The benefits of calorie restriction (CR) have historically been attributed to a reduction in food intake. More recently, reduced fat stores have been proposed as an important mediator of CR, spurring interest into the potential for changes in energy expenditure and body composition as a CR mimetic. In order to better understand the relationship of body composition, energetics, cancer and longevity, four separate studies were performed. In Experimental Aim 1, a mouse model of prostate cancer (TRAMP) was used to determine if leanness rather than reduced food intake is responsible for the cancer-preventative effect of CR. It was found that increasing energy expenditure via thermoregulation under fixed-food intake conditions, resulted in smaller, leaner mice, which had less cancer incidence and progression. This finding suggests that in terms of cancer prevention, leanness rather calorie intake per se, is more closely associated with the benefits associated with CR. In Experimental Aim 2, results suggest that the longevity protein SIRT1 is elevated in mouse and human prostate cancer, and may be paradoxically implicated in tumor promotion. Experimental Aim 3 found that liver SIRT1 was not significantly affected by acute or chronic exercise. Finally, the results from Aim 4 found that exercised mice were significantly leaner than their weight-matched counterparts which were calorie restricted. However, CR and exercise had disparate effects on longevity biomarkers, including more favorable changes in the insulin/IGF-1 axis with CR, while exercisers had less DNA damage. The results of this experiment imply that the inability of exercise in prior studies to increase lifespan could be due to a failure to fully mimic the physiologic effects of CR. More studies are needed to determine if the inability of exercise to fully mimic CR is inherent to exercise itself, or if the life-prolonging action of CR work independently of changes in energy balance and body composition.