Alternate Day Fasting Enhances Intestinal Epithelial Function During Aging by Regulating Mitochondrial Metabolism

ABSTRACT With advancing age, the decline in intestinal stem cell (ISC) function can lead to a series of degenerative changes in the intestinal epithelium, a critical factor that increases the risk of intestinal diseases in the elderly. Consequently, there is an urgent imperative to devise effective dietary intervention strategies that target the alterations in senescent ISCs to alleviate senescence‐related intestinal dysfunction. The 28‐month‐old naturally aging mouse model was utilized to discover that the primary factor contributing to the compromised barrier function and digestive absorption of the small intestine was a decrease in both the number and regenerative capacity of ISCs. The underlying mechanism involves the degeneration of mitochondrial function in ISCs, resulting in insufficient energy supply and decreased metabolic capacity. Additionally, our findings indicate that fasting‐refeeding can influence the mitochondrial metabolism of ISCs, and that alternate day fasting (ADF) can facilitate the restoration of both the quantity and regenerative capabilities of ISCs, thereby exhibiting a notable antiaging effect on the small intestine. In conclusion, this study provides new insights into the potential beneficial role of ADF in ameliorating intestinal aging, thereby establishing a foundation for future investigations into dietary interventions aimed at addressing age‐related intestinal dysfunction.