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。生物钟的破坏与加速衰老有关，也是与年龄有关的疾病（如癌症和糖尿病）的风险因素。然而，这种关联的潜在机制仍然未知。越来越明显的是，除了光，营养物质提供了重要的输入到调制昼夜节律系统，特别是外围时钟。我们假设生物钟通过调节营养素和营养素传感途径的输入来影响衰老和年龄相关疾病。我们建议使用D。melanogaster研究生物钟和衰老之间的联系，原因如下：1）它们的快速世代时间和短寿命，2）易于遗传操作，3）建立了理解衰老和疾病的遗传模型，4）理解生物钟生物学的良好记录，5）哺乳动物和无脊椎动物之间的许多生物过程和信号通路的保护。我们的初步证据表明，在多个层面上的昼夜节律机制和营养传感途径之间的串扰。我们观察到，饮食限制（DR），这是众所周知的延长寿命在许多物种，影响生物钟。DR导致全身各生物钟基因的昼夜节律表达幅度增加。我们已经证明，生物钟也需要DR对寿命的保护作用。此外，我们发现生物钟在增强甘油三酯周转方面起着重要作用，我们最近证明这是DR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，我们将实现以下目标：1）以年龄依赖性和组织特异性方式确定营养素对生物钟的影响，2）研究生物钟对营养素依赖性寿命变化的作用，3）确定昼夜节律如何影响TOR/ILS寿命途径和脂肪代谢，以及4）确定昼夜节律因素对寿命延长的贡献的下游机制。这将使用我们的初步数据进行检查，从昼夜全基因组表达谱DR。我们将确定营养素如何影响生物钟，以及生物钟的调制和它们的目标是否调节寿命。这些研究有可能成为对衰老和年龄相关疾病的理解的范式转变，并启动了“时间老年学”的子学科。除了为年龄相关疾病的治疗提供一种新的适合的靶点外，它们还可以通过证明在与衰老相关的所有操作/测量中需要考虑一天中的时间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.