The advancement of age is accompanied by the increased incidence of various diseases, including neurodegeneration, cancer, and metabolic diseases. At a molecular level, these diseases are associated with a plethora of pathophysiological mechanisms, including deficiency in nutrient sensing, proteostasis, and mitochondrial function. Sirtuins have been implicated in the age-related malfunctioning of these pathways and are thought to be involved in the beneficial effects of caloric restriction. In this chapter, we discuss the current state-of-knowledge regarding the role of sirtuins in aging.