Circadian-Regulated Aging Physiologies

项目概述：衰老是一个进化保守的过程中的身体和精神下降， 晚年的生活。从果蝇到人类的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或24小时功能振荡的丧失， 行为，包括睡眠、进食、新陈代谢和其他组织特异性功能。核心的生物钟 是一个负的转录反馈环：一个异二聚体的转录激活复合物，驱动 数百个基因的表达，包括它们自己的抑制剂，驱动基因表达的昼夜节律振荡。 在果蝇和哺乳动物中，这些生物钟几乎存在于所有测试的组织中。大脑时钟（也称为 中心时钟）协调身体中的许多其他组织特异性时钟（也称为“外围时钟”）。 这些外围时钟驱动着组织特异性基因表达的昼夜节律振荡，这反过来又驱动着 组织特异性昼夜节律振荡的功能。因此，认为与年龄相关的昼夜节律基因表达丧失 影响多种组织并对健康产生病理影响。不幸的是，目前很少有中央 或增强老年人昼夜节律调节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， 延长寿命（15-20%），改善昼夜节律功能，增加果蝇的脂质代谢。TRF是一个 在一个特定的时间段内进食的饮食习惯。我们发现TRF增强了 昼夜节律调节的转录和TRF介导的寿命延长需要昼夜节律调节 和自噬，一种保守的长寿途径。我们还发现，TRF不依赖于自噬， 增加脂质代谢，这是进行TRF的人寻求的最常见的健康益处。 在这里，我们提出测试的假设，TRF增强生物钟在多个组织， 促进抗衰老的健康益处。具体来说，我们将1）调查TRF对不同昼夜节律的影响 时钟（外围和中央），以及检查时钟到时钟的通信; 2）调查TRF 对免疫系统和大脑的健康益处，并确定不同TRF所需的组织特异性时钟 健康益处; 3）研究自噬非依赖性TRF诱导的细胞凋亡的分子机制。 脂质代谢的变化（储存和使用）。这些结果将有助于表征抗衰老作用 并确定潜在的治疗靶点。 果蝇提供了关于昼夜节律调节和衰老的重要信息， 强大的遗传模型系统。昼夜节律调节、新陈代谢和衰老是高度进化的 保守的过程。因此，我们预计，拟议的实验结果将有相关性， 人类健康和与衰老有关的治疗干预。

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.