Circadian clock and dietary restriction

热量限制（CR）已被证明可以延长许多生物体的寿命;然而，CR的机制仍然存在争议。 大部分是未知的。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 在哺乳动物中。我们确定CR通过控制昼夜节律的活动来调节生物钟基因的表达。 转录调节因子BMAL 1和BMAL 11。与此一致，BMAL 1对于充分的代谢益处是必要的 包括寿命延长。事实上，我们发现BMAL 1负调节mTORC 1的活性， 参与调节衰老和CR介导的寿命延长。我们会继续研究， 假设生物钟的募集对于资源分配和CR的全部有益作用是必不可少的， 生理学;特别是，CR通过调节BMAL 1和BMAL 1的水平和活性来募集生物钟 蛋白质，这反过来又有助于mTORC 1和mTORC 2的差异调节。我们将探讨这个假设 通过三个具体目标。目标1。为了通过以下方法来阐明生物钟基因表达的调控机制： CR.目标2.研究CR对mTORC 1和mTORC 2的作用的昼夜节律钟介导的机制 活动和信号。目标3。为了分析在减少或不减少热量摄入的情况下定期喂养对CR的影响， 导致代谢变化和寿命延长。

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.