Modulation of aging through mechanisms of nutrient demand and reward

通过营养需求和奖励机制调节衰老

• 批准号: 10295102
• 负责人: SCOTT PLETCHER
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295102
• 关键词: Acute; Affect; Aggressive behavior; Aging; Amino Acids; Animal Model; Behavior; Behavioral; Biological Models; Biology of Aging; Brain; Branched-Chain Amino Acids; Caenorhabditis elegans; Cells; Chemosensitization; Chromatin; Citric Acid Cycle; Complex; Consumption; Coupled; Creativeness; Data; Dementia; Diet; Disease; Drosophila genus; Drosophila melanogaster; Eating; Economics; Elderly; Engineering; Environment; Etiology; Evaluation; Event; Feeding behaviors; Food; Food Preferences; Fright; Genes; Genetic; Genetic Transcription; Goals; Growth; HTR2A gene; Health; Health Benefit; Health Promotion; Histone H3; Human; Hunger; Influentials; Insulin; Intervention; Lead; Life; Longevity; Malignant Neoplasms; Mammals; Measures; Metabolic; Metabolism; Modification; Molecular; Motivation; Mus; Nature; Nerve; Neurobiology; Neurons; Neurosciences; Nutrient; Nutritional; Organism; Palate; Partner in relationship; Pathology; Pathway interactions; Peripheral; Personal Satisfaction; Physiological; Physiology; Play; Population; Prevalence; Process; Research; Rewards; Risk Factors; Role; Saccharomyces cerevisiae; Satiation; Serotonin; Serotonin Receptor 5-HT2A; Signal Pathway; Signal Transduction; Sirtuins; Societies; System; Techniques; Technology; Testing; Tissues; Work; age related; alpha ketoglutarate; base; dietary; dietary manipulation; epigenetic regulation; experience; feeding; fly; food environment; functional decline; healthy aging; hedonic; innovation; innovative technologies; insight; motivated behavior; neural circuit; novel; optogenetics; pleasure; relating to nervous system; response; screening program; serotonin receptor; tool

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.

项目概要 我们社会中老年人数量的不断增长及其对老年人口患病率的影响 与年龄相关的疾病将在未来二十年对经济和健康产生巨大的影响。 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被人们认识到。 揭示了高龄作为与这些相关的最重要危险因素的机制 疾病状态相对未知。这是一个重要问题，因为单一干预措施会影响 衰老机制有望改善或消除多种病理和疾病。我们是， 因此，不只是谈论延长寿命；在理解衰老的基础生物学方面取得的进展 也会对整体健康产生巨大的好处。我们对哺乳动物衰老的理解是 在过去的十年中，简单模型系统的研究极大地促进了这一领域的发展。可以说，当今最有效的 对小鼠进行与衰老相关的干预，以 Sirtuin 基因以及 TOR 和胰岛素/IGF 信号通路为目标，所有这些 其中首先在酿酒酵母、秀丽隐杆线虫和黑腹果蝇中发现。 近年来，分子神经科学通常使用果蝇等简单的模型生物，提供了 一个明确的框架，用于剖析动机行为的原因和后果。稳态 在这个过程中，驱动力与奖励体验以及神经元和神经回路一样有影响力。 影响觅食、交配和许多其他行为的动机也会影响整个细胞通路 身体，甚至那些被认为在很大程度上是细胞自主的身体。我们有证据表明电路和神经 编码进食动机的状态是衰老的重要调节因素。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生理学的特定机制 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策的影响 根据评估的能量状态做出的反应将深入了解营养物质对身体的广泛影响 包括人类在内的所有类群的长寿。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 复杂有机体的健康。该提案的创新性源于其独特的 果蝇中可用的适当工具以及关于评估重要性的新颖视角 和对寿命的激励神经回路，提供创造力和实验力量来发展和 测试先前未考虑过的有关细胞非自主控制衰老的假设。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 改善人类与衰老相关的功能衰退的创造性干预策略。