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Comment from Dr. Ueli Schibler:
Most biological functions decline with age, and this also applies to the generation of circadian rhythms in behavior (e.g. sleep-wake cycles), physiology, and metabolism. These rhythms are generated by a hierarchically organized timing system, in which a master pacemaker in the brain’s suprachiasmatic nucleus (SCN) synchronizes cellular clocks operating in most body cells. The molecular oscillators are driven by feedback loops in clock gene expression. Briefly, the transcription factors CLOCK and BMAL1 activate the transcription of genes encoding their own repressors, including CRY1, CRY2, PER1 and PER2. Once these repressors reach a critical threshold in abundance and activity, they associate with the CLOCK-BMAL1 heterodimer and annul its transactivation potential. Repressor concentrations then gradually fall below the threshold required for CLOCK-BMAL silencing, and a new cycle of repressor production can ensue. The abundance and activities of the circadian repressor proteins are, however, not only determined by transcription, but also by posttranslational mechanisms affecting their stability and repression potential. Among the known core clock components PER2 is probably the “state variable” of the oscillator. In other words, the oscillation of PER2 determines the “state in time” of the latter. PER2 has previously been shown to be acetylated, resulting in greater stability and thus to a higher accumulation of this core clock component. Moreover, the NAD+-dependent protein deacetylase Sirtuin 1 (SIRT1) has been suggested to deacetylate PER2, thereby promoting its degradation (for review see {1}.
Levine and coworkers observed that PER2 levels are higher throughout the day in the livers of old mice. Consequently, CLOCK-BMAL1-driven transcription is attenuated, and the amplitude and magnitude of CLOCK-BMAL1 target gene expression is dampened. These authors now report that supplying nicotine riboside in the drinking water dramatically increases the NAD+ pool in cells of several organs. This leads to a stimulation of SIRT1-dependent deacetylation of PER2, to a lower accumulation of this repressor protein, and thereby to higher amplitudes and magnitudes CLOCK-BMAL1-mediated transcription. Hence, elevating intracellular NAD+ concentrations rejuvenates the circadian timing system. The study by Levine et al. fills another important gap in the elucidation of NAD+-dependent PER2 accumulation. Using mass spectrometry, they identified K680 as the hyperacetylated lysine within PER2. This lysine is located in a peptide region known to be phosphorylated by various kinases, including casein kinase 1 delta. Indeed, the authors discovered that there is an intricate cross-talk between PER2 acetylation and phosphorylation, and acetylation and deacetylation may actually modulate PER2 stability through establishing stabilizing and destabilizing phosphorylation patterns, respectively. In agreement with a previous report {2}, Levine et al. observed that an elevation of SIRT1 activity also ameliorates the generation of circadian rhythms in the SCN of aged mice, manifesting itself in more robust, juvenile-like rest-activity cycles.