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 25/90 min 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.