Introduction: Ischemic tolerance of heart decreases with age and many cardio protective interventions including percutaneous coronary intervention (PCI) and post-conditioning are less effective in aged individuals. Caloric restriction (CR) is the most reliable intervention to extend lifespan and prevent age-related disorders in various species. We have revealed that both AMPK and SIRT1 signaling pathways are involved in the impairments occurred in aged hearts.
Hypothesis: Cardiac AMPK-SIRT1 signaling cascade mediates the increased tolerance of aged heart to ischemic insults by caloric restriction.
Methods: Aged (18-20 months) mice were randomly 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 hrs of reperfusion.
Results: The body fat composition was significantly decreased in caloric restriction (CR) group versus AL group, moreover, the maximum of oxygen consumption was significantly improved in CR group versus AL group. Importantly, there is a significantly smaller myocardial infarction size induced by ischemia (30 min) and reperfusion (24 hrs) 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-1α phosphorylation were also augmented in CR versus AL group in response to ischemic insults. Intriguingly, the expression levels of a longevity protein, SIRT1, were upregulated in the heart of CR group versus 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 versus icSIRT1 KO AL group.
Conclusions: 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.