Autophagy Suppresses Age-Dependent Ischemia and Reperfusion Injury in Livers of Mice

BACKGROUND & AIMS—As life expectancy increases, there are greater numbers of patients with liver diseases that require surgery or transplantation. Livers of older patients have significantly less reparative capacity following ischemia and reperfusion (I/R) injury, which occurs during these operations. There are no strategies to reduce the age-dependent I/R injury. We investigated the role of autophagy in the age dependence of sensitivity to I/R injury. METHODS—Hepatocytes and livers from 3- and 26-month–old mice were subjected to in vitro and in vivo I/R, respectively. We analyzed changes in autophagy-related proteins (Atg). Mitochondrial dysfunction was visualized using confocal and intravital multiphoton microscopy of isolated hepatocytes and livers from anesthetized mice, respectively. RESULTS—Immunoblot, autophagic flux, genetic, and imaging analyses all associated the increase in sensitivity to I/R injury with age with decreased autophagy and subsequent mitochondrial dysfunction, due to calpain-mediated loss of Atg4B. Overexpression of eithe