This application is to study the effect of aging on ischemia/reperfusion injury. Myocardial injury is increased following ischemia and reperfusion in the aging heart compared to adults, including elderly Fischer 344 rats (24 months old) compared to 6 month old adult controls. The elderly rats have an aging-related decrease in oxidative phosphorylation that is selective to the interfibrillar population of cardiac mitochondria (IFM). IFM from elderly rats have an aging-related decrease in complex III activity in the electron transport chain. The contents of the three catalytic centers of complex III remain unaltered, suggesting that damage or loss of non-catalytic subunit peptide(s) of complex III is the source of the defect. Depletion of non-catalytic subunits that contribute to cytochrome c1, is observed in IFM from the aging heart. The applicant's hypothesize that the aging defect creates a partial block in electron flow in the distal portion of complex III, resulting in greater reduction of more proximal redox centers in complex III, in turn leading to an increased production of reactive oxygen species by complex III in IFM of the aging heart. In addition to the aging defect, myocardial ischemia damages the iron-sulfur protein in the aging heart. The iron-sulfur protein, one of the catalytic centers in complex III, is located immediately proximal to the proposed site of the aging defect. Thus, during reperfusion, IFM in the aging heart have two defects in complex III. They hypothesize that these two defects, acting in concert, create an additional block in complex III, leading to a further reduction of proximal redox centers, setting the stage for additional increases in oxyradical production following the reintroduction of oxygen during reperfusion. The decrease tolerance of the aging heart represents a novel situation in which to examine the interaction of pre-existing aging-related metabolic defects and the added damage caused by subsequent ischemia to the impaired recovery and excess tissue damage present following ischemia and reperfusion in the senescent heart.
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