Small molecule SIRT1 activators for the treatment of aging and age-related diseases

• Sirtuins (SIRT1–7) are NAD+-dependent deacylases that promote homeostasis.
• SIRT1 activation shows promise for the treatment of aging and age-related diseases.
• Natural and synthetic SIRT1 activators (STACs) have been discovered.
• There is a common SIRT1 activation mechanism mediated by an N-terminal domain.
• Clinical trials indicate that STACs are efficacious but questions remain.

Recent studies in mice have identified single molecules that can delay multiple diseases of aging and extend lifespan. In theory, such molecules could prevent dozens of diseases simultaneously, potentially extending healthy years of life. In this review, we discuss recent advances, controversies, opportunities, and challenges surrounding the development of SIRT1 activators, molecules with the potential to delay aging and age-related diseases. Sirtuins comprise a family of NAD+-dependent deacylases that are central to the body's response to diet and exercise. New studies indicate that both natural and synthetic sirtuin activating compounds (STACs) work via a common allosteric mechanism to stimulate sirtuin activity, thereby conferring broad health benefits in rodents, primates, and possibly humans. The fact that two-thirds of people in the USA who consume multiple dietary supplements consume resveratrol, a SIRT1 activator, underscores the importance of understanding the biochemical mechanism, physiological effects, and safety of STACs.