Calorie intake is an important determinant of health. Excessive energy intake is associated with abdominal obesity, type 2 diabetes, cardiovascular disease, cancer, and premature mortality. Calorie restriction (CR) without malnutrition increases maximal lifespan by preventing many age-associated chronic diseases and by preserving function at more youthful-like states in rodents. In overweight and obese humans CR improves metabolic health and reduced mortality for type 2 diabetes, cardiovascular disease and cancer. In middle-aged healthy lean individuals CR causes many of the same cardiometabolic adaptations that occur in long-lived CR rodents, including decreased metabolic, inflammatory, and hormonal risk factors for diabetes, hypertension, cardiovascular disease and cancer Protein and polyphenols intake, and physical activity may have additional beneficial effects in preventing diseases and promoting health. Additional studies are needed to identify the precise calorie, protein and polyphenols intake and amount of exercise needed for optimal health in each individual, depending on his/her age, sex and genetic background.