The mammalian sirtuin protein family (SIRT1–SIRT7) plays a crucial role in metabolism and aging. Sirtuins act in various cellular compartments, including the nucleus, cytoplasm, and mitochondria, by deacetylating histones and transcriptional regulators. They regulate fat and glucose metabolism in response to changes in energy levels, thereby controlling energy homeostasis and healthspan. SIRT1, the best-studied sirtuin, is involved in caloric restriction, aging-related disease prevention, and metabolic homeostasis. SIRT3, localized primarily in mitochondria, controls fatty acid oxidation and mitochondrial function. Other sirtuins, such as SIRT2, SIRT4, and SIRT5, also have specific functions in glucose and lipid metabolism. The regulation of sirtuin activity involves transcriptional regulation, post-translational modifications, protein complex formation, and NAD+ levels. Natural compounds like resveratrol and synthetic compounds like SRT1720 have been identified as activators of sirtuins, showing potential therapeutic benefits in metabolic disorders and aging-related diseases. Sirtuins are emerging as promising targets for the prevention and treatment of age-related diseases and the maintenance of healthspan.The mammalian sirtuin protein family (SIRT1–SIRT7) plays a crucial role in metabolism and aging. Sirtuins act in various cellular compartments, including the nucleus, cytoplasm, and mitochondria, by deacetylating histones and transcriptional regulators. They regulate fat and glucose metabolism in response to changes in energy levels, thereby controlling energy homeostasis and healthspan. SIRT1, the best-studied sirtuin, is involved in caloric restriction, aging-related disease prevention, and metabolic homeostasis. SIRT3, localized primarily in mitochondria, controls fatty acid oxidation and mitochondrial function. Other sirtuins, such as SIRT2, SIRT4, and SIRT5, also have specific functions in glucose and lipid metabolism. The regulation of sirtuin activity involves transcriptional regulation, post-translational modifications, protein complex formation, and NAD+ levels. Natural compounds like resveratrol and synthetic compounds like SRT1720 have been identified as activators of sirtuins, showing potential therapeutic benefits in metabolic disorders and aging-related diseases. Sirtuins are emerging as promising targets for the prevention and treatment of age-related diseases and the maintenance of healthspan.