Caloric Restriction Increases the Resistance of Aged Heart to Myocardial Ischemia/Reperfusion Injury

Ischemic tolerance of heart decreases with age. Caloric restriction (CR) is the most reliable intervention to extend lifespan and prevent age-related disorders. We have revealed that both AMPK and SIRT1 signaling pathways are involved in the impairments occurred in aged hearts. We hypothesize that cardiac AMPK-SIRT1 signaling cascade mediates the increased tolerance of aged heart to ischemic insults by caloric restriction. Aged (18-20 months) mice were divided into 2 groups: al libitum (AL) food intake group and caloric restriction (diet 70% of standard food intake for 6 weeks) (CR) group. Each group was divided into sham operations and ischemia/reperfusion (I/R) semi-groups. I/R groups were subjected to ligation of left anterior descending coronary artery for 30 min of ischemia and 24 hours of reperfusion. The body fat composition was significantly decreased in CR group vs. AL group, moreover, the maximum of oxygen consumption was significantly improved in CR group vs. AL group. Importantly, there is a significantly smaller myocardial infarction size induced by ischemia (30 min) and reperfusion (24 hours) in CR group than that in AL group. The immunoblotting results demonstrated that the impaired ischemic AMPK activation in AL group was augmented in CR group, and the AMPK downstream acetyl CoA carboxylase (ACC) phosphorylation and PGC-1alpha phosphorylation were also augmented in CR vs. AL group in response to ischemic insults. Intriguingly, the expression levels of a longevity protein, SIRT1, were upregulated in the heart of CR group vs. the corresponding AL group. Furthermore, the inducible cardiomyocyte SIRT1 deficiency mice (icSIRT1 KO) did not show any recused impaired ischemic AMPK activation in the CR group vs. icSIRT1 KO AL group. Thus, caloric restriction is a non-pharmacological approach to increase the tolerance of aged heart to ischemic insults. The AMPK-SIRT1 signaling cascade plays a critical role in the cardiac CR benefits in the elderly. Disclosure Z. Guo: None. T. Rousselle: None. J. Li: None.