Modulation of aging through mechanisms of nutrient demand and reward

项目摘要 社会上老年人的人数不断增加，对老年人的普遍性产生了影响， 与年龄有关的疾病将在今后20年中产生严重的经济和健康后果。 尽管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地被 解开，作为与这些疾病相关的最重要的风险因素的高龄的机制 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， 预期衰老机制将改善或消除多种病理和疾病。是的， 因此，不仅仅是谈论延长寿命;在理解衰老的基本生物学方面的进展 对健康也有很大的好处。我们对哺乳动物衰老的理解 在过去的十年里，简单模型系统的研究极大地刺激了这一点。可以说，今天最有效的 小鼠衰老相关的干预措施靶向sirtuin基因，以及TOR和胰岛素/IGF信号通路，所有 其中最早在酿酒酵母、秀丽隐杆线虫和黑腹果蝇中鉴定。 近年来，分子神经科学，经常使用简单的模式生物，如果蝇，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。自我平衡 在这个过程中，驱动力和奖励经验一样有影响力，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会影响整个细胞的细胞通路。 身体，即使是那些被认为是细胞自主的。我们有证据表明 编码进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 评估内部和外部营养物质可用性并启动生理 与饥饿和饱足等状态相关的变化在行为调节中起着重要作用 和寿命。 利用简单模型系统的神经生物学来研究生理决策如何影响 根据评估的能量状态做出的反应，将深入了解营养素对 包括人类在内的所有物种的寿命。它还将提供一个分子细节的理解， 神经元输入如何协调细胞自主和非自主机制，以确保生存， 复杂有机体的健康这一提案的创新性来自于 适当的工具，可在果蝇连同一个新的角度对评价的重要性， 和激励神经回路的寿命，提供了创造力和实验的力量，发展和 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。在 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。

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.