NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging
NAD+ Controls Circadian Reprogramming through PER2 Nuclear Translocation to Counter Aging
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DOI：
10.1016/j.molcel.2020.04.010
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发表时间：
2020-06-04
期刊：
影响因子：
16
通讯作者：
Bass, Joseph
中科院分区：
文献类型：
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作者：
Levine, Daniel C.;Hong, Heekyung;Bass, Joseph
睡眠-觉醒和分子昼夜节律紊乱是与代谢性疾病和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行为和基因组节律尚不清楚。在这里，我们发现补充NAD（+）前体烟酰胺核苷（NR）通过抑制时钟抑制因子PER2显著重编程代谢和应激反应途径，这些途径随着年龄的增长而下降。NR通过PER2K680去乙酰化增强BMAL1染色质全基因组结合，从而在控制核转运和稳定性的结构域内启动PER2磷酸化，并在人类晚期睡眠综合征中发生突变。在老年小鼠中，用NR补充NAD（+）可以将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时的水平。这些结果揭示了NAD（+）通过分子钟的时空控制对代谢和衰老的昼夜节律系统的影响。
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.