Glenn Laboratory for the Science of Aging, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell. 2013 Jun 20;153(7):1448-60. doi: 10.1016/j.cell.2013.05.027.
SIRT1 is a NAD(+)-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here, we show that SIRT1 in the brain governs central circadian control by activating the transcription of the two major circadian regulators, BMAL1 and CLOCK. This activation comprises an amplifying circadian loop involving SIRT1, PGC-1α, and Nampt. In aged wild-type mice, SIRT1 levels in the suprachiasmatic nucleus are decreased, as are those of BMAL1 and PER2, giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 phenocopy these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging. Our findings indicate that SIRT1 activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging.
SIRT1 是一种依赖 NAD(+)的蛋白去乙酰化酶,它调控着许多生理途径,包括外周组织的生物钟节律。在这里,我们发现大脑中的 SIRT1 通过激活两个主要生物钟调节剂 BMAL1 和 CLOCK 的转录来控制中枢生物钟的控制。这种激活包含一个涉及 SIRT1、PGC-1α 和 Nampt 的放大生物钟循环。在老年野生型小鼠中,视交叉上核中的 SIRT1 水平下降,BMAL1 和 PER2 的水平也下降,导致内在周期变长、活动模式更加紊乱,并且无法适应光适应时间表的变化。缺乏大脑 SIRT1 的年轻小鼠表现出与这些与年龄相关的生物钟变化相似的表型,而在大脑中过表达 SIRT1 的小鼠则能免受衰老的影响。我们的研究结果表明,SIRT1 激活中枢起搏器以维持年轻动物中强大的生物钟控制,而这种活性的衰减可能在衰老中起着重要作用。