Circadian-Regulated Aging Physiologies

项目摘要：衰老是一种进化保守的体力和智力衰退过程 晚年的生活。从果蝇到人类，多细胞动物的衰老有许多相似之处。为 无论是苍蝇还是哺乳动物，衰老都会导致昼夜节律的丧失或功能和功能的24小时振荡 行为，包括睡眠、进食、新陈代谢等组织特有的功能。昼夜节律的核心“时钟” 是一个负转录反馈环：一个异二聚体转录激活复合体，驱动 数百个基因的表达，包括它们自己的抑制物，驱动着基因表达的昼夜振荡。 在苍蝇和哺乳动物中，这些时钟几乎存在于每一个被测试的组织中。大脑时钟(也称为 中央时钟)协调体内许多其他组织特有的时钟(也称为外周时钟)。 这些外周时钟驱动组织特异性基因表达的昼夜振荡，进而驱动 功能上的组织特有的昼夜节律振荡。因此，与年龄相关的昼夜节律基因表达缺失被认为是 影响多个组织，对健康有病理影响。不幸的是，目前几乎没有中央 或加强老年人昼夜节律的外周时钟治疗干预。 在初步数据中，我的实验室开发了两种限时喂养(TRF)方案，它们的效果都很好 延长果蝇寿命(15-20%)，改善昼夜节律功能，提高脂肪代谢。扶轮基金会是一项 将饮食限制在特定的每日时间窗口内的饮食养生法。我们发现TRF增强了 昼夜节律调节转录和TRF介导的寿命延长都需要昼夜节律调节 还有自噬，一种保守的长寿途径。我们还发现，与自噬无关，TRF 增加脂肪代谢，这是进行TRF的人寻求的最常见的健康益处。 在这里，我们建议检验这样一个假设，即TRF增强了多个组织中的昼夜节律时钟 推广抗衰老健康福利。具体地说，我们将1)调查TRF对不同生理周期的影响 时钟(外设和中央)，以及检查时钟对时钟的通信；2)调查TRF 对免疫系统和大脑的健康有益，并确定不同TRF所需的组织特异性时钟(S) 有益健康；3)研究自噬非依赖性转录因子诱导的分子机制(S) 脂类代谢的变化(储存和使用)。这些结果将有助于表征其抗衰老作用。 并确定潜在的治疗靶点。 果蝇提供了关于昼夜节律和衰老的关键信息，果蝇是一种 强大的遗传模型系统。昼夜节律、新陈代谢和衰老是高度进化的 守恒的过程。因此，我们预计拟议实验的结果将与以下方面有关 人类健康与老龄化相关的治疗干预。

PROJECT SUMMARY: Aging is an evolutionarily conserved process of physical and mental decline in the later years of life. The aging of multicellular animals from fruit flies to humans share many similarities. For both flies and mammals, aging leads to loss of circadian rhythms or 24-hour oscillations in function and behavior, including sleep, feeding, metabolism, and other tissue-specific functions. The core circadian "clock" is a negative transcriptional feedback loop: a heterodimeric transcriptional activating complex that drives the expression of hundreds of genes, including their own inhibitors, driving circadian oscillation of gene expression. In both flies and mammals, these clocks exist in nearly every tissue tested. The brain clock (also called the central clock) coordinates many other tissue-specific clocks in the body (also called "peripheral clocks"). These peripheral clocks drive circadian oscillations in tissue-specific gene expression, which in turn drive tissue-specific circadian oscillations in function. Thus, age-related loss of circadian gene expression is thought to affect multiple tissues and have pathologic effects on health. Unfortunately, there are currently few central or peripheral clock therapeutic interventions that enhance circadian regulation in the elderly. In preliminary data, my lab developed two time-restricted feeding, or TRF, regimens that robustly extend lifespan (15-20%), improve circadian function, and increase lipid metabolism in Drosophila. TRF is a dietary regimen in which eating is restricted to a specific daily time window. We found that TRF enhanced circadian-regulated transcription and that TRF-mediated lifespan extension required both circadian regulation and autophagy, a conserved longevity pathway. We also found that, independent of autophagy, TRF increases lipid metabolism, the most common health benefit sought by people who undertake TRF. Here we propose to test the hypothesis that TRF enhances circadian clocks in multiple tissues that promote anti-aging health benefits. Specifically, we will 1) investigate the impact of TRF on different circadian clocks (both peripheral and central), as well as examining clock-to-clock communication; 2) investigate TRF health benefits for the immune system and brain and identify tissue-specific clock(s) required for diverse TRF health benefits; 3) investigate the molecular mechanism(s) underlying autophagy-independent TRF-induced changes in lipid metabolism (storage and usage). These results will help to characterize the anti-aging effects of TRF and identify potential therapeutic targets. Drosophila have provided crucial information about circadian regulation and aging and the fly is a powerful genetic model system. Circadian regulation, metabolism, and aging are highly evolutionarily conserved processes. Thus, we expect that the results of the proposed experiments will have relevance for human health and aging-related therapeutic intervention.