Oxidative stress-associated intestinal stem cell dysfunction during aging is attenuated by chlorogenic acid in a CncC-dependent manner

Aging-associated intestinal dysfunction is characterized by impaired epithelial homeostasis, excessive intestinal stem cell (ISC) proliferation, and progressive barrier deterioration. Although oxidative stress is widely recognized as a major driver of intestinal aging, the mechanisms linking redox imbalance to ISC dysregulation remain incompletely understood. In this study, we investigated the effects of dietary chlorogenic acid (CGA) treatment using Drosophila models of physiological aging, H₂O₂-induced oxidative stress, and high-sucrose feeding. CGA treatment was associated with reduced ROS accumulation, DNA damage response, and aberrant ISC proliferation under stress conditions. Genetic analysis further demonstrated that CncC, the Drosophila ortholog of NRF2, is required for these protective effects, although our data do not establish direct activation of CncC by the parent CGA molecule or its metabolites. Transcriptomic analysis revealed CGA-associated changes in pathways related to antioxidant defense, genome maintenance, and cell cycle regulation. CGA treatment improved intestinal barrier integrity and reduced stress-associated autophagic responses. Collectively, our findings demonstrate that the intestinal protective effects observed following CGA treatment are associated with attenuation of oxidative stress and require CncC-dependent capacity. These findings extend the redox-protective effects observed following dietary CGA treatment to aging-associated ISC and epithelial homeostasis and provide a framework for further investigation of dietary bioactive compounds in aging.