Human plasma-derived eNAMPT-containing extracellular vesicles promote NAD⁺ biosynthesis and thermogenesis in mice

Age-associated decline in tissue NAD⁺ levels contribute to functional impairments, recognized as aging. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme crucial for NAD⁺ biosynthesis in mammals, is encapsulated in extracellular vesicles (EVs) and secreted into the bloodstream. The importance of extracellular NAMPT-containing EVs (eNAMPT-EVs) in hypothalamic NAD⁺ biosynthesis has been demonstrated in several mouse models. However, whether eNAMPT-EVs derived from human plasma can also act as a physiological NAD⁺ booster remains unclear. Here we show that administration of human plasma-derived, highly purified eNAMPT-EVs can elevate hypothalamic NAD⁺ levels in mice. Furthermore, eNAMPT-EV administration led to an increase in body temperature and suppression of hypothalamic Npy gene expression. These responses were negated by pharmacological NAMPT inhibition. We also found that exercise increases in plasma eNAMPT and hypothalamic NAD⁺ levels. These findings suggest that enhancing circulating eNAMPT-EVs can be an effective strategy for NAD⁺ boosting and potentially an effective anti-aging intervention in humans.