期刊
MOLECULAR CELL
卷 78, 期 5, 页码 835-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.04.010
关键词
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资金
- National Cancer Institute Cancer Center Support Grant, United States [P30 CA060553]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK090625, R01DK100814, 1R01DK113011-01A1, 5K01DK105137-03, 1R03DK116012-01]
- Chicago Biomedical Consortium, United States [S-007]
- National Institute on Aging (NIA) [P01AG011412]
- National Research Service Award (NRSA) [F30DK116481]
- Swedish Research Council [2014-6888]
- Swedish Society for Medical Research
- National Institute of Neurological Disorders and Stroke (NINDS) [R21NS099813]
- National Heart, Lung, and Blood Institute (NHLBI) [R01HL147545]
- Roy J. Carver Trust
- NSF-Simons Center for Quantitative Biology (Simons Foundation/SFARI, United States [597491-RWC]
- National Science Foundation [1764421]
- [P41 GM108569]
Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD(+), yet whether changes in nucleotide metabolism control circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD(+) precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD(+) repletion to youthful levels with NR. These results reveal effects of NAD(+) on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
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