Calorie restriction (CR) is the most evaluated nutritional intervention to increase lifespan in a variety of animal species, including human beings. CR has also been shown to delay the onset or reduce the incidence of many age-related diseases. The mechanism that could explain the effect of calorie intake on aging is related to the reduction of body fat and insulin signaling as well as reactive oxygen species produced during breathing. These phenomena cause oxidative damage to DNA and RNA promoting the process of aging and increasing the risk of illnesses. However, the effect of CR on longevity in human beings is not fully established and further studies are necessary in order to identify the molecular and cellular mechanisms for the therapeutic effect of RC. Moreover, it is necessary to set up the differences between the beneficial effects of caloric restriction from those related to dietary healthy habits.