<p>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 <i>Npy</i> 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.</p>