N Nature Aging · Dec 03, 2025 Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer. Ageing Cancer biology mouse experiments
N Nature Aging · Nov 26, 2025 Organ-specific proteomic aging clocks predict disease and longevity across diverse populations Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer’s disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations. Wang, Xiao and colleagues develop and validate organ-specific proteomic aging clocks across large population cohorts in the UK, the USA and China, which show strong performance in tracking organ aging and predicting the risk of morbidity and mortality. Ageing Endocrine system and metabolic diseases Neurological disorders Predictive markers Psychiatric disorders biology
N Nature Aging · Nov 26, 2025 Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging Epigenetic drift is a key feature of aging and is associated with age-related diseases including cancer, yet the underlying molecular mechanisms remain unclear. Here, by analyzing DNA methylation and gene expression data from healthy and cancerous human colon samples, we identify an aging and colon cancer-associated DNA methylation (DNAm) drift. We find evidence that this drift is conserved in the mouse intestinal epithelium, where we demonstrate its origin within intestinal stem cells and identify its cell-intrinsic and non-mitotic characteristics, finding that its expansion is regulated via crypt clonality and fission. Mechanistically, we find that this drift is driven by age-related inflammation and reduced Wnt signaling, which dysregulate iron metabolism and impair TET activity. Despite CpG-level heterogeneity, we find that DNAm changes are consistent at the gene level, suggesting potential functionality. Our findings shed light on the epigenetic mechanisms of aging and provide a mechanistic basis for the hypermethylation observed in cancer. Ageing Cancer stem cells DNA methylation biology mouse experiments
N Nature Aging · Nov 25, 2025 Anti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms. Ageing Cell therapies Senescence biology mouse experiments
N Nature Aging · Nov 24, 2025 Dissecting the genetic and proteomic risk factors for delirium Delirium is an acute change in cognition, common in hospitalized older adults, and associated with high healthcare and human cost; however, delirium’s genetic and proteomic background remains poorly understood. Here we conducted a genetic meta-analysis on delirium using multi-ancestry data from the UK Biobank, FinnGen, All of Us Research Program and Michigan Genomics Initiative cohorts (n=1,059,130; 11,931 cases), yielding theApolipoprotein E(APOE) gene as a strong delirium risk factor independently of dementia. A multi-trait analysis of delirium with Alzheimer disease identified five delirium genetic risk loci. Plasma proteins associated with up to 16-year incident delirium in UK Biobank (n=32,652; 541 cases) revealed protein biomarkers implicating brain vulnerability, inflammation and immune response processes. Incorporating proteomic and genetic evidence via Mendelian randomization, colocalization and druggability analyses, we indicate potentially useful drug target proteins for delirium. Combining proteins,APOE-ε4 status and demographics significantly improved incident delirium prediction compared to demographics alone. Our results provide insight into delirium’s etiology and may guide further research on clinically relevant biomarkers. Ageing Genome-wide association studies Neurological disorders Proteomics biology
N Nature Aging · Nov 24, 2025 Clonal hematopoiesis in apparent treatment-resistant hypertension, insights from multiple medical centers and community-based cohorts Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and has been linked to cardiovascular disease. Apparent treatment-resistant hypertension (aTRH) is a severe, age-associated form of hypertension with poor response to therapy. Here we show that CHIP is enriched in patients with aTRH and is independently associated with poorer treatment response and adverse cardiac remodeling. In a multicenter discovery cohort and two community-based validation cohorts, CHIP was detected in ~23% of patients with aTRH versus ~7% of matched controlled-hypertension controls. CHIP carriers exhibited larger left ventricular dimensions, lower ejection fraction, elevated proinflammatory cytokines, smaller reductions in systolic and diastolic blood pressure after medication intensification and a substantially lower likelihood of achieving clinically controlled aTRH. Higher variant allele fraction and loss-of-function variants were linked to worse outcomes. These results identify CHIP as a common, clinically relevant biomarker in aTRH and suggest that targeting CHIP-related inflammation could improve antihypertensive treatment efficacy and outcomes. Ageing Genetic association study Genomics Haematological diseases biology
N Nature Aging · Nov 24, 2025 Targeting RhoA nuclear mechanoactivity rejuvenates aged hematopoietic stem cells Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechanosignaling, but its role in mechanotransduction in stem cell aging remains unclear. Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lympho/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function. Adult stem cells Ageing Epigenetic memory biology mouse experiments
N Nature Aging · Nov 20, 2025 Reprogramming the GRHL2−CDK19 axis by gene therapy alleviates prostate aging The prostate is a multifunctional organ of the male reproductive system whose aging process impairs sexual and urinary function and fertility and increases disease susceptibility, thereby compromising quality of life. However, the mechanisms underlying human prostate aging remain poorly understood. Here we integrated single-nucleus transcriptomics and histological analyses to elucidate the aging mechanisms of the primate prostate. We identified epithelial cell senescence, chronic inflammation and fibrosis as key hallmarks of prostate aging. In young epithelial cells, GRHL2 promotesCDK19transcription, which sequesters p53, leading to the suppression ofp21Waf1/Cip1. Aging-related downregulation of GRHL2 releases p53 from the CDK19−p53 complex, activatingp21Waf1/Cip1transcription and inducing cell senescence. Accordingly, a single injection of a GRHL2-based gene therapy strategy delayed prostate aging and alleviated age-related urinary dysfunction in vivo. Our findings elucidate key mechanisms of primate prostate aging and provide a foundation for developing therapies targeting prostate aging and associated pathologies. Ageing Predictive markers Senescence Transcription biology mouse experiments
N Nature Aging · Nov 17, 2025 Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis Somatic mutation is now recognized as a cause of multiple human diseases other than cancer. Osteoarthritis (OA), a highly prevalent age-related disease, has been associated with increased chromosomal abnormalities in articular cartilage. Here we characterize the somatic mutational landscape of chondrocytes during normal aging and in affected cartilage of patients with OA. We used single-cell whole-genome sequencing to analyze single-nucleotide variants (SNVs) and small insertions and deletions (InDels) in 100 chondrocytes isolated from the cartilage of hip femoral heads of 17 research participants aged 26−90 years, including 9 patients with OA and 8 non-OA donors. Both SNVs and InDels accumulate with age in chondrocytes with a clock-like mutational signature. Surprisingly, the age-related accumulation rate in OA chondrocytes is lower than that in non-OA control chondrocytes. Differences in mutational signatures and Gene Ontology term enrichment were found between OA and non-OA control samples. In this study, to understand the role of somatic mutation in the pathogenesis of OA, we characterized somatic SNV and InDel mutations. With further progress in analytical approaches, structural variations in the chondrocyte genome are also expected to provide valuable information. Somatic mutations accumulate with age and have been linked to functional decline and disease. Single-cell analysis of human cartilage samples from donors with and without osteoarthritis shows that somatic mutations accumulate with age, but, in osteoarthritis, they show distinct mutational patterns and slower accumulation, possibly due to DNA-damage-induced chondrocyte death. Ageing Genomic instability biology
N Nature Aging · Nov 10, 2025 Multilingualism protects against accelerated aging in cross-sectional and longitudinal analyses of 27 European countries Aging trajectories are influenced by modifiable risk factors, and prior evidence has hinted that multilingualism may have protective potential. However, reliance on suboptimal health markers, small samples, inadequate confounder control and a focus on clinical cohorts led to mixed findings and limited applicability to healthy populations. Here, we developed biobehavioral age gaps, quantifying delayed or accelerated aging in 86,149 participants across 27 European countries. National surveys provided individual-level positive (functional ability, education, cognition) and adverse (cardiometabolic conditions, female sex, sensory impairments) factors, while country-level multilingualism served as an aggregate exposure. Biobehavioral factors predicted age (R2= 0.24,r= 0.49, root mean squared error = 8.61), with positive factors linked to delayed aging and adverse factors to accelerated aging. Multilingualism emerged as a protective factor in cross-sectional (odds ratio = 0.46) and longitudinal (relative risk = 0.70) analyses, whereas monolingualism increased risk of accelerated aging (odds ratio = 2.11; relative risk = 1.43). Effects persisted after adjusting for linguistic, physical, social and sociopolitical exposomes. These results underscore the protective role of multilingualism and its broad applicability for global health initiatives. Ageing Biomarkers Computational biology and bioinformatics other
N Nature Aging · Nov 06, 2025 Fluorescence lifetime clocks quantify senescence and aging Epigenetic and omics-based clocks have provided invaluable tools to quantify aging, yet these clocks do not provide direct readouts of aging in real-time in living systems. As methylation changes in nucleolar ribosomal DNA are reliably associated with aging and cellular senescence, we hypothesized that shifts in rRNA species could be leveraged to generate image-based clocks using selective dyes. Here we engineer sensitive and photostable hybrid polymethine dyes selective for rRNA. We present a fluorescence lifetime imaging strategy to visually quantify age- and cellular senescence-dependent nucleolar RNA changes that bypasses requirements for extensive sample preparation such as DNA isolation and enables in vivo, real-time age quantification. We demonstrate resolution through cellular to organismal scales and demonstrate translatability by generating clocks from cells and tissues, as well asCaenorhabditis elegans, mice and human samples. Our fluorescence lifetime imaging strategy thus enables in vivo measurements of aging and senescence and expands the toolbox for aging biology research and translation. Ageing Fluorescence imaging RNA biology mouse experiments
N Nature Aging · Nov 04, 2025 Cell populations in human breast cancers are molecularly and biologically distinct with age Aging is associated with increased breast cancer risk, and the oldest and youngest patients have worse outcomes, irrespective of subtype. It is unknown how age affects cells in the breast tumor microenvironment or how they contribute to age-related pathology. Here we discover age-associated differences in cell states in human estrogen receptor-positive and triple-negative breast cancers using analyses of existing bulk and single-cell transcriptomic data. We generate and apply an Age-Specific Program ENrichment (ASPEN) analysis pipeline, revealing age-related changes, including increased tumor cell epithelial–mesenchymal transition and cancer-associated fibroblast inflammatory responses in triple-negative breast cancer. Estrogen receptor-positive breast cancer displays increasedESR1expression and reduced vascular and immune cell metabolism with age. Cell interactome analysis reveals candidate signaling pathways that drive age-related cell states. Spatial analyses across independent clinical cohorts support the computational findings. This work identifies potential targets for age-adapted therapeutic interventions for breast cancer. Ageing Cancer Computational biology and bioinformatics biology estrogen mouse experiments
N Nature Aging · Nov 04, 2025 Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression Most cancers are diagnosed in people over 60 years of age, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation (widely understood to contribute to cancer risk) it is associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses oncogenic KRAS-driven tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K–AKT pathway, weakened disproportionately. Single-cell transcriptomic analysis revealed that neoplastic cells in aged mice retain age-related transcriptomic changes, showing that the impact of age persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings underscore the interconnectedness of the pathways involved in aging and tumorigenesis and document tumor-suppressive effects of aging that may contribute to the deceleration in cancer incidence with age. Ageing Cancer models Tumour-suppressor proteins biology mouse experiments
N Nature Aging · Nov 04, 2025 Hospital-treated infectious diseases and the risk of epilepsy in older age Infectious diseases are known to trigger acute seizures, but their long-term impact on epilepsy, especially in later life, is unclear. We conducted nested case–control studies of newly diagnosed epilepsy after age 50 in the UK Biobank (2,486 cases; 12,430 controls) and Swedish registers (56,266 cases; 281,330 controls), including a sibling comparison. Previous hospital-treated infections were associated with a persistently elevated epilepsy risk (for example, >10 years after infection: odds ratio (OR) 1.68, 95% confidence interval: 1.39–2.04 in UK Biobank; 1.46, 1.41–1.51 in Sweden). Associations were robust in sibling analyses and across infection types and sites. We further found that infections, together with a high cardiovascular genetic risk (OR 2.62, 2.22–3.08), a high cardiovascular risk score (OR 3.14, 2.68–3.68) or cardiovascular disease history (OR 4.77, 4.64–4.91), were associated with the highest epilepsy risk. Hospital-treated infections exert prolonged impact on epilepsy risk in older age, especially when in combination with cardiovascular risk factors. Ageing Epilepsy Infectious diseases biology
N Nature Aging · Nov 03, 2025 A versatile cohesion manipulation system probes female reproductive age-related egg aneuploidy Female reproductive aging is accompanied by a sharp increase in egg aneuploidy rates. Premature loss of chromosome cohesion proteins and early separation of chromosomes are thought to cause high aneuploidy rates during maternal aging. However, because cohesion loss occurs gradually throughout a woman’s reproductive lifespan, and because cytoskeletal defects alone can lead to chromosomal abnormalities, the main causes of the rapid rise in aneuploidy at older reproductive ages are still unclear. In this study, we created a versatile and tunable cohesion manipulation system that enables rapid, dose-dependent degradation of the meiotic cohesin REC8 in live mouse oocytes. By coupling this system with quantitative high-resolution live imaging, we directly observed cohesion protein behavior during meiosis and tested the longstanding threshold model of aneuploidy development. Our results show that premature sister chromatid separation sharply increases only when REC8 levels drop below a critical threshold, supporting the idea of a nonlinear, vulnerability-triggering cohesion limit. We also used our system to examine how other age-related issues, such as cytoskeletal disruption and partial centromere dysfunction, can exacerbate chromatid separation in the context of weakened cohesion. This work provides a tractable oocyte platform for modeling and dissecting the multifactorial mechanisms driving female reproductive age-related egg aneuploidy. Ageing Centromeres Chromosome segregation Cohesion Meiosis biology mouse experiments
N Nature Aging · Oct 31, 2025 Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day−1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83;P= 0.0437) while also increasing CD8+fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99;P= 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+cells, increased peripheral CD56dimCD16brightNK cells, and nonclassical CD14loCD16himonocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number:NCT05735886. Ageing Inflammation Lymphocytes biology mouse experiments
N Nature Aging · Oct 29, 2025 Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling Sarcopenia, the age-related decline in muscle mass, strength and function, is characterized by impaired muscle homeostasis, reduced regenerative potential of muscle stem cells (MuSCs) and increased fibrosis. Here we report that aged MuSCs can autonomously instruct fibro-adipogenic progenitors (FAPs) to proliferate and acquire a fibrogenic phenotype, independent of other cell types. Both the polycomb-deficientEzh2−/−mouse model and aged mice exhibited defective regeneration, FAP expansion, fibrosis and elevated secretion of interleukin 6 (IL-6) and secreted phosphoprotein 1 (Spp1; osteopontin) by MuSCs. In aged MuSCs, reduction of the histone H3K27me3 repressive mark at theNfbk1gene correlated with its increased expression and enhanced chromatin recruitment to theIL6andSpp1genes, leading to their activation. Pharmacological inhibition of IL-6 and Spp1 signaling in co-culture systems or in aged mice reduced FAP proliferation and muscle fibrosis. These findings indicate that epigenetic dysregulation of aged MuSCs contributes to aged-related muscle fibrosis. Ageing Muscle stem cells biology mouse experiments
N Nature Aging · Oct 29, 2025 Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer’s pathogenesis Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer’s disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD. Ageing Mechanisms of disease Neuroimmunology biology mouse experiments
N Nature Aging · Oct 24, 2025 Single-cell analysis of human thymus and peripheral blood unveils the dynamics of T cell development and aging Age-related thymic involution increases vulnerability to cancers and infection in older adults, yet the driving mechanisms and its impact on peripheral T cells remain unclear. Using single-cell sequencing, we here analyzed 387,762 cells from human thymus and peripheral blood of young and aged individuals. Within thymus, we found aging reduced T-lineage potential in early thymic progenitors but increased innate lymphocyte lineage potential. Aged thymus were enriched in mature T cells with low SOX4 expression and inflammatory profiles but depleted of thymic epithelial cells and expression of tissue-restricted antigens. In the periphery, we identified transcriptional features of T cell aging and established a naive T cell-based model for immune age prediction. Furthermore, we identified CD38 as a marker of recent thymic emigrants. Finally, single-cell T cell receptor (TCR) repertoire sequencing identified shifts in TCR repertoire diversity within memory/effector T cells and expanded virus-specific T cells during aging. Collectively, our data offer insights into human thymic involution and peripheral T cell aging and could inform strategies to restore compromised T cell immunity. Profiling the human thymus and peripheral blood, Deng and colleagues demonstrate impaired T cell development and compromised thymic microenvironment during aging, reveal inflammatory characteristics of T cell aging and generate a naive T cell-based model for immune age prediction. Ageing Lymphocytes biology
N Nature Aging · Oct 17, 2025 Heme and iron toxicity in the aged spleen impairs T cell immunity through iron deprivation Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with immune and stromal cells. Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging. Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice. This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging. Ageing Cytokines Lymphocytes Metabolism biology mouse experiments
N Nature Aging · Oct 08, 2025 The secreted metabolite sensor CtBP2 links metabolism to healthy lifespan Within each cell, metabolite-sensing factors respond to coordinate metabolic homeostasis. How metabolic homeostasis is regulated intercellularly and how this may become dysregulated with age, however, remains underexplored. Here we describe a system regulated by a metabolite sensor, CtBP2. CtBP2 is secreted via exosomes in response to reductive metabolism, which is suppressed by oxidative stress. Exosomal CtBP2 administration extends lifespan in aged mice and improves healthspan in particular by reducing frailty. Mechanistically, we identify activation of CYB5R3 and AMPK downstream of exosomal CtBP2. Consistently, serum CtBP2 levels decrease with age and are negatively associated with cardiovascular disease incidence in humans yet are elevated in individuals from families with a history of longevity. Together our findings define a CtBP2-mediated metabolic system with potential for future clinical applications. Ageing Endocrine system and metabolic diseases Metabolism Molecular biology biology mouse experiments
N Nature Aging · Oct 07, 2025 CD4 T cells acquire Eomesodermin to modulate cellular senescence and aging Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases. Senescent cells (SCs) accumulate with age, but how the immune system regulates their burden is unclear. Here we show that CD4 T cells differentiate into Eomesodermin (Eomes)+CCL5+T lymphocytes (CD4-Eomes) in a SC-rich environment and that a reduction in the SC load, achieved using senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4-Eomes cells at advanced age by selectively deleting the Eomes transcription factor in CD4 T cells results in increased accumulation of SCs, profound physical deterioration and a decreased lifespan. In liver cirrhosis, a model of localized chronic inflammation, CD4-Eomes cell elimination increased fibrosis, SC load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4-Eomes cells in modulating tissue senescence, with implications for age-related diseases and longevity. Ageing Lymphocytes Senescence Immunology Mouse Drug Development
N Nature Aging · Oct 03, 2025 Genome-wide analysis of brain age identifies 59 associated loci and unveils relationships with mental and physical health Neuroimaging and machine learning are advancing research into the mechanisms of biological aging. In this field, ‘brain age gap’ has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual’s biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of 23–29% attributable to common genetic variants and highlighted 59 associated loci (39 novel). The leading locus encompassesMAPT, encoding the tau protein central to Alzheimer’s disease. Genetic correlations revealed relationships with mental health, physical health, lifestyle and socioeconomic traits, including depressed mood, diabetes, alcohol intake and income. Mendelian randomization indicated a causal role of high blood pressure and type 2 diabetes in accelerated brain aging. Our study highlights key genes and pathways related to neurogenesis, immune-system-related processes and small GTPase binding, laying the foundation for further mechanistic exploration. Ageing Brain Genetics of the nervous system Genome-wide association studies Neural ageing Neuroscience Genomics Machine Learning Human
N Nature Aging · Sep 30, 2025 ZDHHC11-mediated palmitoylation alleviates chondrocyte senescence and serves as a therapeutic target for osteoarthritis Osteoarthritis (OA) is a whole-joint disorder that interferes with the quality of life in older individuals. Here we report that ZDHHC11 is highly expressed in articular chondrocytes but is downregulated in the degenerated cartilage of aged mice and patients with OA. ZDHHC11 prevents chondrocyte senescence and promotes cartilage anabolism, culminating in an improved OA phenotype. The deletion ofZdhhc11in mice (Zdhhc11fl/fl) exacerbates OA progression in a destabilized medial meniscus model. Specifically, we identify ZDHHC11 as a key palmitoyltransferase whose depletion leads to a GNB2-dependent E3 ubiquitin ligase-mediated proteasomal degradation of APOD. Mechanistically, ZDHHC11-mediated palmitoylation alleviates OA progression by deactivating the GATA4–P65 signaling pathway. We also propose an original lipid nanoparticle-based platform forZdhhc11mRNA delivery to rejuvenate impaired cartilage by specifically targeting chondrocytes in vivo. Collectively, ZDHHC11-dependent palmitoylation is essential for ameliorating OA, and the targeted delivery of ZDHHC11 may serve as a promising strategy for future OA treatment. Ageing Mechanisms of disease Post-translational modifications Senescence Developmental Biology Mouse Human Drug Development Cell Biology
N Nature Aging · Sep 29, 2025 Elastin-derived extracellular matrix fragments drive aging through innate immune activation The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n= 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response. Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals. Ageing Drug discovery Immunology Predictive markers Immunology Mouse Human Drug Development Clinical
N Nature Aging · Sep 25, 2025 A distinct population of CD8+T cells expressing CD39 and CD73 accumulates with age and supports cancer progression Age-related increases in cancer have traditionally been attributed to compromised antitumor immunity of exhausted and dysfunctional CD8⁺ T cells. Here we provide an alternative mechanism: in aging, cancer also progresses with the help of fully functional CD8⁺ T cells. These transcriptionally and epigenetically distinct cells (termed double-positive CD8+T cells (DP8)) express CD39, CD73, CD101 and CXCR6 on their surface and accumulate during healthy aging in mice, requiring B cells presenting cognate antigens. In aged mice, progressing tumors recruit DP8 cells via the CXCL16–CXCR6 axis to suppress antitumor CD4+T cells in an ADP/adenosine-dependent manner, and targeting DP8 cell function or recruitment can reverse tumor growth in aged mice. This tumor-promoting mechanism of DP8 cells appears to be conserved in older humans, as we detected DP8-like cells in various tumors, including late-onset breast cancer. We propose that this tumor-promoting role of CD8+T cells should be considered in the development of therapeutics tailored for older humans. Ageing Cancer models Lymphocytes Immunology Cancer Mouse Human Drug Development
N Nature Aging · Sep 24, 2025 Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improvespink-1-dependent heat stress resilience inCaenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion. Ageing Experimental models of disease High-throughput screening Metabolic disorders Mitophagy Metabolism Mouse C. elegans Drug Development Developmental Biology
N Nature Aging · Sep 15, 2025 Systems Age: a single blood methylation test to quantify aging heterogeneity across 11 physiological systems Aging occurs at different rates across individuals and physiological systems, but most epigenetic clocks provide a single age estimate, overlooking within-person variation. Here we developed systems-based DNA methylation clocks that measure aging in 11 distinct physiological systems—Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone and Metabolic—using data from a single blood draw. By integrating supervised and unsupervised machine learning with clinical biomarkers, functional assessments and mortality risk, we derived system-specific scores that outperformed existing global clocks in predicting relevant diseases and aging phenotypes. We also created a composite Systems Age score to capture overall multisystem aging. Clustering individuals based on these scores revealed distinct biological aging subtypes, each associated with unique patterns of health decline and disease risk. This framework enables a more granular and clinically relevant assessment of biological aging and may support personalized approaches to monitor and target system-specific aging processes. Ageing Machine learning Prognostic markers Genomics Machine Learning Human Clinical
N Nature Aging · Sep 10, 2025 Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan Membraneless organelles assembled by liquid–liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. InCaenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid–liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress. Ageing Mitochondria C. elegans Cell Biology Metabolism Developmental Biology
N Nature Aging · Sep 10, 2025 Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia Aging is a major risk factor for various neurological disorders, including Alzheimer’s disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment withTspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy. Ageing Monocytes and macrophages Neural ageing Neuroscience Immunology Mouse Cell Biology
N Nature Aging · Sep 10, 2025 Plasma proteomic associations with Alzheimer’s disease endophenotypes Clinical Alzheimer’s disease is currently characterized by cerebral β-amyloidosis associated with cognitive impairment. However, most cases of Alzheimer’s disease are associated with multiple neuropathologies at autopsy. The peripheral protein changes associated with these disease endophenotypes are poorly understood. In this study, we analyzed the plasma proteomes of individuals from four cohorts (n= 2,139 participants) to identify proteins and pathways associated with cerebral β-amyloidosis and other neuropathologies, including tau, Lewy bodies, TDP43, cerebral amyloid angiopathy, atherosclerosis, arteriolosclerosis and infarcts as well as cognitive function. Analyses in a cohort with paired brain data showed that known neuropathologies could account for only half of proteins associated with cognitive function and that many plasma proteins associated with these neuropathologies are not strongly correlated to levels in brain, suggesting a potential contribution of peripheral factors to the development of Alzheimer’s disease endophenotypes. Targeting pathways represented by these peripheral proteins may modify Alzheimer’s disease risk or disease progression. Ageing Alzheimer's disease Neurodegeneration Proteomic analysis Systems analysis Neuroscience Proteomics Human Clinical
N Nature Aging · Sep 05, 2025 A blood-based DNA damage signature in patients with Parkinson’s disease is associated with disease progression Aging is the main risk factor for Parkinson’s disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson’s Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit, this DNA damage signature was detected only in patients with more severe progression of motor symptoms over 3 years, suggesting its potential as a predictor of disease severity. We validated this signature in independent PD cohorts and confirmed increased DNA damage in peripheral blood cells and dopamine neurons of the substantia nigra pars compacta in postmortem PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies potential markers of disease progression, providing a diagnostic platform to prognosticate disease progression. Ageing Parkinson's disease Predictive markers Neuroscience Genomics Human Clinical
N Nature Aging · Sep 03, 2025 The aging factor EPS8 induces disease-related protein aggregation through RAC signaling hyperactivation Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington’s disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperactivation of EPS8/RAC signaling inCaenorhabditis eleganspromotes the pathological aggregation of Huntington’s disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown ofeps-8orRACorthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases. Ageing Mechanisms of disease Protein aggregation Ubiquitylation Neuroscience C. elegans Human Developmental Biology Drug Development
N Nature Aging · Aug 26, 2025 Mevalonate metabolites boost aged oocyte quality through prenylation of small GTPases Declining oocyte quality is the major contributor to female subfertility in aged mammals. Currently, there are no effective interventions to ameliorate aged oocyte quality. Here we found that oocytes at metaphase I from the cumulus–oocyte complexes of aged mice showed reduced cortical F-actin and lower levels of mevalonate (MVA) pathway metabolites, including MVA, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate. We further showed that MVA supplementation improved FPP levels, cortical F-actin and the quality of aged oocytes. Mechanistically, we found that MVA supplementation induced granulosa cells to synthesize FPP, which was subsequently transferred to aged oocytes. Transported FPP increased the prenylation of small GTPases, including CDC42 and RAC1, and promoted membrane localization of CDC42–N-WASP–Arp2/3 and RAC1–WAVE2–Arp2/3 complexes, promoting cortical F-actin reassembly and reducing aneuploidy of aged oocytes. We also identified a natural chemical compound, 8-isopentenyl flavone, with an isopentenyl side chain fromEpimedium brevicornuMaxim, which could increase CDC42 and RAC1 prenylation, improving the cortical F-actin and the competence of aged oocytes, and ameliorating reproductive outcomes in aged female mice. Collectively, increasing the prenylation of small GTPases via MVA metabolites or 8-isopentenyl flavone provides a therapeutic approach for boosting female fertility during reproductive aging. Ageing Reproductive disorders Senescence Developmental Biology Mouse Metabolism Drug Development
N Nature Aging · Aug 20, 2025 Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength Aging is associated with a progressive decline in tissue function and regenerative capacity, partly due to genomic instability, one of the hallmarks of aging1,2. Genomic instability encompasses DNA damage and the accumulation of somatic mutations in post-zygotic cells, yet the specific impact of these mutations on age-related tissue dysfunction remains poorly understood. To address this, we developed a mouse model in which genomic instability was induced specifically in muscle progenitor cells3through targeted deletion of theMsh2(ref.4) andBlm5genes. This allowed us to assess how elevated DNA damage and somatic mutations, from single-nucleotide variants (SNVs) to structural variants, affect muscle regeneration following injury. These mice exhibited impaired muscle regeneration, characterized by smaller muscle fibers, reduced muscle mass gain and decreased grip strength. Importantly, similar muscle deficits were observed in a second mouse model where somatic mutations were elevated with less substantial DNA damage. These findings provide evidence that the accumulation of somatic mutations can potentially compromise the function of somatic cells, contributing to the aging phenotype in skeletal muscle. Ageing Diseases DNA mismatch repair Experimental models of disease Genomic instability Genetics Mouse Developmental Biology
N Nature Aging · Aug 19, 2025 Targeting iron-associated protein Ftl1 in the brain of old mice improves age-related cognitive impairment Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that impairs cognition. Using transcriptomic and mass spectrometry approaches, we detect an increase in neuronal FTL1 in the hippocampus of aged mice, the levels of which correlate with cognitive decline. Mimicking an age-related increase in neuronal FTL1 in young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting neuronal FTL1 in the hippocampi of aged mice improves synaptic-related molecular changes and cognitive impairments. Using neuronal nuclei RNA sequencing, we detect changes in metabolic processes, such as ATP synthesis, and boosting these metabolic functions through NADH supplementation mitigated pro-aging effects of neuronal FTL1 on cognition. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation. Ageing Cognitive ageing Hippocampus Molecular neuroscience Neural ageing Neuroscience Mouse Metabolism Genomics Proteomics
