@article{951e059414ad47dbaa25ceae2bbd04a9,
title = "Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice",
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.",
keywords = "EV, NAD+, adipose tissue, aging, eNAMPT, exosome, extracellular vesicle, hypothalamus, longevity, metabolism",
author = "Mitsukuni Yoshida and A. Satoh and Lin, {Jonathan B.} and Mills, {Kathryn F.} and Yo Sasaki and Nicholas Rensing and Michael Wong and Apte, {Rajendra S.} and Imai, {Shin ichiro}",
note = "Funding Information: We thank Cindy Brace and Suellen Greco for their technical assistance. We also thank Erik Herzog for his support to wheel-running activity measurements, David Wozniak for locomotor activity analysis in the Animal Behavior Core, members of the Imai lab for critical comments and suggestions on this study, and staff members in the Core Facilities provided by the Diabetes Research Center ( P30 DK020579 ) and Nutrition Obesity Research Center ( P30 DK56341 ). This work was mainly supported by grants to S.I. from the National Institute on Aging ( AG037457 , AG047902 ), the American Federation for Aging Research , and the Tanaka Fund. A part of this study was also performed in a facility supported by the NCRR grant C06 RR015502 . A.S. is supported by the JSPS KAKENHI ( JP18H03186 ), AMED ( JP18gm5010001h0001 ), the Takeda Science Foundation , and the Research Fund for Longevity Sciences from the National Center for Geriatrics and Gerontology (28–47). S.I. and A.S. are also collaborating in the Project for Elucidating and Controlling Mechanisms of Aging and Longevity, organized by the Japan Agency for Medical Research and Development (AMED). S.I. is also supported by the Uehara Memorial Foundation at the Institute of Biomedical Research and Innovation (IBRI). M.W. and his lab members are supported by U54 HD087011 ( Intellectual and Developmental Disabilities Research Center ). R.S.A and his lab members are supported by the NIH R01 EY019287 , P30 EY02687 (Vision Core grant), U54 HD087011 (Intellectual and Developmental Disabilities Research Center), the Starr Foundation Carl Marshall Reeves and Mildred Almen Reeves Foundation , the Bill and Emily, Kuzma Family Gift for retinal research, a Physician-Scientist Award and a Nelson Trust Award from Research to Prevent Blindness, the Jeffrey Fort Innovation Fund, the Thome Foundation, and an unrestricted grant to the Department of Ophthalmology and Visual Sciences of Washington University School of Medicine from Research to Prevent Blindness . J.B.L. was supported by the Washington University in St. Louis Medical Scientist Training Program (NIH grant T32 GM007200 ), the Washington University Institute of Clinical and Translational Sciences (NIH grants UL1 TR002345 , TL1 TR002344 ), and the VitreoRetinal Surgery Foundation. Funding Information: We thank Cindy Brace and Suellen Greco for their technical assistance. We also thank Erik Herzog for his support to wheel-running activity measurements, David Wozniak for locomotor activity analysis in the Animal Behavior Core, members of the Imai lab for critical comments and suggestions on this study, and staff members in the Core Facilities provided by the Diabetes Research Center (P30 DK020579) and Nutrition Obesity Research Center (P30 DK56341). This work was mainly supported by grants to S.I. from the National Institute on Aging (AG037457, AG047902), the American Federation for Aging Research, and the Tanaka Fund. A part of this study was also performed in a facility supported by the NCRR grant C06 RR015502. A.S. is supported by the JSPS KAKENHI (JP18H03186), AMED (JP18gm5010001h0001), the Takeda Science Foundation, and the Research Fund for Longevity Sciences from the National Center for Geriatrics and Gerontology (28–47). S.I. and A.S. are also collaborating in the Project for Elucidating and Controlling Mechanisms of Aging and Longevity, organized by the Japan Agency for Medical Research and Development (AMED). S.I. is also supported by the Uehara Memorial Foundation at the Institute of Biomedical Research and Innovation (IBRI). M.W. and his lab members are supported by U54 HD087011 (Intellectual and Developmental Disabilities Research Center). R.S.A and his lab members are supported by the NIH R01 EY019287, P30 EY02687 (Vision Core grant), U54 HD087011 (Intellectual and Developmental Disabilities Research Center), the Starr Foundation Carl Marshall Reeves and Mildred Almen Reeves Foundation, the Bill and Emily, Kuzma Family Gift for retinal research, a Physician-Scientist Award and a Nelson Trust Award from Research to Prevent Blindness, the Jeffrey Fort Innovation Fund, the Thome Foundation, and an unrestricted grant to the Department of Ophthalmology and Visual Sciences of Washington University School of Medicine from Research to Prevent Blindness. J.B.L. was supported by the Washington University in St. Louis Medical Scientist Training Program (NIH grant T32 GM007200), the Washington University Institute of Clinical and Translational Sciences (NIH grants UL1 TR002345, TL1 TR002344), and the VitreoRetinal Surgery Foundation. M.Y. and S.I. conceived this study and designed the experiments. M.Y. performed most of the experiments and S.I. supervised the entire study. A.S. N.R. and M.W. conducted sleep analyses. M.Y. and K.F.M. performed IPGTTs and ITTs. J.B.L. and R.S.A. conducted ERGs and analyzed photoreceptor functions. Y.S. conducted the mass spectrometric analysis of isotopically labeled metabolites. M.Y. and S.I. analyzed the entire data and wrote the manuscript. S.I. receives a part of patent-licensing fees from MetroBiotech (USA) and Teijin Limited (Japan) through Washington University. R.S.A. is a co-founder of Metro Midwest Biotech. All other authors declare no financial interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = aug,
day = "6",
doi = "10.1016/j.cmet.2019.05.015",
language = "English",
volume = "30",
pages = "329--342.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "2",
}