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Abstract
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.