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.

睡眠-觉醒和分子昼夜节律紊乱是与代谢疾病和 NAD ⁺水平降低相关的衰老特征，但核苷酸代谢的变化是否控制昼夜节律行为和基因组节律仍不清楚。在这里，我们发现补充 NAD ⁺前体烟酰胺核苷 (NR) 可以通过抑制时钟抑制子 PER2 显着重新编程随年龄增长而下降的代谢和应激反应途径。 NR 通过 PER2 ^K680脱乙酰化增强全基因组范围内的 BMAL1 染色质结合，进而引发控制核转运和稳定性的域内的 PER2 磷酸化，该域在人类晚期睡眠阶段综合征中发生突变。在年老小鼠中，NAD ⁺补充 NR 可使受抑制的 BMAL1 染色质结合、转录振荡、线粒体呼吸节律和深夜活动恢复到年轻水平。这些结果揭示了 NAD ⁺通过分子钟的时空控制对新陈代谢和昼夜节律系统的影响。