Sirtuins are a family of NAD+-dependent enzymes that regulate aging and disease. Since their discovery in yeast, research has shown that sirtuins influence multiple pathways that enhance lifespan and health. In mammals, sirtuins—SIRT1–SIRT7—play key roles in metabolism, inflammation, and disease. SIRT1 is particularly important for calorie restriction (CR) benefits, including improved glucose homeostasis and protection against metabolic diseases. Sirtuins are regulated by NAD+ biosynthesis, with Nampt and PNC1 playing critical roles in maintaining NAD+ levels. SIRT1 is also involved in circadian rhythms and mitochondrial function, and its activity is linked to metabolic homeostasis. SIRT3–SIRT5 are localized in mitochondria and regulate energy metabolism, while SIRT4 and SIRT5 have roles in amino acid metabolism and ammonia clearance. Sirtuins are also involved in cancer, where they can promote or suppress tumor growth depending on the context. Overall, sirtuins are critical for maintaining health and longevity, and their regulation is a promising target for therapeutic interventions in aging-related diseases.Sirtuins are a family of NAD+-dependent enzymes that regulate aging and disease. Since their discovery in yeast, research has shown that sirtuins influence multiple pathways that enhance lifespan and health. In mammals, sirtuins—SIRT1–SIRT7—play key roles in metabolism, inflammation, and disease. SIRT1 is particularly important for calorie restriction (CR) benefits, including improved glucose homeostasis and protection against metabolic diseases. Sirtuins are regulated by NAD+ biosynthesis, with Nampt and PNC1 playing critical roles in maintaining NAD+ levels. SIRT1 is also involved in circadian rhythms and mitochondrial function, and its activity is linked to metabolic homeostasis. SIRT3–SIRT5 are localized in mitochondria and regulate energy metabolism, while SIRT4 and SIRT5 have roles in amino acid metabolism and ammonia clearance. Sirtuins are also involved in cancer, where they can promote or suppress tumor growth depending on the context. Overall, sirtuins are critical for maintaining health and longevity, and their regulation is a promising target for therapeutic interventions in aging-related diseases.