Aging human subjects display increased incidence of cardiovascular disease and complications of myocardial infarction and heart failure. We have demonstrated that flux via the polyol pathway is partly responsible for impaired myocardial glycolysis and energy production. When hearts from aged rats are subjected to ischemia, the ability to generate sufficient high energy phosphates for maintaining myocyte viability and sodium homeostasis is severely compromised. Our work, as well as that of others, has shown that enhancement of glycolytic metabolism during ischemia is a feasible approach to maintain myocyte viability, energy metabolism and sodium homeostasis. In this revised application, we show that in human aging, that is, without superimposed cardiovascular disease or diabetes, and in aged Fischer 344 rats, expression and activity of aldose reductase (AR) is increased in the heart. Induction of ischemia further increases AR activity in aged hearts, and is associated with increased myocardial ischemic injury and poor functional recovery on reperfusion. Inhibition of the polyol pathway (AR) or the next enzyme in the pathway, sorbitol dehydrogenase (SDH) reduced ischemic injury, attenuated changes in intracellular sodium homeostasis, and improved functional and metabolic recovery after ischemia in aged hearts. Thus, we hypothesize that in aging, increased activity of the polyol pathway enzyme AR increases myocardial vulnerability to ischemic injury, and that this can be attenuated by polyol pathway inhibitors. The proposed studies will probe the mechanisms by which aging increases myocardial polyol pathway activity, and how this augmented activity in aging and ischemia acts to increase myocardial damage Distinct strategies including pharmacological inhibitors of AR and SDH, Fischer 344 rats, and human AR expressing transgenic mice will be employed to test these concepts. Further, to enhance understanding of SDH in aging in the heart, SDH null mice will be bred into the transgenic mouse background in which human-relevant levels of AR are expressing. We will utilize NMR spectroscopy, biochemical, and molecular techniques in our experiments. Project 1 is closely linked to Projects 2&3, as each studies aging-linked enhanced vulnerability to I/R stress in vascular cells and cardiomyocytes. Project 1 shares mouse/rat models with Projects 2 and 3. Project 1 will utilize all three Cores of the Program Project during all five years of the grant.