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

描述（由申请人提供）：已知暴露于无营养不良或饮食限制（DR）的低营养饮食可延迟生理和行为衰退的发生和进展。膳食蛋白质被认为是介导DR延长寿命的关键常量营养素。有趣的是，在无脊椎动物模型果蝇中进行的研究表明，暴露于主要蛋白质来源的气味，在果蝇的情况下是膳食酵母，足以限制DR对寿命的益处。这项研究引发了一个令人兴奋的可能性，即饮食蛋白质的感官知觉在衰老的调节中发挥作用。然而，关于感觉信息如何被处理或它如何引发生理学的广泛变化（包括衰老）的知识仍然是基本的。这项建议的主要目标是建立膳食蛋白质感知的神经感觉机制，并通过DR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，血清素，一种重要的神经递质，可能是区分食物中蛋白质的关键因素。为了阐明膳食蛋白质如何被感知的具体机制以及相关的感觉信号如何在中枢神经系统（CNS）中表现，我们将使用果蝇研究中可用的强大遗传和神经科学工具仔细解剖5-羟色胺信号通路。然后，我们将通过揭示介导膳食蛋白质诱发的5-羟色胺信号传导的神经内分泌细胞来推进我们对膳食蛋白质的感官知觉如何协调全球生理变化的知识。我们从这些实验中收集到的全面知识将使我们处于一个独特的有利地位，以测试膳食蛋白质的感知与通过血清素信号传导的饮食介导的长寿延长之间的功能联系。我们提出的研究结果将为基础生物学和临床老年医学研究带来新的见解。首先，在果蝇中建立中枢神经系统功能和饮食依赖性寿命之间的联系将为研究更复杂生物体中的类似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，将促进临床研究，以针对营养摄入或年龄相关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.