Circadian clock and dietary restriction

卡路里限制(CR)在许多生物体中被证明可以延长寿命；然而，CR的机制仍然是 大部分都是未知的。在我们以前的研究中，我们发现生物钟是CR机制的重要组成部分 在哺乳动物身上。我们证实，CR通过控制生物钟的活动来调节生物钟基因的表达 转录调控因子BMAL1和CRY1。与此一致，BMAL1对于代谢的全部益处是必需的 包括延长使用寿命的CR。事实上，我们发现BMAL1负向调节mTORC1的活性，这是 与调节衰老和CR介导的延长寿命有关。我们将继续研究，探索我们的 假设生物钟招募对资源分配是必不可少的，以及CR对 生理学；具体地说，CR通过调节CRY1和BMAL1的水平和活性来招募生物钟 蛋白质，这反过来有助于对mTORC1和mTORC2的不同调控。我们将探索这一假说 通过三个具体目标。目的1.破译生物钟基因表达的调控机制。 CR.目的2.研究CR对mTORC1和mTORC2施加影响的昼夜节律机制 活动和信号。目的3.分析有或没有减少卡路里摄入量的定期喂养对CR的影响。 诱导代谢变化，延年益寿。

Calorie restriction (CR) was shown to extend longevity in many organisms; however, the mechanisms of CR are still mostly unknown. In our previous study we found that the circadian clock is an important component of CR mechanisms in mammals. We established that CR regulates expression of the circadian clock genes by controlling activity of circadian transcriptional regulators BMAL1 and CRY1. In agreement with that, BMAL1 is necessary for the full metabolic benefits of CR including lifespan extension. Indeed, we found that BMAL1 negatively regulates activity of mTORC1, which is implicated in the regulation of aging and CR-mediated increase in longevity. We will continue the study by exploring our hypothesis that circadian clock recruitment is essential for resource allocation and the full beneficial effects of CR on physiology; in particular, CR recruits the circadian clocks by regulating the level and activity of CRY1 and BMAL1 proteins, which in turn contributes to differential regulation of mTORC1 and mTORC2. We will explore the hypothesis through three specific aims. Aim 1. To decipher the mechanisms of regulation of the circadian clock gene expression by CR. Aim 2. To investigate circadian clock-mediated mechanisms of CR-imposed effects on mTORC1 and mTORC2 activity and signaling. Aim 3. To dissect the effects of periodic feeding with or without reduced calorie intake on CR- induced metabolic changes and longevity.