Life-long caloric restriction elicits pronounced protection of the aged myocardium: a role for AMPK.

Short-term caloric restriction (CR) protects the young myocardium against ischemia/reperfusion (I/R) injury through a mechanism involving AMP-activated protein kinase (AMPK). Here we ask whether a life-long CR intervention can extend this protection to the aged myocardium, and whether AMP-activated protein kinase (AMPK) plays a role in that protection. Hearts from ad libitum fed (AL) and life-long calorically restricted (LCR) mice were examined at 30 months of age by 25/90min global I/R, with and without AMPK inhibition (AraA). LCR hearts were protected from infarction (AL, 28±4% vs. LCR, 10±1%, p<0.01) and post-ischemic functional deficit (LVDP recovery: AL, 65±8% vs. LCR, 93±7%, p<0.01). Pre-ischemic AraA impaired both of these protective effects (Infarct size: LCR+AraA, 22±4%; LVDP recovery: LCR+AraA, 82±9%, both p vs. AL >0.1). AMPKα phosphorylation was dramatically increased in LCR hearts prior to I/R (AL, 1.18±0.01 vs. LCR, 1.68±0.04, ratio, p<0.0001), and accompanied by a more modest increase in total AMPKα (AL, 2.18±0.03 vs. LCR, 2.39±0.08 ratio, p<0.05). These results indicate that life-long caloric restriction profoundly protects the aged heart against I/R injury, and suggest that AMPK may play a role in that protection.