Age-Associated Impairment of Paneth Cells Driven by microRNA-152 Promotes Intestinal Epithelial Vulnerability to Pathological Stress.

Advanced age is a well-known risk factor for severe complications in surgical patients with critical illnesses, partly due to declined intestinal mucosal defense, but the underlying mechanism remains largely unknown. Our study provided direct evidence from older human and mouse small intestines of the adverse impact of aging on Paneth cell functionality by impaired mitochondrial metabolism. Mechanistic investigation revealed a specific elevation of Paneth cell enriched microRNA-152 (miR-152) in aging small intestinal epithelium. Increased miR-152 impaired Paneth cells of aging small intestine by inhibiting mitochondrial protein Prohibitin1 (PHB1) expression and disrupting mitochondrial respiration. Moreover, the levels of circHIPK3, an intestinal circular RNA that counters the function of miR-152, also declined in older intestines, further enabling miR-152-mediated deterioration in Paneth cell function. Conversely, antagonizing miR-152 improved mitochondrial metabolism by restoring PHB1 levels and ameliorated the functional decline of old Paneth cells. Our findings indicate that dysregulated miR-152 expression and activity play a central role in the loss of Paneth cell homeostasis in the aging small intestine, offering translational insights for protecting intestinal mucosal integrity in older patients.