Age-Associated Differences in Activation of Akt/GSK-3β Signaling Pathways and Inhibition of Mitochondrial Permeability Transition Pore Opening in the Rat Heart

Pretreatment with isoflurane decreased myocardial infarction size in young rats (3-5 months) but not in old rats (20-24 months). To understand the mechanisms underlying the failure to protect the old myocardium, differences in phosphorylation of Akt/GSK-3 beta and age-associated differences in mitochondrial permeability transition pore (mPTP) opening in the aging heart in vivo were measured. Isoflurane significantly increased Akt and GSK-3 beta phosphorylation in the young groups. In contrast, levels of p-Akt and p-GSK-3 beta were highly elevated in the old sham control groups. Isoflurane preconditioning significantly reduced the fall in NAD(+) levels induced by ischemia/reperfusion injury in the young animals, reflecting the inhibition of mPTP opening. In the old animals, however, isoflurane failed to prevent the fall in NAD(+) levels induced by ischemia/reperfusion injury. Lack of isoflurane-induced cardioprotective effects, seen in the old animals, can be explained by age-related differences in Akt/GSK-3 beta signaling pathway and the inability to reduce mPTP opening following ischemia/reperfusion injury.