Abstract: AIM Research shows that aging hearts have less tolerance to myocardial ischemia reperfusion (I/R) injury and this leads to the design of investigating the role of necroptosis in senescent myocardial I/R injury. METHODS Male C57BL/6 mice aged 22-24 months were randomized into I/R group and vehicle control group. Adult male (3-4 months) C57BL/6 mice served as control group. The left anterior descending artery was ligated for 30 min followed by 4 h reperfusion to establish the acute myocardial I/R mouse model. Myocardial tissue was obtained after reperfusion. Western blot was used to detect necroptosis-related protein expression. Co-immunoprecipitation was used to detect the modification of the necroptosis-related protein. RESULTS Necroptosis was commonly increased in hearts of aged mice (P<0.05). The expression of necroptosis biomarker, RIP1 and RIP3, is increased (P<0.05). Expression and activity of the regulator protein deacetylase SIRT2 increased as well as the deacetylation of RIP1 (P<0.05). Meanwhile, inhibiting necroptosis by using the inhibitor necrostatin-1 (Nec-1) reduced the infarct size in aged hearts (P<0.05). CONCLUSIONN ecroptosis displays an increased expression in aged myocardial I/R injury, indicating the important role necroptosis plays in age-related myocardial ischemia injury.