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1. Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice.

Author

Yoshida M, Satoh A, Lin JB, Mills KF, Sasaki Y, Rensing N, Wong M, Apte RS, and Imai SI

Subjects
Adult, Aged, Aged, 80 and over, Animals, Cells, Cultured, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Aging, Cytokines metabolism, Extracellular Vesicles metabolism, Longevity, Nicotinamide Phosphoribosyltransferase metabolism
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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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2. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH.

Author

Satoh A, Brace CS, Rensing N, Cliften P, Wozniak DF, Herzog ED, Yamada KA, and Imai S

Subjects
Animals, Body Temperature, Female, Hypothalamus metabolism, Male, Mice, Mice, Transgenic, Mitochondria metabolism, Mitochondria pathology, Motor Activity, Muscle, Skeletal metabolism, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins genetics, Orexin Receptor Antagonists, Orexin Receptors genetics, Orexin Receptors metabolism, Phenotype, Promoter Regions, Genetic, RNA Interference, RNA, Small Interfering metabolism, Signal Transduction, Sirtuin 1 antagonists & inhibitors, Sirtuin 1 genetics, Sirtuin 1 metabolism, Thyroid Nuclear Factor 1, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Transcription, Genetic, Up-Regulation, Aging, Longevity, Nuclear Proteins metabolism, Transcription Factors metabolism
Abstract

The mammalian Sir2 ortholog Sirt1 plays an important role in metabolic regulation. However, the role of Sirt1 in the regulation of aging and longevity is still controversial. Here we demonstrate that brain-specific Sirt1-overexpressing (BRASTO) transgenic mice show significant life span extension in both males and females, and aged BRASTO mice exhibit phenotypes consistent with a delay in aging. These phenotypes are mediated by enhanced neural activity specifically in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), through increased orexin type 2 receptor (Ox2r) expression. We identified Nk2 homeobox 1 (Nkx2-1) as a partner of Sirt1 that upregulates Ox2r transcription and colocalizes with Sirt1 in the DMH and LH. DMH/LH-specific knockdown of Sirt1, Nkx2-1, or Ox2r and DMH-specific Sirt1 overexpression further support the role of Sirt1/Nkx2-1/Ox2r-mediated signaling for longevity-associated phenotypes. Our findings indicate the importance of DMH/LH-predominant Sirt1 activity in the regulation of aging and longevity in mammals., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Published
2013
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