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营养依赖的变化。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。生物钟紊乱与加速衰老有关，是癌症和糖尿病等与年龄相关疾病的风险因素。然而，这种关联的潜在机制尚不清楚。越来越明显的是，除了光，营养物质对调节昼夜节律系统，特别是外围时钟提供了重要的输入。我们假设生物钟通过调节营养物质和营养感知途径的输入来影响衰老和与年龄相关的疾病。我们建议利用d.m anologaster来研究生物钟与衰老之间的联系，原因如下：1)它们的生成时间快，寿命短；2)易于遗传操作；3)建立了理解衰老和疾病的遗传模型；4)对生物钟生物学的理解有良好的记录；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护。我们的初步证据表明，昼夜机制和营养感知途径在多个层面上相互作用。我们观察到，饮食限制（DR）会影响生物钟，而众所周知，饮食限制可以延长许多物种的寿命。DR导致全身各种生物钟基因的昼夜节律表达幅度增加。我们已经证明，DR对寿命的保护作用也需要生物钟。此外，我们发现生物钟在促进甘油三酯代谢方面发挥着重要作用，我们最近证明了甘油三酯代谢是延长DR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，我们将开展以下目标：1)确定营养物质对生物钟的年龄依赖性和组织特异性影响，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，4)确定昼夜节律因子对寿命延长贡献的下游机制。我们将利用dr上的昼夜节律基因组广泛表达谱的初步数据来检验这一点。我们将确定营养物质如何影响昼夜节律钟，以及昼夜节律钟及其靶点的调节是否会调节寿命。这些研究有可能成为理解衰老和年龄相关疾病的范式转变，并开创“老年病学”的子学科。除了为治疗与年龄相关的病理提供一种新的可适应的靶点外，它们还可以通过证明在所有与衰老相关的操作/测量中都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.