Vol.5, No.1, 1-7 (2013) Health http://dx.doi.org/10.4236/health.2013.51001 Aged rat heart: Modulation of age-related respiratory defects decreases ischemic-reflow injury Edward J. Lesnefsky 1 , Charles L. Hoppel 2* 1 Departments of Medicine, Biochemistry and Physiology, McGuire Veterans Affairs Medical Center-Virginia Commonwealth Uni- versity, Richmond, USA 2 Center for Mitochondrial Diseases, Departments of Medicine and Pharmacology, Case Western Reserve University, Cleveland, USA; * Corresponding Author: charles.hoppel@case.edu Received 1 August 2012; revised 2 September 2012; accepted 9 November 2012 ABSTRACT Myocardial injury increases in the elderly heart during ischemia and reperfusion. Mitochondria, the key targets and sources of injury during ischemia and reperfusion, sustain ischemic damage to the electron transport chain that is superimposed upon age-related defects. In the adult heart, interventions to activate endoge- nous cytoprotective signaling systems meet in mitochondria to decrease cardiac injury. Unfor- tunately, these systems are largely ineffective in the aged heart. Thus, new treatment concepts are needed to reduce injury in the aged heart. Our group chose a strategy to directly treat the effector of cardiac injury in the aged heart, the mitochondria. We further utilized a novel ap- proach to ask if the reversal of aging defects in cardiac mitochondria before ischemia could de- crease ischemia-reperfusion injury in the heart. Three hours following treatment with the small molecule, nutriceutical acetylcarnitine (AcCN), oxidative phosphorylation as well as age-in- duced defects in electron transport chain com- plexes III and IV was corrected in the heart. When such hearts were then exposed to ische- mia and reperfusion, cardiac injury was mark- edly reduced. Contraction during reperfusion improved and recovery became similar to that in adult hearts. Cardiac cell death was substan- tially reduced. Thus, age-related defects in elec- tron transport are a key mechanism of the in- creased myocardial injury in the elderly heart during ischemia and reperfusion. Modulation of aging-induced defects in mitochondrial metabo- lism reduces cardiac injury from ischemia and reperfusion, and is a novel strategy to protect myocardium in the elderly patient at risk for an acute myocardial infarction. Keywords: Mitochondria; Cytochrome Oxidase; Complex III; Myocardial Infarction; Aging 1. THE CLINICAL CHALLENGE OF MYOCARDIAL INFARCTION IN THE ELDERLY: INCREASED CARDIAC INJURY CONCOMITANT WITH DECREASED RESPONSIVENESS TO INNATE CYTOPROTECTION During the course of an acute myocardial infarction, elderly patients experience an increased mortality and sustain greater cardiac damage compared to younger pa- tients despite timely and successful reperfusion [1]. The aged heart suffers greater damage during ischemia and reperfusion in both experimental and clinical settings [1-6]. In a National Institutes on Aging rat model of ag- ing, the Fischer 344 rat (F344), isolated, buffer-perfused hearts from aged rats (24 mo.) exhibit decreased hemo- dynamic recovery and greater cardiomyocyte death fol- lowing ischemia and reperfusion compared to hearts from adult (6 mo.) controls [4-7]. Age-enhanced cardiac injury during ischemia and reperfusion has been observed in other rat strains [3] and species [2,8] as well. Mitochondria are key targets of ischemic damage as well as effectors of cardiac injury during ischemia and reperfusion [2,3,9,10]. Mitochondria-driven effector me- chanisms, especially relevant to the aged heart, include oxidative damage [6], calcium accumulation [2], and activation of apoptosis [5]. In the aged heart, ischemic damage to mitochondria is superimposed upon pre-ex- isting age-related alterations in mitochondrial metabo- lism [10,11]. We posited that intervention to improve aging-induced defects in mitochondrial function would decrease myocardial injury during subsequent ischemia and reperfusion. Mitochondria-directed strategies to limit cardiac injury during ischemia and reperfusion are highly relevant to the protection of the aged heart and the ultimate im- Copyright © 2013 SciRes. OPEN ACCESS