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In this study, we identify peroxisomal dysfunction as a critical driver of age-associated ISC mis-differentiation. Using\n                    <jats:italic>Drosophila<\/jats:italic>\n                    and mouse colonic organoids, we demonstrate that reduced PEX5 expression in aged ISCs impairs peroxisomal matrix protein import, leading to very long-chain fatty acids (VLCFAs) accumulation. In addition, we found that RAB7-dependent late endosome maturation and SOX21A were downstream of the peroxisome in controlling aged ISC differentiation. Aspirin, a classic anti-inflammatory drug, restores ISC lineage fidelity by enhancing PEX5-mediated peroxisomal \u03b2-oxidation of VLCFAs. Taken together, these findings highlight peroxisomal dysfunction and VLCFA metabolism as pivotal regulators of ISC aging and suggest new therapeutic strategies for combating age-related intestinal decline.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003552","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T18:27:09Z","timestamp":1766168829000},"page":"e3003552","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Aging-related peroxisomal dysregulation disrupts intestinal stem cell differentiation through alterations of very long-chain fatty acid 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