In otherwise healthy adults, moderate aerobic exercise extends life span and likely health span by 2-6 years. Exercise improves blood sugar regulation, and resistance exercise increases or maintains muscle mass and is associated with improved cognitive function. On the other hand, evidence for anti-oxidant supplements increasing longevity in humans is lacking. On the contrary, transient hormetic increases in reactive oxygen species (ROS), for example, associated with exercise, are actually associated with increased mammalian health span and life span. Recent studies in humans suggest that anti-oxidants such as vitamins C, E, resveratrol, and acetyl-N-cysteine blunt the beneficial effects of exercise on glucose sensitivity and blood sugar regulation, likely through direct inhibition of ROS signaling. Alternately, other studies suggest that vitamin C has beneficial effects on exercise-associated dysfunction, inhibiting exercise-induced bronchioconstriction. These data suggest that there are tradeoffs between potential benefits and harm from anti-oxidant dietary supplementation. Specific biomolecular interactions for each antioxidant also will be important. Omega-3 (n-3) polyunsaturated fattty acids (PUFAs) have anti-inflammatory activity that is not mediated through direct ROS inhibition. Although data are limited in humans, n-3 PUFAs do not seem to blunt blood sugar regulatory benefits of aerobic exercise and actually increase anabolic activity in skeletal muscle. However, another kind of tradeoff may exist with PUFAs, at least for men. A recent large clinical trial demonstrates an association of omega-3 fatty acids blood levels with increased incidence of prostate cancer, especially aggressive prostate cancer. Together these results suggest that there are significant tradeoffs in the use of dietary supplementation for prevention and treatment of diseases associated with aging. Such tradeoffs may result from underlying intertwined homeostatic mechanisms. For most individuals, moderate exercise is of significant benefit. Careful attention to individual and family medical history and personal genomic data may prove essential to make wise dietary and supplement choices to be combined with exercise.