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 20, 2025 Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. Here we show that 49 proteins are associated with MRI markers of cSVD, most prominently in cerebrospinal fluid. We highlight associations that are consistent across platforms and ancestries, and supported by complementary observational analyses, and we explore differences between fluids. The proteins are enriched in pathways related to the extracellular matrix, immune response and microglial activity. Many also associate with stroke and dementia, and several correspond to existing drug targets. Together, these findings reveal a robust biological fingerprint of cSVD and highlight opportunities for biomarker and drug discovery and repositioning. Cerebrovascular disorders Neurovascular disorders biology
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
