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Aging-related peroxisomal dysregulation disrupts intestinal stem cell differentiation through alterations of very long-chain fatty acid oxidation

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Listed:
  • Xiaoxin Guo
  • Gang Du
  • Juanyu Zhou
  • Fang Fu
  • Yu Yuan
  • Xingzhu Liu
  • Haiou Chen
  • Qianyi Wan
  • Bo Gong
  • Haiyang Chen

Abstract

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.Aging disrupts intestinal stem cell (ISC) lineage fidelity, impairing epithelial barrier function, but the mechanisms underlying this process are unclear. This study shows that PEX5 reduction impairs peroxisomal matrix protein import leading to ISC mis-differentiation, and that Aspirin enhances the β-oxidation of very long-chain fatty acids, mediated by PEX5, restoring the process.

Suggested Citation

  • Xiaoxin Guo & Gang Du & Juanyu Zhou & Fang Fu & Yu Yuan & Xingzhu Liu & Haiou Chen & Qianyi Wan & Bo Gong & Haiyang Chen, 2025. "Aging-related peroxisomal dysregulation disrupts intestinal stem cell differentiation through alterations of very long-chain fatty acid oxidation," PLOS Biology, Public Library of Science, vol. 23(12), pages 1-25, December.
    • Handle: RePEc:plo:pbio00:3003552
    DOI: 10.1371/journal.pbio.3003552
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