Role of Circadian Clocks in Aging using Drosophila

描述(由申请人提供)：本提案的目标是确定昼夜节律如何影响寿命中的营养依赖性变化。昼夜节律系统通过协调整个生物体的基因表达和代谢过程来组织关键的生理和行为功能。生物钟的紊乱与加速衰老有关，也是与年龄相关的疾病的风险因素，如癌症和糖尿病。然而，这种联系的潜在机制仍然不清楚。越来越明显的是，除了光之外，营养物质还为调节昼夜节律系统提供了重要的输入，特别是外围时钟。我们假设，生物钟通过调节营养物质和营养感应途径的输入来影响衰老和与年龄相关的疾病。我们建议使用黑腹毛虫来研究生物钟和衰老之间的联系，原因如下：1)它们的快速生成时间和短寿命，2)易于遗传操作，3)建立了理解衰老和疾病的遗传模型，4)了解生物钟的生物学记录，以及5)哺乳动物和无脊椎动物之间许多生物过程和信号通路的保守。我们的初步证据表明，昼夜节律机制和营养感知途径之间在多个水平上存在串扰。我们观察到，饮食限制(DR)，这是已知的延长许多物种的寿命，影响生物钟。DR导致各种生物钟基因在全身的昼夜节律表达幅度增加。我们已经证明，生物钟对于DR对寿命的保护作用也是必需的。此外，我们还发现，生物钟在促进甘油三酯周转方面发挥着重要作用，这是我们最近证实的延长寿命所必需的。为了了解生物钟影响衰老的机制，特别是在DR的背景下，我们将进行以下目标：1)以年龄和组织特异性的方式确定营养对生物钟的影响，2)研究生物钟在营养依赖性寿命变化中的作用，3)确定昼夜节律如何影响TOR/ILS长寿途径和脂肪代谢，以及4)确定昼夜因素对寿命延长贡献的下游机制。这将使用我们对Dr.的昼夜节律全基因组表达谱的初步数据进行检验。我们将确定营养物质如何影响昼夜节律时钟，以及昼夜节律时钟及其目标是否调节寿命。这些研究有可能转变理解衰老和与年龄相关的疾病的范式，并启动“时间老年学”这一分支学科。除了为年龄相关疾病的治疗提供一个新的顺从目标外，他们还可以通过证明在与衰老有关的所有操作/测量中考虑一天中的时间的必要性来改变生物医学实验室的研究实践。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine how circadian rhythms impact nutrient dependent changes in lifespan. Circadian systems organize critical physiological and behavioral functions by coordinating gene expression and metabolic processes throughout the organism. Disruption of circadian clocks has been linked to accelerated aging and is a risk factor for age-related diseases, such as cancer and diabetes. However, the underlying mechanisms of this association remain unknown. It is becoming evident that in addition to light, nutrients provide significant input into modulating circadian systems, especially peripheral clocks. We hypothesize that circadian clocks impact aging and age-related disease by modulating inputs from nutrients and nutrient sensing pathways. We propose to use D. melanogaster to investigate the link between circadian clocks and aging for the following reasons: 1) their fast generation time and short lifespan, 2) ease of genetic manipulation, 3) established genetic models for understanding aging and disease, 4) an excellent track record for understanding of the biology of circadian clocks, and 5) the conservation of many biological processes and signaling pathways between mammals and invertebrates. Our preliminary evidence demonstrates cross-talk between circadian mechanisms and nutrient sensing pathways on multiple levels. We observed that dietary restriction (DR), which is known to extend lifespan in many species, impacts the circadian clocks. DR led to an increase in amplitude of circadian expression of various circadian clock gene in the whole body. We have demonstrated that circadian clocks are also required for the protective effects of DR on lifespan. Furthermore, we have found that circadian clocks play an important role in enhancing triglyceride turnover which we recently demonstrated is required for the lifespan extension upon DR. To understand the mechanisms by which circadian clocks impact aging, especially in the context of DR, we will undertake the following aims: 1) Determine the impact of nutrients on circadian clocks in an age- dependent and tissue-specific manner, 2) Investigate the role of circadian clocks on nutrient-dependent lifespan changes, 3) Determine how circadian influence the TOR/ILS longevity pathways and fat metabolism, and 4) Determine the downstream mechanisms underlying the contribution of circadian factors to lifespan extension. This will be examined using our preliminary data from circadian genome wide expression profiling upon DR. We will determine how nutrients impact the circadian clocks and whether modulation of circadian clocks and their targets modulate lifespan. These studies have the potential to be paradigm-shifting for the understanding of aging and age-related diseases and initiate the sub-discipline of 'chronogerontology'. In addition to providing a novel amenable target for treatments for age-associated pathologies, they could change research practice in biomedical labs by demonstrating the need to take time-of-day into account in all manipulations/measurements related to aging.