Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD+ availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD+ levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD+ biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD+ biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans. Yoshida et al. demonstrate that the levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) decline with age in mice and humans. Increasing eNAMPT promotes NAD+, counteracting aging and extending healthspan. eNAMPT is contained in extracellular vesicles (EVs). Supplementing eNAMPT-containing EVs improves physical activity and extends mouse lifespan, suggesting a potential anti-aging intervention.

Original languageEnglish
Pages (from-to)329-342.e5
JournalCell metabolism
Issue number2
StatePublished - Aug 6 2019


  • EV
  • NAD+
  • adipose tissue
  • aging
  • eNAMPT
  • exosome
  • extracellular vesicle
  • hypothalamus
  • longevity
  • metabolism


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