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 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 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 · 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
