Calorie restriction (CR), which usually refers to a 20–40% reduction in calorie intake, can effectively prolong lifespan preventing most age-associated diseases in several species. However, recent data from both human and nonhumans point to the ratio of macronutrients rather than the caloric intake as a major regulator of both lifespan and health-span. In addition, specific components of the diet have recently been identified as regulators of some age-associated intracellular signaling pathways in simple model systems. The comprehension of the mechanisms underpinning these findings is crucial since it may increase the beneficial effects of calorie restriction making it accessible to a broader population as well.