Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism

A novel stress-inducible protein, Sestrin2 (Sesn2), declines in the heart with aging. AMPK has emerged as a pertinent stress-activated kinase that has been shown to have cardioprotective capabilities against myocardial ischemic injury. We identified the interaction between Sesn2 and AMPK in the ischemic heart. To determine whether ischemic AMPK activation—modulated by the Sesn2-AMPK complex in the heart—is impaired in aging that sensitizes the heart to ischemic insults, young C57BL/6 mice (age 3–4 mo), middle-aged mice (age 10–12 mo), and aged mice (age 24–26 mo) were subjected to left anterior descending coronary artery occlusion for in vivo regional ischemia. The ex vivo working heart system was used for measuring substrate metabolism. The protein level of Sesn2 in hearts was gradually decreased with aging. Of interest, ischemic AMPK activation was blunted in aged hearts compared with young hearts (P < 0.05); the AMPK downstream glucose uptake and the rate of glucose oxidation were significantly impaire...