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: 9005964
• 负责人: SCOTT PLETCHER
• 金额: $ 31.28万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005964
• 关键词: Affect; Afferent Neurons; Aging; Amino Acids; Animal Model; Animals; Behavior; Behavioral; Biological; Biological Models; Biology of Aging; Brain; Brain region; Caenorhabditis elegans; Cells; Complex; Corticotropin-Releasing Hormone; Creativeness; Data; Decision Making; Dementia; Diet; Disease; Diuretics; Drosophila genus; Drosophila melanogaster; Elderly; Environment; Evaluation; Feedback; Food; Food Preferences; Genes; Growth; Health; Health Benefit; Homologous Gene; Hormones; Hour; Human; Hunger; Individual; Insulin; Intake; Intervention; Ion Channel; Laboratories; Lead; Life; Link; Longevity; Malignant Neoplasms; Mammals; Maps; Metabolic; Metabolism; Molecular; Molecular Genetics; Mus; Nature; Nervous system structure; Neurobiology; Neurologic; Neurons; Neuropeptides; Nutrient; Nutritional; Organism; Outcome; Output; Pain; Partner in relationship; Pathology; Pathway interactions; Peripheral; Phenotype; Physiological; Physiology; Play; Population; Prevalence; Process; Proteins; Regulation; Reporting; Reproduction; Research; Rewards; Risk Factors; Role; Saccharomyces cerevisiae; Satiation; Sensory; Serotonin; Signal Pathway; Signal Transduction; Societies; Starvation; Stress; System; TRP channel; Taste Perception; Taxon; Testing; Tissues; Work; age related; detection of nutrient; dietary manipulation; experience; fly; functional decline; genetic analysis; health economics; healthy aging; innovation; insight; loss of function; mortality; neural circuit; novel; preference; protein intake; public health relevance; relating to nervous system; response; sensory input; sensory system; serotonin receptor; success; tool

 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.

 描述(申请人提供)：我们社会中老年人数量的持续增长及其对与年龄相关的疾病流行的影响将在未来20年内产生与经济和健康相关的重大后果。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慢慢揭开，但作为与这些疾病状态相关的最重要风险因素，高龄背后的机制相对未知。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，我们谈论的不仅仅是延长寿命；在了解衰老的基本生物学方面的进步也将对整体健康产生巨大的好处。在过去的十年里，通过对简单模型系统的研究，我们对哺乳动物衰老的理解得到了极大的刺激。可以说，今天对小鼠进行的最有效的衰老相关干预措施针对的是sirtuin基因，以及TOR和胰岛素/IGF信号通路，所有这些都是在酿酒酵母、秀丽线虫和黑腹果蝇中首次发现的。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结果提供了一个明确的生物学框架。从规范的感觉系统和内部平衡机制进入大脑的信息被接收、整合和发送，以协调周围组织的变化。我们认为，这些“决定”是影响衰老的重要因素。更具体地说，我们的假设是，评估内部和外部营养可获得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调节行为和寿命方面发挥着重要作用。利用简单模型系统的神经生物学来研究如何根据评估的能量状态做出生理决定的影响，将有助于深入了解营养物质对包括人类在内的不同类群寿命的广泛影响。它还将提供关于神经元输入如何协调细胞自主和非自主机制以确保复杂有机体中的生存和健康的分子细节的理解。这一提议的创新本质来自于果蝇可用的独特合适的工具，以及关于评估和感官影响对寿命的重要性的新视角，为开发和测试关于细胞非自主控制衰老的假设提供了创造力和实验力量，这是以前从未考虑过的。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，改善人类与衰老相关的功能衰退。