The role of serotonin in dietary protein perception and diet-dependent longevity

描述(由申请人提供)：众所周知，在没有营养不良或饮食限制(DR)的情况下，接触营养减少的饮食会随着时间的推移延缓生理和行为衰退的发生和发展。有趣的是，在无脊椎动物模型--黑腹果蝇中进行的研究表明，接触主要蛋白质来源--果蝇的膳食酵母--的气味足以限制DR对寿命的好处。这项研究提出了一种令人兴奋的可能性，即对食物蛋白质的感官感知在调节衰老方面发挥了作用。然而，关于感官信息是如何处理的，或者它是如何引发包括衰老在内的广泛的生理变化的知识仍然是初级的。这项建议的主要目标是建立食物蛋白质感知的神经感觉机制，并评估其在延长寿命中的作用。我们的初步数据以及最近发表的结果表明，作为一种重要的神经递质，5-羟色胺可能是区分食物中蛋白质的关键角色。为了阐明食物蛋白质如何被感知以及相关感觉信号如何在中枢神经系统(CNS)中表达的具体机制，我们将利用果蝇研究中可用的强大遗传和神经科学工具，对5-羟色胺信号通路进行仔细的剖析。然后，我们将通过揭示神经内分泌细胞来促进我们的知识，了解对饮食蛋白质的感觉如何协调全球生理变化，神经内分泌细胞介导由饮食蛋白质引起的5-羟色胺信号。我们从这些实验中收集的全面知识将使我们处于一个独特的强大地位，以测试对饮食蛋白质的感知和通过5-羟色胺信号的饮食介导的延长寿命之间的功能联系。我们建议的研究结果将为基础生物学和临床老年学研究带来新的见解。首先，在果蝇中枢神经系统的功能和依赖饮食的寿命之间建立联系，将为在更复杂的生物体中检验类似的机制提供一个基本框架。其次，了解营养信号是如何被感知的，以及这些信息是如何被处理的，这将促进临床研究，以针对营养摄入或与年龄相关的疾病进展的神经调节。

DESCRIPTION (provided by applicant): Exposure to a reduced-nutrient diet without malnutrition, or dietary restriction (DR), is known to delay the onset and progression of physiological and behavioral decline over time. Dietary protein has been implicated as a key macronutrient that mediates life-extension by DR. Interestingly, research done in an invertebrate model, Drosophila melanogaster, has revealed that exposure to the smell of a major protein source, dietary yeast in the case of Drosophila, is sufficient to limit the benefits of DR on lifespan. This study evoked an exciting possibility that sensory perception of dietary protein plays a role in the modulation of aging. However, knowledge about how sensory information is processed or how it initiates widespread changes in physiology, including aging, remains rudimentary. The major objectives of this proposal are to establish neurosensory mechanisms of dietary protein perception and to evaluate its role in life-extension by DR. Our preliminary data, together with recently published results, suggested that serotonin, an important neurotransmitter, may be a key player in distinguishing protein in a food. To elucidate the specific mechanisms underlying how dietary proteins are perceived and how the relevant sensory signals are represented in the central nervous system (CNS), we will undertake careful dissection of serotonin signaling pathways using powerful genetic and neuroscience tools available in Drosophila research. We will then advance our knowledge in how sensory perception of dietary protein orchestrates global physiological changes by uncovering neuroendocrine cells that mediate dietary protein-evoked serotonin signaling. Comprehensive knowledge we gathered from these experiments will put us in a uniquely strong position to test a functional link between perception of dietary protein and diet-mediated longevity extension through serotonin signaling. The findings from our proposed studies will bring new insights into basic biology and clinical geriatric research. First, establishing connectivity between the functio of the CNS and diet-dependent longevity in fruit flies will provide a basic framework to examine similar mechanisms in more complex organisms. Second, understanding how nutrient signals are perceived and how this information is processed will foster clinical research to target neurological regulation of nutrient intake or age-associated disease progression.