NAMPT (NAD+ salvage pathway)

NAMPT (nicotinamide phosphoribosyltransferase) is the rate-limiting enzyme of the NAD+ salvage pathway — the primary route by which mammalian cells regenerate NAD+ from nicotinamide (NAM), the breakdown product of NAD+-consuming enzymes such as sirtuins and PARPs. NAMPT converts NAM and PRPP into nicotinamide mononucleotide (NMN); NMNAT completes the synthesis to NAD+. Two forms exist: intracellular iNAMPT, driving NAD+ biosynthesis within the cell, and secreted eNAMPT, which circulates in extracellular vesicles and delivers NMN-synthesizing capacity to the hypothalamus, hippocampus, and retina. Circulating eNAMPT follows a circadian oscillation — peaking in the early afternoon in humans — entraining hypothalamic NAD+ synthesis, SIRT1/SIRT2–FOXO1 signaling, and locomotor activity (Park et al., 2023). NAMPT expression declines with age; Yoshida et al. (2019, Cell Metabolism) showed that plasma eNAMPT correlates linearly with remaining lifespan in individual mice, and adipose-specific NAMPT overexpression extended median female lifespan by ~13%. Whether eNAMPT manipulation translates to human longevity benefit is an open question — evidence is largely preclinical, with human NMN trials showing effects on skeletal-muscle insulin sensitivity but not yet on lifespan endpoints.