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 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.

Keywords: NAD(+); SIRT1; aging; circadian; clock; heat shock factor 1; liver; nicotinamide mononucleotide; nicotinamide riboside; transcriptomics.