A Novel Mechanism for SIRT1 Activators That Does Not Rely on the Chemical Moiety Immediately C-Terminal to the Acetyl-Lysine of the Substrate.

SIRT1, an NAD-dependent deacetylase, catalyzes the deacetylation of proteins coupled with the breakdown of NAD into nicotinamide and 2'-O-acetyl-ADP-ribose (OAADPr). Selective SIRT1 activators have potential clinical applications in atherosclerosis, acute renal injury, and Alzheimer's disease. Here, we found that the activity of the potent SIRT1 activator CWR is independent of the acetylated substrate.