Single-nucleus interrogation of primate small intestinal aging reveals NCoR1 decline as a conserved feature that is...

How the small intestine ages at the cellular and molecular level has been unclear. Here we profile single nuclei from young and aged primate small intestine and find that aging brings barrier dysfunction, chronic inflammation and a shift in stem cell differentiation away from absorptive cells toward secretory cells. Through integrative multimodal analysis, we identify the transcriptional corepressor NCoR1 as a key player whose decline is conserved in the aging human gut. In human intestinal epithelial cells and organoids, knocking down NCOR1 recapitulates aging phenotypes including senescence, disrupted junctions and lineage imbalance, whereas overexpressing NCoR1 alleviates them. Metformin-a geroprotective drug-restores NCoR1 levels and delays intestinal aging in nonhuman primates. Our work points to NCoR1 as a central regulator of small intestinal aging and suggests a pharmacologically actionable strategy to counter age-related intestinal decline.