Modulation of aging through mechanisms of nutrient demand and reward

项目摘要 我们社会中老年人数量的持续增长及其对老年人患病率的影响 与年龄相关的疾病将在未来20年产生巨大的经济和健康相关后果。 尽管包括癌症和痴呆症在内的许多疾病的起因和后果正在缓慢地 作为与这些疾病相关的最重要的风险因素，高龄背后的机制已经揭开 疾病状态相对未知。这是一个重要的问题，因为单一的干预措施会影响 衰老机制有望改善或消除多种病理和疾病。我们是, 因此，不仅仅是谈论延长寿命，而是在理解衰老的基本生物学方面取得了进展 也会带来巨大的整体健康益处。我们对哺乳动物衰老的理解是 在过去的十年里，通过对简单模型系统的研究，极大地刺激了这一进程。可以说，今天最有效的 小鼠的衰老相关干预以sirtuin基因以及TOR和胰岛素/IGF信号通路为靶点，所有这些都是 其中，在酿酒酵母、秀丽线虫和黑腹果蝇中首次发现。 近年来，分子神经科学，通常使用像果蝇这样的简单模式生物，已经提供了 一个定义明确的框架，用于剖析动机行为的原因和后果。动态平衡 驱动力在这一过程中的影响与有益的经历一样重要，而神经元和神经回路 影响觅食、交配和许多其他行为的动机也影响整个细胞通路 身体，甚至那些被认为在很大程度上是细胞自主的。我们有证据表明这些电路和神经 编码摄食动机的状态是衰老的重要调节器。更具体地说，我们的假设是 评估内部和外部养分可获得性并启动生理 与饥饿和饱腹感等状态相关的变化在行为调节中发挥着重要作用 和寿命。 利用简单模型系统的神经生物学来研究生理决定如何影响 对评估的能量状态做出的反应将使人们深入了解营养物质对 包括人类在内的不同分类群的长寿。它还将提供对分子细节的理解 神经元输入如何协调细胞自主和非自主机制以确保生存和 在一个复杂的有机体中的健康。这项建议的创新性质源于独特的 在果蝇中可用的适当工具，以及关于评估重要性的新视角 以及关于寿命的激励神经回路，提供了创造力和实验力量来开发和 测试关于细胞对衰老的非自主控制的假设，这些假设以前没有被考虑过。在……里面 除了为发现衰老的基本机制提供机会外，我们的工作还可能导致 创造性的干预策略，改善人类衰老相关的功能衰退。

Project Summary 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, molecular neuroscience, often using simple model organisms like Drosophila, has provided a well-defined framework for dissecting the causes and consequences of motivated behaviors. Homeostatic drives are as influential in this process as are rewarding experiences, and the neurons and neural circuits that influence motivation for foraging, mating, and many other behaviors also affect cellular pathways throughout the body, even those thought to be largely cell-autonomous. We have evidence that the circuits and neural states that encode feeding motivations 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, including 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 motivational neural circuits 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.