Aging is associated with myocardial insulin resistance and mitochondrial dysfunction

Aging is associated with myocardial insulin resistance and mitochondrial dysfunction. Am J Physiol Heart Circ Physiol 293: H3063-H3071, 2007. First published September 14, 2007; doi: 10.1152/ajpheart.00163.2007. - Aging is associated with insulin resistance, often attributable to obesity and inactivity. Recent evidence suggests that skeletal muscle insulin resistance in aging is associated with mitochondrial alterations. Whether this is true of the senescent myocardium is unknown. Twelve young (Y, 4 years old) and 12 old (O, 11 years old) dogs, matched for body mass, were instrumented with left-ventricular pressure gauges, aortic and coronary sinus catheters, and flow probes on left circumflex artery. Before surgery, all dogs participated in a 6-wk exercise program. Dogs underwent measurements of hemodynamics and plasma substrates before and during a 2-h hyperinsulinemic-euglycemic clamp to measure whole body and myocardial glucose and nonesterified fatty acid uptake. Following the protocol, myocardial and skeletal samples were obtained to measure components of the insulin-signaling cascade and mitochondrial structure. There was no difference in plasma glucose ( Y, 90 +/- 4 mg/dl; O, 87 +/- 4 mg/dl), but old dogs had higher ( P < 0.02) nonesterified fatty acids ( Y, 384 +/- 48 mu mol/ l; O, 952 +/- 97 mu mol/ l) and plasma insulin ( Y, 39 +/- 11 pmol/l; O, 108 +/- 18 pmol/l). Old dogs had impaired total body glucose disposition ( Y, 11.5 +/- 1 mg center dot kg(-1) center dot min(-1); O, 8.0 +/- 0.5 mg center dot kg(-1) center dot min(-1); P < 0.05) and insulin-stimulated myocardial glucose uptake ( Y, 3.5 +/- 0.3mg center dot min(-1) center dot g(-1); O, 1.8 +/- 0.3 mg center dot min(-1)center dot g(-1); P < 0.05). The impaired insulin action was associated with altered insulin signaling and glucose transporter (GLUT4) translocation. There were myocardial mitochondrial structural changes observed in association with decreased expression of uncoupling protein-3. Aging is associated with both whole body and myocardial insulin resistance, independent of obesity and inactivity, but involving altered mitochondrial structure and impaired cellular insulin action.