All data expressed as meansSEM == Fig.4. strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality. Keywords:Age-related adiposity, Body composition, Sarcopenia, Reninangiotensin system, Physical function, Muscle quality == Introduction == Age-related changes in body composition have important clinical implications, given that loss of muscle and gain of fat mass are independently associated with declining performance as well as increased risk for disability and mortality in older persons (Goodpaster et al.2001,2006; Newman et al.2003; Visser et al.1998). Behavioral interventions, such as moderate calorie restriction and physical exercise, have proven beneficial against age-associated changes in body composition in experimental settings; however, pharmacological approaches may be particularly relevant AURKA late in life, since not all older individuals benefit from or are capable of participating in traditional AM-2394 diet and/or exercise programs. Therefore, the present set of studies was designed to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor (ACEi) enalapril and the angiotensin receptor blocker (ARB) losartan on body composition, muscle quality, and physical function, when administered late in life to aged rats. Developing preclinical models of late-life intervention strategies for combating declining physical function has enormous significance (de Grey2007; Rae et al.2010). With the continued graying of the worldwide population, the number of individuals at risk of developing physical disability continues to increase and the skyrocketing social, emotional, and economic cost (Olshansky et al.2009) of caring for such individuals mandates the need for testing the effectiveness of health-promoting interventions within this cohort. To address this need, we have used the Fischer 344 Brown Norway AM-2394 (F344BN) rat as our model, since several studies have shown that this strain proceeds from 80% to 50% mortality between 24 and 30 months of age. In humans, this same pattern of survival mirrors an exponential increase in disability. In fact, in both rats and humans, assessment of functional limitations in the 50% survival range is highly predictive of future disability and ultimately mortality (Carter et al.2002; Guralnik et al.1994). In the context of changing body composition, a similar association exists (Newman et al.2001,2003; Goodpaster et AM-2394 al.2006). In the F344BN, there is a gradual increase in both lean and fat mass through 24 months of age, a decrease in muscle, a further increase in fat through 27 months, and a decrease in both compartments thereafter (Carter et al.2004; Rice et al.2005). The similarity between the F344BN rat strain and humans in terms of timing of age-related body composition changes and declining performance makes this strain a reasonable model for studying the relationship between age, adiposity, muscle quality, and physical function. Observational studies in humans and converging evidence from our history of preclinical studies suggest that the use of ACEis attenuates age-related increases in whole-body adiposity and physical performance decline in the absence of any sizeable muscle hypertrophic effect (Bahi et al.2004; AM-2394 Foianini et al.2000; Gayagay et al.1998; Carter et al.2004,2005; Onder et al.2002). These data lend credence to the hypothesis that it is not necessary to optimize the quantity of muscle that is preserved with an intervention but.