Objective To determine the effect of aldehyde dehydrogenase 2 (ALDH2) activation on the cardioprotection of ischemic preconditioning (IPC) in the elderly mice, and analyze the possible mechanism on aging-related IPC cardioprotection decline by investigating the difference of silent information regulator related enzyme 1 (SIRT1) activity during the IPC process between the adult and aged mice. Methods Male C57BL/6 adult (2 months old) and aged (20 months old) mice (6 in each group) were subjected to IPC (left anterior descending coronary artery was occluded for 3×5min, interspersed with 5min of reperfusion) and followed by ischemia/reperfusion (I/R, 30min ischemia/4h reperfusion) injury. Hearts from aged C57BL/6 mice were Langendorff-perfused and subjected to in vitro IPC and I/R injury for cardiac function recording. At the end of reperfusion, ALDH2 and SIRT1 activity and protein carbonylation in the myocardial tissue in vivo and in vitro were measured. Results Compared with the adult hearts, IPC treatment failed to decrease I/R injury nor increase SIRT1 activity in the aged myocardium (P＜0.05). A significant decrease in ALDH2 activity was observed in the aged hearts (P＜0.05), which then resulted in enhanced carbonyl stress in I/R aged hearts (P＜0.05). Also, IPC treatment failed to improve ALDH2 activity nor decrease carbonyl stress in the aged myocardium (P＜0.05). ALDH2 Activation inhibited the carbonylation level and restored the IPC-induced SIRT1 activation in aged hearts (P＜0.05), which further promoted the recovery of systolic and diastolic function after I/R injury in aged hearts. Conclusion Activating myocardial ALDH2 significantly improves the cardioprotection of IPC in aged hearts, which might be due to SIRT1 inactivation induced by suppressing carbonyl stress.