Fight Aging!

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