NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging

Daniel C. Levine; Heekyung Hong; Benjamin J. Weidemann; Kathryn M. Ramsey; Alison H. Affinati; Mark S. Schmidt; Jonathan Cedernaes; Chiaki Omura; Rosemary Braun; Choogon Lee; Charles Brenner; Clara Bien Peek; Joseph Bass

doi:10.1016/j.molcel.2020.04.010

NAD⁺ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging

Daniel C. Levine, Heekyung Hong, Benjamin J. Weidemann, Kathryn M. Ramsey, Alison H. Affinati, Mark S. Schmidt, Jonathan Cedernaes, Chiaki Omura, Rosemary Braun, Choogon Lee, Charles Brenner, Clara Bien Peek, Joseph Bass^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

122 Scopus citations

Abstract

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 PER2^K680 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.

Original language	English (US)
Pages (from-to)	835-849.e7
Journal	Molecular cell
Volume	78
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2020.04.010
State	Published - Jun 4 2020

Funding

We thank all members of the Bass, Barish, and Allada laboratories for helpful discussions, and Biliana Marcheva for help with the figures. Proteomics services were performed by the Northwestern Proteomics Core Facility, supported by National Cancer Institute Cancer Center Support Grant P30 CA060553 , United States awarded to the Robert H. Lurie Comprehensive Cancer Center and the National Resource for Translational and Developmental Proteomics supported by P41 GM108569 , United States. Research support was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( R01DK090625 , R01DK100814 , and 1R01DK113011-01A1 to J.B. and 5K01DK105137-03 and 1R03DK116012-01 to C.B.P.); the Chicago Biomedical Consortium S-007 , United States (to J.B.); the National Institute on Aging (NIA) ( P01AG011412 to J.B. and C.B.); the National Research Service Award (NRSA) ( F30DK116481 to B.J.W.); the Swedish Research Council ( 2014-6888 to J.C.); the Swedish Society for Medical Research (to J.C.); the National Institute of Neurological Disorders and Stroke (NINDS) ( R21NS099813 to C.L.); the National Heart, Lung, and Blood Institute (NHLBI) ( R01HL147545 to C.B.); the Roy J. Carver Trust (to C.B.); the NSF-Simons Center for Quantitative Biology ( Simons Foundation/SFARI 597491-RWC , United States; to R.B.); and the National Science Foundation ( 1764421 to R.B.).

Keywords

NAD
SIRT1
aging
circadian
clock
heat shock factor 1
liver
nicotinamide mononucleotide
nicotinamide riboside
transcriptomics

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.molcel.2020.04.010

Cite this

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title = "NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging",

abstract = "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.",

keywords = "NAD, SIRT1, aging, circadian, clock, heat shock factor 1, liver, nicotinamide mononucleotide, nicotinamide riboside, transcriptomics",

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AU - Schmidt, Mark S.

AU - Cedernaes, Jonathan

AU - Omura, Chiaki

AU - Braun, Rosemary

AU - Lee, Choogon

AU - Brenner, Charles

AU - Peek, Clara Bien

AU - Bass, Joseph

PY - 2020/6/4

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N2 - 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.

AB - 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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