Declining NAD+ levels are correlated with the manifestation of many hallmarks of aging.
NAD+ and the hallmarks of aging
To help describe the progressive functional decline and increased vulnerability to diseases that comes with the aging process, aging has been categorized into nine ‘hallmarks’. Declining NAD+ levels are correlated with the manifestation of many hallmarks of aging. Figure from Aman et al18.
Mammalian cells mostly rely on intracellular generation of NAD+ to fuel NAD+ levels. One of the key pharmacological approaches to enhancing NAD+ biosynthesis is via dietary supplementation with a direct NAD+ precursor: NMN. To maintain the pool of cellular NAD+, mammals largely use a biosynthetic route called the ‘salvage pathway’ In this pathway, nicotinamide (NAM), a byproduct generated by the activities of NAD+-consuming enzymes, is converted to NMN by the rate-limiting enzyme NAMPT (nicotinamide phosphoribosyltransferase). NMN can also be generated from another NAD+ precursor, nicotinamide riboside (NR), by NR kinases (NRKs). During the last step of the salvage pathway, NMN is converted to NAD+ by NMN adenylyltransferases (NMNATs).
NAD+ intermediates in the salvage pathway
Mammals largely use a biosynthetic route called the ‘salvage pathway’ to create NAD+. In this pathway, NMN is the final step in NAD+ synthesis. Adapted from Yoshino et al. (2018)15.