinical/cognitive domains. SAGs correlated with phosphorylated tau (p-Tau217) in AD and social exposome in HCs and AD. Brain clocks (structural/functional/combined) were associated with SAG in AD, nldFTD, and ldFTD. Epigenetic age correlated with SAGs in HCs and AD across Hannum, Retroclock, and OMICmAge, whereas ldFTD associations were limited to Retroclock and OMICmAge. These results indicate that SAGs capture cross-sectional multilevel aging-related variation and may offer a scalable, culturally adaptable, low-cost biomarker candidate for research in underrepresented global settings.

Link: https://doi.org/10.1126/sciadv.aef9864

Added to the growing list of specific ways in which the gut microbiome can contribute to degenerative aging, researchers here note that indole produced by gut microbiobes provokes a chain of events that worsens the maladaptive inflammatory immune response to the damage of an ischemic stroke, increasing the overall harm done. Like many of these recent single metabolite discoveries, there is a single point of intervention that may be used to reduce the impact of indole on the immune system, and thereby improve stroke outcomes.

The gut microbiota modulates systemic immunity and neurological diseases, yet the underlying mechanisms remain unclear. Here, we identify the enrichment of indole-producing Escherichia coli being associated with worse outcomes in mice and patients with ischemic stroke. Microbial indole triggers an aryl hydrocarbon receptor (AHR)-dependent response in dendritic cells (DCs). DC-specific AHR deletion improves stroke outcomes and preserves intestinal conventional type 1 DCs. AHR deletion also promotes immunoregulatory and migratory transcriptional signatures and enhances CCR7-dependent migration in vitro.

Pharmacological AHR inhibition favors gut-derived DC accumulation in the meninges, accompanied by increased regulatory T cells (Tregs) and reduced neuroinflammation, while Treg depletion abolishes the neuroprotection conferred by AHR inhibition. Detrimental effects of indole-producing Escherichia coli, indole administration, and microbiota transplantation from patients with stroke are attenuated in DC-specific AHR-deficient mice. These findings define a microbiota-AHR axis that programs intestinal immune responses before brain injury and highlight microbial tryptophan metabolism as a tractable therapeutic target.

Link: https://doi.org/10.1016/j.cell.2026.09.013

Cancer survivors who underwent chemotherapy or radiotherapy in the course of putting their cancer into remission have been shown to exhibit an increased burden of senescent cells relative to healthy peers. This is thought to explain the observed reduction in life expectancy and increased odds of unrelated cancers in cancer survivors. In general, these individuals are aging more rapidly than would be the case with a lesser burden of senescent cells, as these errant cells generate inflammatory signaling that is disruptive to tissue structure and function throughout the body.

Evidence suggests that interventions like exercise that upregulate the cellular maintenance processes of autophagy can reduce the pace at which cells become senescent, and perhaps help to spur greater immune mediated clearance of lingering senescent cells over time. This is one of the mechanisms by which exercise can improve late life health and reduce mortality risk, though of course it is challenging to identify the relative importance of the many and varied plausible mechanisms at work. Exercise changes a great deal of the operation of cellular biochemistry for the better.

Cancer survivors make a good natural experiment: how well exercise works to improve health in these individuals provides a point of comparison with the extensive data on the aged population in general, one that might help pinpoint the importance of cellular senescence in human aging. Today's open access paper is a report of such a study conducted in cancer survivors, and one might compare the results with any number of similarly structured studies conducted in similarly aged people without cancer.

Exercise slows biological aging in breast cancer survivors: secondary analysis of a randomized trial

Sedentary breast cancer survivors within 5 years of diagnosis were randomized to a remotely delivered exercise intervention or a contact-matched health and wellness condition. Whole blood samples and cognitive assessments were obtained at baseline, 6, and 12 months. Epigenetic ages and differential methylation were calculated. A subsample of 124 participants with complete data was analyzed.

The Exercise arm showed slower epigenetic aging than the Health and Wellness arm over the 12-month study, according to GrimAge2 and DNAmFitAge clocks. Changes in epigenetic aging were significantly correlated with alterations in attention and self-reported cognition, with faster epigenetic aging associated with greater cognitive decline. Furthermore, genome-wide analysis of the blood epigenome identified differentially methylated CpG sites, some mapping to genes enriched for brain-derived neurotrophic factor (BDNF) signaling pathways.

The first human application of partial epigenetic reprogramming of aged tissues, using adeno-associated viral (AAV) vectors, was not in fact the first patient dosed in the recently launched Life Biosciences clinical trial for optic neuropathy. Instead, a few older and entrepreneurial individuals in the longevity community made use of the AAV gene therapy experience accumulated in recent years by organizations in the more reputable end of the medical tourism industry (e.g. Triple Helix Science in particular, but also BioViva and others with lower profiles) in order to responsibly manufacture and use reprogramming therapy. The medical tourism community tends not to generate formally published and peer-reviewed data, sadly, but in this case some of those involved may choose to share data further along the line, given enough time to see results.

AAV is something of a special case among modes of advanced therapy. Many of the good AAV serotypes with well defined behavior are in the public domain, there is broad, ongoing industry experience in manufacture and use in clinical trials to draw upon, and manufacture is relatively straightforward. Other forms of gene therapy vector remain locked down by patent holders, or are much harder to work with safely, or have relatively little of a manufacturing and development community. That will change over time. That AAV gene therapy is now more democratized, more accessible, and spreading into the medical tourism community is a preview of how things will be in the future for a much larger range of advanced medicine: both more accessible, but at the same point in time robust data on effects and effectiveness will be harder to uncover.

Kenneth Scott was born in 1942 and Helga Sands was born in 1938. Their KHL Foundation works with scientists, physicians, and biotechnology developers to help develop and adapt promising rejuvenation technologies for practical human application, beginning with the generation that needs them now. To this end a small number of people have received an experimental 11-gene therapy containing reprogramming factors OCT4, SOX2, and KLF4 (OSK) developed through a Triple Helix Science initiative. One of those recipients, Christine Scott, received the treatment on March 11, 2026. The therapy was administered submucosally with cognitive function as its principal target. Expression of the OSK components is controlled through a doxycycline activation regimen.

The underlying gene-therapy initiative is led by Patrick Sewell, MD, and Triple Helix Science. KHL is supporting the initiative, including through the participation and monitoring of Christine Scott, who in prior years had experienced substantial cognitive and neurological decline following a severe adverse reaction attributed to ciprofloxacin. To the best knowledge of Sewell, Scott, and Sands, these treatments represent the first administrations of OSK to humans. KHL has identified no publicly documented earlier human OSK administration and is continuing to assemble and review the treatment chronology before making an unqualified worldwide-first claim.

"This is not an announcement that we have proved that OSK reverses cognitive decline. It is an announcement that human application has begun. Now we can monitor what actually happens, learn from it and adapt. Gene therapy is becoming increasingly practical. I've already seen the cost of the technology fall dramatically. The next challenge is moving credible science into responsible human application and learning from what happens."

Link: https://khlfoundation.com/resources-center/madrid-2026-press-release/

AMPK is the target of a range of interventions known to modestly slow aging in short-lived species. Like much of the complex array of evolved machinery that responds to various forms of cellular stress with improved maintenance, repair of damage, and a consequent slowing of aging, AMPK is involved in the regulation of energy metabolism. Many of these interventions, such as metformin, are far from robust. The animal data is mixed. One might argue that this is in part because the effects on the behavior of AMPK are indirect, as researchers do in this paper. Still, their direct approach to activating AMPK still produces only a modest effect on life span, and does so in species known to be far more receptive to life extension via metabolic alteration than is the case for humans. One wouldn't expect great things to emerge from attempting this in our species.

AMP-activated protein kinase (AMPK) is a fundamental sensor of metabolic status and stress, which is universal throughout eukaryotes. AMPK plays a central role in energy homeostasis and is therefore an attractive therapeutic target in health and disease. AMPK consists of a heterotrimer, with a catalytic α subunit and regulatory β and γ subunits, and displays strong evolutionary conservation across eukaryotes, as evident from sequence alignments between the human, fly, worm, and yeast orthologues. Maximal kinase activity of AMPK requires phosphorylation of a conserved threonine in the α subunit.

Many studies utilise pharmacological targeting of AMPK, for instance by the anti-diabetic drug metformin, which activates AMPK indirectly by altering the cellular AMP/ADP:ATP ratio. To overcome the complexity and non-specificity of metformin, studies with direct AMPK activators are essential to fully appreciate the therapeutic potential of AMPK in health and ageing. Here, we apply the direct AMPK activator compound 991 in yeast, worms, flies and mice to investigate its potential pro-longevity effects. We demonstrate that direct activation of AMPK with the compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans, and Schizosaccharomyces pombe. In mice, 991 treatment induces a pro-longevity proteomic profile, highlighting the potential for translation to mammals. Overall, our study provides important proof-of-principle for AMPK as a pharmacological target with longevity benefits.

Link: https://doi.org/10.1111/acel.70721

Hundreds of mitochondria in every cell work to produce adenosine triphosphate (ATP), a chemical energy store molecule needed to power cell activities. Mitochondria evolved from symbiotic bacteria, and are now fully integrated as components of the cell, with much of their original DNA moved into the cell nucleus. Mitochondria become dysfunctional with age, reducing their production of ATP, increasing oxidative byproducts, and causing maladaptive inflammatory reactions. This is an important contribution to the disruption of cell and tissue function that takes place in aged tissues.

Unfortunately, mitochondrial dysfunction, while well established and readily measured, is also enormously complex and incompletely understood. Many different contributing mechanisms are plausible, but it is a challenge to determine which of them are more or less important than the others. So far, attempts to improve mitochondrial function in older individuals via pharmacology and supplements have struggled to improve on the effects of exercise, suggesting that the mechanisms targeted are not those with the largest effects on function, or at least are not in and of themselves sufficient to improve function.

In today's open access paper, researchers outline one of the many contributing issues to mitochondrial dysfunction. Their focus is on muscle tissue, but much of the underlying problem generalizes to other tissues. The structure of the inner mitochondrial membrane relies upon the presence of cardiolipin, but cardiolipin production declines with age. This triggers changes in mitochondrial function that muscle tissue reacts to with remodeling of the distribution of fiber type in additional to any other issues that arise. Experiments in a mouse lineage engineered to lack cardiolipin suggests that replacing lost cardiolipin can help to restore function, but one would want to see that same study repeated in aged mice before taking it at face value.

Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ

Skeletal muscle is composed of fiber types that span a continuum of contractile and metabolic properties, enabling the tissue to meet diverse functional demands. Along this spectrum, slow-twitch (type I) fibers show high mitochondrial oxidative capacity, whereas fast-twitch fibers comprise both oxidative (type IIa) and glycolytic (type IIx and IIb) subtypes that rely differently on oxidative versus glycolytic metabolism for force generation. Diminished mitochondrial function disrupts systemic energy homeostasis and is a hallmark of myopathies and aging. Yet, seemingly paradoxically, myopathies and aging also lead to selective atrophy of glycolytic fibers and a shift toward oxidative metabolism. The timing and mechanisms driving this fiber-type-specific shift remain unclear. Whether diminished mitochondrial function has a causal role in eliciting adaptive measures or is merely a marker of age- and disease-related decline is unknown.

Mitochondrial function is heavily shaped by the inner mitochondrial membrane (IMM), which coordinates cellular and organismal homeostasis by modulating macronutrient exchange, bioenergetic capacity, fusion and fission, and interactions with other organelles. The IMM's distinct curvature is conferred by a unique lipid composition, most notably the phospholipid cardiolipin (CL). Here we show that synthesis of cardiolipin causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle.

By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell-autonomously orchestrate fiber-type adaptations in aging and myopathies.

The immune system of the brain and body are distinct from one another, separated by the blood-brain barrier that lines blood vessels passing through the central nervous system. In health and youth, only small numbers of immune cells from the body pass in the brain, but this number increases considerably with advancing age and the presence of neurodegenerative disease. The blood-brain barrier leaks, and immune cells from the body finding their way into the brain in ever greater numbers are thought to maladaptively promote inflammation, causing dysfunction and damage in brain tissue. Here, researchers find an approach to slowing down this passage of immune cells into the brain, producing benefits in a mouse model of neurodegeneration.

CXCR3 is a well-defined chemokine receptor expressed by T cells, predominantly on activated T helper 1 (Th1)-polarized CD4+ and cytotoxic CD8+ T cells. Its canonical chemokine ligands, CXCL9, CXCL10, and CXCL11, are induced by interferon gamma (IFNγ) and are abundant during chronic inflammation. Upon homing to tissues, activated T cells amplify immune responses by secreting chemokines and cytokines such as IFNγ to facilitate cellular damage. In peripheral tissues, CXCR3-ligand interactions orchestrate T cell recruitment and infiltration into tissues, and some lines of evidence suggest a role in neuroinflammatory conditions.

We hypothesized that the CXCR3 axis is an important chemotactic gradient for brain-infiltrating T cells in tauopathy, thereby linking peripheral immune activation to tau-driven brain injury. To address this, we established an acute model of brain T cell infiltration via stereotaxic injections of recombinant IFNγ into the hippocampus. Using this model allowed us to confirm that antibody-mediated blockade of CXCR3 and genetic deletion of Cxcr3 or Cxcl10 prevented brain T cell infiltration. This confirmed that acute central nervous system injection of IFNγ could result in brain T cell infiltration and a putative role for CXCL10 and CXCR3 in this infiltration.

In a mouse model of tauopathy and neurodegeneration, chronic systemic anti-CXCR3 treatment markedly reduced parenchymal CD4+ and CD8+ T cell accumulation, attenuated neurodegeneration, and improved aspects of cognition. CXCR3 blockade decreased microglial major histocompatibility complex (MHC)-II expression without broadly suppressing classical disease-associated inflammatory phenotypes. Single-cell RNA sequencing and flow cytometry further revealed a reduction in the proportion of activated CD4+ T cell populations and elevated CD8+ T cell terminal exhaustion in the brain.

Link: https://doi.org/10.1016/j.neuron.2026.08.030

Researchers here discuss the chronic inflammation of aging as a contribution to the bidirectional relationship between the loss of bone mineral density leading to osteoporosis and neurodegenerative pathology leading to cognitive impairment. As they point out, the best interpretation of the correlation between these two aspects of aging is that underlying processes contribute to both forms of degenerative aging. The chronic inflammatory signaling characteristic of aging is one of the best candidate mechanisms, given what is known of its effects on bone tissue and brain tissue at the detail level.

This review consolidates existing evidence into an integrative immunopathological framework in which inflammaging - the chronic, low-grade, sterile systemic inflammatory state driven by senescent cells and their senescence-associated secretory phenotype (SASP) - is examined as a shared upstream driver that concurrently reconfigures skeletal remodeling and central neuroimmune dynamics through the bone-brain axis. Meta-analytical evidence indicates that osteoporosis is associated with a substantially elevated risk of cognitive impairment (odds ratio = 2.01), and that cognitive impairment carries a reciprocally increased risk of osteoporosis (risk ratio = 1.56) - with Alzheimer's disease conferring a particularly high risk (risk ratio = 1.70). This bidirectional association is best interpreted as the shared output of multiple interlocking aging mechanisms rather than as a direct causal relationship between the two conditions.

At the molecular level, persistently elevated SASP-derived cytokines (IL-6, IL-1β, TNF-α) engage RANKL-dependent osteoclastogenesis in bone and prime microglial neuroinflammation in the central nervous system. Chronic NF-κB signaling and NLRP3 inflammasome activation, amplified in preclinical models by mitochondrial DNA release via the cGAS-STING axis, sustain this dual pathological output. Within the bone-brain axis, bone-derived endocrine signaling is remodeled during aging: osteocalcin (OCN) secretion declines, while osteocyte-derived sclerostin (SOST) rises and may antagonize Wnt/β-catenin signaling in both compartments. Blood-brain barrier disruption and peripheral immune-cell infiltration further amplify central neuroinflammation.

Candidate bone-brain dual-targeting interventions - senolytics (dasatinib plus quercetin), NLRP3 inhibitors, cGAS-STING blockade, GLP-1 receptor agonists, and microbiota-targeted strategies - are discussed with explicit reference to current evidence level, safety concerns, and translational limitations, rather than as established co-therapies. Dual-endpoint randomized trials enriched for elevated inflammaging biomarkers are needed before any of these agents can be positioned for clinical use in bone-brain comorbidity.

Link: https://doi.org/10.3389/fimmu.2026.1874465

An important goal in the research community is to build a robust measure of biological age, the burden of age-related damage and dysfunction contributing to disease and mortality, that can be used to rapidly assess the quality of any potential intervention to slow or reverse aging. One of the reasons why the longevity field moves slowly is that, in the absence of a robust measure of biological age, it takes a long time to assess any given therapy by running life span studies in mice, and repeating such studies in humans is infeasible. So there is relatively little drive to compare, contrast, and optimize approaches shown to slow or reverse aging in laboratory species. One might hope that a robust measure of biological age would speed up the research community's efforts to build a basis for greater human longevity.

There are obviously a great many existing biomarkers of aging, some of which are very straightforward to measure. Grip strength is a popular one, and today's open access paper advocates for imaging of the degree of fat infiltration into muscle tissue. The issue is that these measures are not known to be robust. Either their relationship with outcomes in aging varies greatly from individual to individual, or they cannot be trusted to accurately reflect effects on outcomes produced by interventions. Any measure of aging can be calibrated against any specific form of treatment for aging, to determine whether or not it is helpful in that case, but then one is back to needing long-running, expensive studies to make progress. It doesn't help the bigger picture because it doesn't accelerate the field.

Myosteatosis: an emerging biomarker of aging

Adipose tissue infiltration into skeletal muscle (i.e., myosteatosis) has emerged as an independent contributor to metabolic disorders and declines in skeletal muscle function with age. It remains unclear whether myosteatosis is a marker of aging or simply a consequence of disease or disuse. This review summarizes evidence from population-based epidemiologic studies that utilized non-invasive imaging to measure myosteatosis and to evaluate age-related changes among community-dwelling middle aged and older adults.

Myosteatosis consistently increased with age, independent of weight change, and the burden of myosteatosis was greater among women, and non-White racial and Hispanic ethnic groups after accounting for physical activity levels, chronic disease burden, and overall body size. Myosteatosis accumulation is not uniform throughout the body and is differentially associated with clinically meaningful age-related outcomes, including changes to gait, balance, muscle strength, and physical function. Hormonal, cellular, genetic, and lifestyle differences comprise the biological pathways that may lead to age-related increases in myosteatosis.

Future work in diverse populations using standardized imaging methodologies could include longitudinal measures of biological markers to better understand the biological precursors that accompany the phenotypic change. In conclusion, while myosteatosis does not accumulate uniformly with age across sex, race, or anatomical location, evidence from several well-characterized epidemiologic studies supports myosteatosis as a potential marker of aging, independent of weight change, body size, activity level, or chronic disease burden.

Any sufficiently complex biological data that changes with age can be used to construct an aging clock. Here, researchers report on a clock derived from images of the nuclei of hematopoietic stem cells. Nuclear DNA exhibits structural changes in response to circumstances, regulated by epigenetic decorations to DNA and its supporting proteins, as regions unfold or are compacted. The structure of DNA determines which gene sequences are exposed to translation machinery, and thus whether or not a given gene is expressed. Some of these structural changes are characteristic of aging, and thus machine learning approaches should be able to visualize age-related differences in imaging.

The functional decline of the hematopoietic system during aging affects organismal function and contributes to reduced healthspan. Quantifying hematopoietic aging holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of aging that encode rich and informative signatures of the aging process, yet they remain largely unexplored as quantitative markers.

Here, we present an interpretable deep learning approach based on convolutional neural networks, ChromAgeNet, that learns changes in the spatial features of chromatin architecture upon aging of hematopoietic stem cells (HSCs). We trained our algorithm on 3D microscope images of DAPI-stained HSC nuclei to discriminate between young and aged murine HSCs, achieving an area under the receiver operating characteristic curve (AUROC) of 0.77 ± 0.03. This approach outperforms classical machine learning models trained on handcrafted chromatin features from the same dataset. We then applied explainable artificial intelligence techniques, identifying chromatin entropy, peripheral heterochromatin, and chromatin condensates as predictive markers.

As a proof of concept, we evaluated the potential of our model as a phenotypic screening tool for aged HSCs treated with epigenetic drugs to detect rejuvenation. Altogether, we demonstrate that changes in chromatin organization can be modeled via machine learning to predict age-associated chromatin states in the hematopoietic compartment. Our developed framework, ChromAgeNet, serves as an interpretable algorithm to unravel the intricate relationship between chromatin changes and stem cell aging, and advance high-throughput drug screening for rejuvenation therapies.

Link: https://doi.org/10.1111/acel.70656

The antimicrobial drug K21 acts via disruption of bacterial membranes, but is also known to produce improved wound healing, which suggests the involvement of mechanisms other than antimicrobial activity. Here, K21 is shown to favorably modulate macrophage activity, in that exposure improves the operation of the mitochondrial quality control processes of mitophagy in macrophages, which in turn improves mitochondrial function. Delivery of K21 to nematode worms resulted in longer life spans, as one might expect from any intervention that improves mitochondrial function without meaningful side effects.

Here, we sought to use single-cell RNA-seq to explore the diversity of the innate immune response and to understand its potential to be reprogrammed by antimicrobial therapy. Antimicrobials primarily target specific aspects of the pathogen's lifecycle to inhibit its spread, yet few drugs can effectively control viruses, bacteria, and other pathogens, including fungi, while improving cellular health. The only possible way to achieve this is to alter the host immune repertoire to effectively inhibit pathogenic survival. We chose to study the antimicrobial compound K21, a quaternary ammonium silane compound that not only exhibits broad-spectrum effects against viruses, bacteria, and fungi but also demonstrates potent wound healing activity.

As macrophages and macrophage polarization orchestrate the phases of wound-healing, shifting from pro-inflammatory signaling that combats infection to pro-regenerative signaling that recruits fibroblasts and keratinocytes to repair the epithelial tissue, we reasoned that K21 might operate by modulating macrophage properties, classes, and/or dynamics. We chose to examine the effects of K21 on monocyte-derived macrophages from human peripheral blood monocytes (PBMCs) because of their technical accessibility, their ability to be isolated in a relatively naïve state and co-cultured with other cell types, and their controllable M1/M2 polarization.

We found that supplementing cytokine and cell-surface marker profiling with scRNA-seq transcriptomic analysis provides unparalleled resolution of macrophage diversity and plasticity, allowing us to demonstrate how treatment with K21 remodels the macrophage repertoire both inside and outside the cell. We show that a key aspect of K21 treatment is the induction of mitochondrial fission and autophagy (mitophagy). We turned to the distantly related model system C. elegans to examine whether the mechanism used by K21 is used systemically in vivo and evolutionarily conserved. K21 induced DRP-1-mediated mitochondrial fission and mitophagy in vivo without impairing viability, development, or fertility; indeed, it reprogrammed metabolic gene expression and extended lifespan in these nematodes, consistent with its effects observed in mammalian cells.

Link: https://doi.org/10.26508/lsa.202603852

Aging clocks have yet to fulfill their promise, which is to produce a robust measure of biological aging that can be used to rapidly assess the results of potential therapies to slow or reverse the progression of aging, such as via repair of underlying cell and tissue damage that causes aging. This is because these clocks are produced by machine learning approaches applied to data from a patient population, such as omics data, that changes with age. Exactly why any specific combinations of measures identified in this way, such as the state of DNA methylation at scores of specific CpG sites on the nuclear genome in the case of epigenetic clocks, can predict age or mortality risk is a mystery. There is no way at present to connect a given CpG site or protein expression level or feature in imaging data to what is known of mechanisms of aging. Thus a clock cannot be trusted to assess a new approach to treating aging without calibrating it against that approach in slow, expensive life span studies. Which defeats the point of the exercise.

One of the ways in which researchers approach this challenge is to gathering as much data as possible for as many clocks as possible, in a search for patterns and understanding that will allow clocks to be better trusted. Prospective memory is the ability to remember to follow through on a previously made plan. Like all forms of memory function, it declines with age as the mechanisms of aging produce progressively greater neurodegeneration in brain tissue. In today's open access paper, researchers report on correlations in existing data between epigenetic age acceleration measured in the 40s and prospective memory dysfunction a decade later. The study wasn't large enough and the approach used to assess memory dysfunction was not robust enough to detect correlations at a given age between epigenetic age acceleration and memory function at that time. This suggests that early midlife is an important foundation for later health.

Linking epigenetic age acceleration to self-reported daily memory lapses: evidence from the National Study of Daily Experiences

DNA methylation algorithms, such as DunedinPACE, are increasingly used to study the mechanisms of aging and to identify associations with risk factors in adult development and aging. Growing evidence suggests that an increased pace of epigenetic aging is associated with cognitive impairment and dementia, but the correlation between epigenetic aging and subjective cognitive complaints (eg, forgetting a name or forgetting to take your medication), an early marker of dementia risk, remains unexplored.

Using data from The National Study of Daily Experiences (NSDE) and Midlife in the United States (MIDUS; N = 232), we examined the relationship between epigenetic aging rate (ie, DunedinPACE) and self-reported daily memory lapses (ie, occurrence, irritation, interference) in midlife and older adults. We found no significant main effects of the rate of epigenetic aging on self-reported memory lapses; however, a significant chronological age interaction indicates that among the comparatively younger adults in the sample (age 40-49), faster than average rates of aging (ie, higher DunedinPACE) were associated with more prospective memory lapses approximately a decade later as well as greater reports of prospective memory lapse irritation and interference. Additionally, for respondents in their forties, a higher DunedinPACE was associated with both greater prospective memory lapse irritation and interference.

These results suggest that early midlife may be a sensitive period during which the rate of epigenetic aging is more influential on cognitive health outcomes.

First generation stem cell therapies have become widespread; they are readily accessed in medical tourism clinics, and are also available for a range of issues in more regulated parts of the world. Initially it was hoped that transplanted cells would engraft and survive to assist tissues in repair and regeneration, but it has become clear that this is not how the therapies produce benefits. Rather it is a matter of signals generated by the transplanted cells in the short time they survive that beneficially alter the behavior of native cells. Unfortunately, while effects such as months-long suppression of chronic inflammation are fairly reliable, other hoped for improvements such as the stimulation of greater regeneration or regression of disease remain highly unreliable outcomes. One might ask where the field goes from here, and the consensus seems to be (a) attempts to make the generation of stem cells for transplantation much more robust and the outcomes more reliable, and (b) moving away from cells to instead manufacturing secretome or extracellular vesicle therapies derived from stem cell cultures.

Mesenchymal stem/stromal cells (MSCs) continue to drive innovation in regenerative medicine, yet the field is undergoing a critical evolution from the early concept of cellular engraftment to complex paracrine-mediated tissue repair. While MSCs were initially thought to repair tissues via direct engraftment and differentiation, accumulating evidence demonstrates that functional recovery relies predominantly on paracrine effects rather than direct cellular replacement. Through paracrine signaling, MSCs secrete a rich array of bioactive molecules - including cytokines, chemokines, growth factors, and extracellular vesicles (EVs) - that stimulate tissue regeneration, promote angiogenesis, and modulate inflammation, apoptosis, and fibrosis.

Despite these biological advantages and their ability to be expanded ex vivo for therapeutic use, the clinical outcomes of MSC-based interventions remain highly variable across different disease models. While MSCs have demonstrated promising regenerative capacity, their efficacy in complex organ regeneration and chronic inflammatory diseases is often inconsistent. Differences in tissue source, donor characteristics, manufacturing protocols, and the host disease microenvironment collectively influence therapeutic efficacy

To bridge this translational gap, a systematic reassessment of MSC therapies is urgently needed. Beyond the biological characteristics and general applications of MSCs, this review provides a critical, translational perspective on overcoming current clinical bottlenecks. It is our perspective that overcoming present limitations demands a strategic pivot towards precise cell-free MSC-EV therapies and advanced bioengineering strategies.

Link: https://doi.org/10.1016/j.scib.2026.09.057

The commensal microbes of the gut microbiome generate a range of metabolites that are beneficial or necessary to cell function. Levels of a number of these metabolites have been shown to decline with age as the composition of the gut microbiome changes for the worse. Overall the gut microbiome clearly makes a meaningful contribution to health and longevity, as demonstrated by the sizeable benefits resulting from providing a young microbiome to an old animal, but it isn't clear as to how much of these effects derive from changes in the production of any specific metabolite.

Metabolites produced by gut bacteria are taken up by the host and have a direct impact on its health. However, to our knowledge, no studies have investigated the effects of gut bacterial metabolites on the lifespan of the host using gnotobiotic animals colonized with gut bacteria deficient in biosynthetic genes involved in the production of specific metabolites.

Polyamines, such as putrescine and spermidine, are among the most important metabolites of gut bacteria. Previous studies have shown that increasing polyamines in the colon of mice extends their lifespan and biological functions. In this study, we produced gnotobiotic flies colonized with Escherichia coli, in which polyamine biosynthetic genes were deleted or complemented. Gnotobiotic flies were fed a polyamine-free diet, and the effects of metabolites derived solely from gut bacteria on the lifespan of the host were analyzed.

The results showed that polyamines derived from gut bacteria significantly prolonged the lifespan of the flies. Furthermore, the expression of TotM and Halo was suppressed in flies monocolonized with polyamine-producing E. coli compared with those monocolonized with mutant bacteria incapable of producing polyamines.

Link: https://doi.org/10.1128/mbio.01484-26

The effects of calorie restriction and even larger effects of growth hormone receptor knockout on the lifespan of mice have proven to be hard to beat. In large part, this is because (a) aging is the result of a number of very different causes, (b) producing comprehensive rejuvenation will require a number of very different therapies applied in combination, and (c) next to no-one is assessing the results of combination therapies targeting the root causes of aging. One of the other consequences of aging having multiple distinct (but interacting) causes is that it is in principle possible to make good progress on treating a cause of aging without producing an appreciable gain in healthspan or lifespan, or without reversing a given class of age-related disease, because that particular cause is not the limiting cause. If dysfunction results from several different mechanisms, then removing one of them may or may not help, and may or may not help in a sizable way, because the other mechanisms are still sufficient on their own to cause dysfunction. Nonetheless, all of the mechanisms will have to be dealt with to remove that dysfunction.

We can see examples in the development of rejuvenation therapies from recent years that illustrate the range of possible outcomes. Firstly, senolytics to clear senescent cells are very good at reversing age-related conditions in mice, but don't extend life to the same degree as calorie restriction, indicating a strong contribution to age-related disease, but a complex relationship with other aspects of degenerative aging - and those other aspects are enough in and of themselves to produce mortality. Secondly, clearance of amyloid-β aggregates is in principle a good idea, as that protein aggregation can cause pathology in the aging brain, but that clearance does little for patients in later stages of Alzheimer's disease, because other mechanisms become dominant in driving disease progression. With this in mind, today's opinion piece argues for a greater weight to be placed on the assessment of the ability of individual therapies to achieve their stated goal in reduction of specific forms of age-related cell and tissue damage, rather than effects on healthspan or lifespan, and for a greater focus on funding the assessment of therapies in combination, rather than individually.

When Lifespan, Healthspan, and their Surrogates are the Wrong Metrics for the Aging/Longevity Field

Aging is multifactorial. It is several diverse and distinct molecular subproblems. Very effective treatment of aging will clearly require the intelligent combination of several elements (several separate therapeutic interventions). Lifespan and healthspan extension are the ultimate result of very effective comprehensive treatment of adult biological aging pathology. They are the obvious outcome metrics for any final or somewhat comprehensive solution to aging. However, that does not make them, or their surrogates, the right metrics for testing individual interventions or for tracking progress of the field.

To illustrate the essence of the claim about how to evaluate individual interventions, consider a simpler imaginary system in which their are only two subproblems that limit functional lifespan. Pretend that a boat must ferry cargo across a body of water but suffers from 2 main problems: (1) Its hull is old and develops small holes regularly due to direct exposure to the corrosive water, and if uncorrected these holes slowly expand. (2) It must travel over some kelp some of which extends from the bottom close enough to the surface to become tangled in the boats propeller or rudder.

Now consider three interventions: A. Repair/patch the holes in the hull periodically. B. Remove the kelp strands from the propeller periodically. C. Replace the containers that the cargo is carried in with lighter-weight containers such that the boat rides higher in the water, causing both less of the hull to be exposed directly to the water causing fewer holes to develop and causing the propeller and rudder to ride higher where it encounters fewer kelp strands causing fewer to become tangled. Imagine the following: Studies of the effect of intervention C alone show that it extends the useful life of the boat vs. no intervention. Studies of the effect of intervention A alone and separate studies of intervention B alone show that neither alone increases the useful life of the boat vs. no therapy at all. Should we conclude that interventions A and B have no value? No, of course not. The monotherapy studies of A or B alone each left the unaddressed subproblem to eventually worsen to the point of ending the boat's useful life.

Multiple things go wrong in aging. Multiple interventions will eventually be required to do the best job possible at mitigating all these problems to the best extent possible. All that matters is: what is the best overall combination of interventions (for each person at each time). How important each intervention is depends almost entirely on how well it helps the ultimate endpoint of interest within the overall suite of interventions and hardly at all on how well it works with respect to the ultimate endpoint when used by itself, a way in which no one will use it in the long run. Some people want lifespan extension from monotherapy use to demonstrate relevance. This is misguided.

Why is the APOEε2 variant of the APOE gene associated with a lower risk of Alzheimer's disease and slightly longer life expectancy? Past research has investigated the role of APOE in cholesterol metabolism and inflammation in microglia, the innate immune cells of the brain implicated in neurodegenerative conditions. Here, researchers focus instead on pericytes and their role in maintaining the blood-brain barrier. The barrier prevents unwanted molecules and cells from entering the brain, but becomes leaky with age. This leakage of the blood-brain barrier generates inflammation and damage in the brain, and is thought to be an early inciting event in the onset of neurodegenerative conditions.

Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity.

To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation.

Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated lipid droplet accumulation in APOE3 and APOE4 pericytes.

Link: https://doi.org/10.1093/brain/awag311

Given a wildly successful drug, the standard pharmaceutical industry playbook is to push as hard as possible to find new uses for that drug, an effort that will tend to increase publication on the topic in the academic literature. The drive to classify GLP-1 receptor agonists as an anti-aging drug rather than a weight loss drug is an example of this behavior. While, yes, there are a few interesting preclinical studies suggesting interesting biology going on in the brain at doses too low to cause weight loss, for the most part we are discussing an attempt to find additional anti-aging effects of a drug that makes patients engage in calorie restriction, the most robust anti-aging intervention known to date.

Calorie restriction produces sweeping, incompletely understood, beneficial changes to the operation of metabolism throughout the body, changes that, in preclinical studies in mice, outweigh every pharmacological approach demonstrated to date to slow aging - and most of that pharmacology merely mimics portions of the response to calorie restriction. It seems unlikely that one can analyze the human GLP-1 receptor agonist study data obtained to date and responsibly claim that GLP-1 receptor agonism is doing something meaningfully more for aging than only reducing calorie intake. Maybe it is, maybe it isn't - but this is trying to find a tree in the forest.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events, all-cause mortality, and systemic inflammation in randomized controlled trials, with effect sizes exceeding those predicted from glycemic and weight-related improvements alone. The convergence of these findings with a maturing body of evidence linking metabolic dysfunction to accelerated epigenetic aging has prompted renewed interest in GLP-1 RAs as candidate gerotherapeutic agents. The present review synthesizes contemporary preclinical, mechanistic, and clinical evidence relevant to this question.

The SELECT trial demonstrated a 19% reduction in all-cause mortality (hazard ratio [HR] 0.81) in patients with obesity without diabetes, the FLOW trial demonstrated a 24% reduction in the primary kidney composite endpoint (HR 0.76), and the first randomized evidence of GLP-1 RA modulation of validated DNA methylation clocks was reported in 2025, with significant deceleration of DunedinPACE, PCGrimAge, and PhenoAge over 32 weeks of semaglutide therapy. Mechanistic studies have identified convergent pathways involving the hypothalamic GLP-1 receptor, AMPK/SIRT1 signaling, and microbiome-derived short-chain fatty acid production. The aggregate evidence supports the framing of GLP-1 RAs as a candidate class of geroprotective therapeutics, although definitive trials with prespecified epigenetic aging endpoints, durability follow-up, body-composition assessment, prespecified sex-stratified analyses, and adequate representation of diverse populations remain to be conducted.

Link: https://doi.org/10.1016/j.exger.2026.113325