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-3β 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-3β phosphorylation in the young groups. In contrast, levels of p-Akt and p-GSK-3β 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-3β signaling pathway and the inability to reduce mPTP opening following ischemia/reperfusion injury.