NAD+ controls circadian reprogramming through PER2 nuclear translocation to counter aging

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 which 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. Overall design: 199 libraries were generated in this study. They include ChIP-Seq, RNA-Seq, and ATAC-seq experiments to determine the effect of NAD+ on SIRT1, BMAL1, HSF1, H3K9Ac, and H3K27Ac during aging. Replicates are indicated in the final position of the title of each library. Inputs for ChIP-Seq experiments consist of equimolar pools of replicates within each group.