Recently it has been discovered that Sirtuins represent pivotal regulators of lifespan. Caloric restriction (CR) enhances longevity from yeast to mammals. Whereas the relationship between Sirt-1 and CR is clear, the molecular mechanisms by which Sir2 increases longevity are still unknown. In mammals, CR induces physiological and behavioral changes, and many studies have shown that CR decreases production of reactive oxygen species production thus minimizing oxidative damage, leading to the hypothesis that CR by reducing oxidative stress extends the lifespan by counteraction of aging. In fact, the pathophysiology of aging and age-related diseases involves oxidative stress as an early stage in its development. Recently we found that in aged rats the SIRT1 activity was decreased in heart and adipose tissue, showing as aging is characterized in vivo by a reduced efficiency of this key-regulator of longevity. Whereas several studies have reported that increased physical activity can improve mean life span presumably by reducing mortality risk from many age-related diseases, exercise and longevity studies have failed to document an exercise effect on maximum life span. However, in aged rats a moderate prolonged exercise training is able to induce increase in SIRT1 activity, suggesting that this tool could counteract age-related dysfunctions.