Modulation of aging through mechanisms of nutrient demand and reward

 描述（由申请人提供）：在我们的社会中，老年人数量的不断增长以及由此对年龄相关疾病流行的影响将在未来二十年内产生巨大的经济和健康相关后果。虽然包括癌症和痴呆症在内的许多疾病的原因和后果正在慢慢解开，但作为与这些疾病状态相关的最重要风险因素的高龄的机制相对未知。这是一个重要的问题，因为影响衰老机制的单一干预措施有望改善或消除多种病理和疾病。因此，我们不仅仅是在谈论延长寿命;对衰老基本生物学的理解的进步也会带来巨大的健康益处。在过去的十年里，我们对哺乳动物衰老的理解受到简单模型系统研究的极大刺激。可以说，今天在小鼠中最有效的衰老相关干预措施靶向sirtuin基因，以及TOR和胰岛素/IGF信号通路，所有这些都首先在酿酒酵母，秀丽隐杆线虫和果蝇中发现。近年来，现代分子遗传学，通常使用简单的模式生物，为理解决策的原因和后果提供了一个明确的生物学框架。从典型的感觉系统和内部自我平衡机制进入大脑的信息被接收、整合和发送，以协调外周组织的变化。我们相信这些“决定”是衰老的重要调节器。更具体地说，我们的假设是，评估内部和外部营养可用性并启动与饥饿和饱腹感等状态相关的生理变化的特定机制在行为和寿命的调节中发挥重要作用。利用简单模型系统的神经生物学来研究生理决策如何响应评估的能量状态的影响，将深入了解营养素对包括人类在内的所有分类群寿命的广泛影响。它还将提供有关神经元输入如何协调细胞自主和非自主机制的分子细节的理解，以确保复杂生物体的生存和健康。这一提议的创新性，它来自于果蝇中提供的独特的适当的工具，以及对寿命的评价和感官影响的重要性的新视角，提供了创造力和实验能力来开发和测试关于细胞非自主控制衰老的假设，这些假设以前没有考虑过。除了提供发现衰老基本机制的机会外，我们的工作还可能导致创造性的干预策略，改善人类与衰老相关的功能衰退。

 DESCRIPTION (provided by applicant): Unrelenting growth in the number of elderly in our society and the resulting impact on the prevalence of age- related disease will have dramatic economic and health-related consequences over the next two decades. Although the causes and consequences of many diseases, including cancer and dementia, are slowly being unraveled, the mechanisms that underlie advanced age as the most significant risk factor associated with these disease states are relatively unknown. This is an important issue because single interventions that impact mechanisms of aging would be expected to ameliorate or eliminate multiple pathologies and diseases. We are, therefore, not just talking about extending lifespan; advances in understanding the basic biology of aging would have tremendous general health benefits as well. Our understanding of mammalian aging has been greatly stimulated over the past decade by research in simple model systems. Arguably, today's most effective aging-related interventions in mice target sirtuin genes, as well as TOR and insulin/IGF signaling pathways, all of which were first identified in Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster. In recent years, modern molecular genetics, often using simple model organisms, has provided a well-defined biological framework for understanding the causes and consequences of decision-making. Information entering the brain from canonical sensory systems and internal homeostatic mechanisms is received, integrated, and dispatched to orchestrate changes in peripheral tissues. We believe that these 'decisions' are important modulators of aging. More specifically, our hypothesis is that specific mechanisms that evaluate internal and external nutrient availability and initiate physiological changes associated with states such as hunger and satiety play important roles in the modulation of behavior and lifespan. Harnessing the neurobiology of simple model systems to study the impact of how physiological decisions are made in response to evaluated energy status will yield insights into the broad influence of nutrients on longevity across taxa, includin humans. It will also provide an understanding of the molecular details about how neuronal inputs orchestrate cell-autonomous and non-autonomous mechanisms to insure survival and health in a complex organism. The innovative nature of this proposal, which derives from the uniquely appropriate tools available in Drosophila together with a novel perspective about the importance of evaluative and sensory influences on lifespan, provides the creativity and experimental power to develop and test hypotheses about the cell non-autonomous control of aging that have not been previously considered. In addition to providing an opportunity to discover basic mechanisms of aging, our work may also lead to creative intervention strategies that ameliorate aging-related functional decline in humans.