We propose to use a rodent model of age-related physical decline to conduct pre-clinical testing of two promising pharmacologic interventions with the potential to forestall frailty-associated physical decline, angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARE) and to study pathophysiologic changes postulated to play important roles in frailty. The current PA (FRAILTY IN OLD AGE: PATHOPHYSIOLOGY AND INTERVENTIONS:PAS-03-122) recommends the preclinical testing of promising interventions with the potential to forestall frailty-associated physical decline such as ACEi. Preliminary studies presented in this application suggest that ACEi use in aged rats attenuates age-related declines in physical performance and is associated with a reduction in total body fat mass. This is of great interest in the context of frailty given the growing body of evidence linking differences in fat mass and fat distribution to muscle function and physical decline. However, it is unclear how ACEi may contribute to declining performance or whether the effects seen with ACEi are mediated by the angiotensin receptor or other mechanisms. Long-term clinical trials in hypertensive persons using either ARBs, which only block the action of ANGII by antagonizing the AT1 receptor, or ACEi have shown that both treatments reduce the risk for the development of metabolic abnormalities in fat and muscle associated with type II diabetes. There is still some debate as to how each intervention affects these changes. Alterations in either pathway have profound metabolic consequences, most notably in conditions of hypertension, obesity and insulin resistance. One primary and two secondary aims will be addressed in this application: 1) Determine the effect of Enalapril and Losartan vs. saline control treatment on physical performance across a portion of the lifespan of male Brown Norway x F344 rats; 2) Determine the time course of age-related changes and the effect of Enalapril vs. Losartan treatment on whole body insulin sensitivity and glucose tolerance and changes in adipose tissue and skeletal muscle physiology; 3) relate these findings to declining physical performance. These data will lay the groundwork for characterizing the role of long-term ACEi and ARB treatment in reversing these changes, as well as provide preliminary data for planning randomized clinical trials in humans for the prevention of the age related decline in physical function.
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