Aging disrupts intestinal stem cell (ISC) lineage fidelity, impairing epithelial barrier function and then promoting systemic health decline. In this study, we identify peroxisomal dysfunction as a critical driver of age-associated ISC mis-differentiation. Using Drosophila 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 β-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.
Copyright: © 2025 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.