Discovery of a Potent Nicotinamide Phosphoribosyltransferase Activator for Improving Aging-associated Dysfunctions

Nicotinamide adenine dinucleotide (NAD⁺) plays a crucial role in the cellular energy metabolism pathway. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme involved in the biosynthesis of NAD⁺. Herein, a series of new NAMPT activators were designed to increase the NAD⁺ levels and improve aging-associated dysfunctions. In particular, compound C8 effectively activated NAMPT and promoted the biosynthesis of NAD⁺. Furthermore, we demonstrated that NAMPT activator C8 possessed excellent antiaging effects both in vitro and in vivo. Activator C8 showed potent activity in delaying aging in senescent HL-7702 cells and extended the lifespan of Caenorhabditis elegans. In a naturally aging mouse model, compound C8 effectively alleviated age-related dysfunctions and markers. Therefore, NAMPT activator C8 represented a promising lead compound for the treatment of age-related diseases.