This review provides an overview of the advances in understanding the role of mammalian sirtuins in aging and disease. Sirtuins, a family of NAD+-dependent deacetylases and ADP-ribosyltransferases, have been shown to extend lifespan and improve health in various organisms, including yeast, worms, and mammals. The discovery that sirtuins can be regulated by calorie restriction (CR) and small molecules has opened up new avenues for therapeutic intervention in age-related diseases. The review discusses the enzymatic activities and regulation of mammalian sirtuins, their subcellular localization, and their roles in metabolic diseases such as diabetes and obesity. It also explores the potential of sirtuins in cancer and the complex roles they play in tumor suppression and cell survival. The review highlights the challenges and future directions in the field, emphasizing the need for further research to fully understand the mechanisms and therapeutic potential of sirtuins.This review provides an overview of the advances in understanding the role of mammalian sirtuins in aging and disease. Sirtuins, a family of NAD+-dependent deacetylases and ADP-ribosyltransferases, have been shown to extend lifespan and improve health in various organisms, including yeast, worms, and mammals. The discovery that sirtuins can be regulated by calorie restriction (CR) and small molecules has opened up new avenues for therapeutic intervention in age-related diseases. The review discusses the enzymatic activities and regulation of mammalian sirtuins, their subcellular localization, and their roles in metabolic diseases such as diabetes and obesity. It also explores the potential of sirtuins in cancer and the complex roles they play in tumor suppression and cell survival. The review highlights the challenges and future directions in the field, emphasizing the need for further research to fully understand the mechanisms and therapeutic potential of sirtuins.