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.

睡眠-觉醒节律与分子生物钟节律紊乱，是伴随代谢疾病及烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD+）水平降低的衰老特征，但核苷酸代谢改变是否能够调控生物钟行为与基因组节律，目前仍未明确。本研究发现，补充烟酰胺腺嘌呤二核苷酸前体烟酰胺核糖（nicotinamide riboside, NR），可通过抑制生物钟阻遏蛋白PER2（Period 2），显著重塑随衰老进程衰退的代谢与应激反应通路。烟酰胺核糖可通过PER2第680位赖氨酸残基的去乙酰化，增强BMAL1（Brain and Muscle ARNT-Like 1）的全基因组染色质结合能力，进而在调控核转运与蛋白稳定性的结构域内触发PER2磷酸化；该结构域的突变与人类重度睡眠相位提前综合征相关。在老年小鼠体内，BMAL1染色质结合能力减弱、转录振荡节律异常、线粒体呼吸节律紊乱以及晚间晚期活动量降低的表型，可通过烟酰胺核糖补充提升烟酰胺腺嘌呤二核苷酸水平，恢复至年轻小鼠的正常水平。本研究结果揭示了衰老过程中，烟酰胺腺嘌呤二核苷酸通过时空调控分子生物钟，对代谢系统与生物钟系统的调控作用。