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: 9923541
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923541
• 关键词: Acute; 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; Economics; 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; Modernization; 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; Sirtuins; Societies; Starvation; Stress; System; TRP channel; Taste Perception; Testing; Tissues; Work; age related; detection of nutrient; dietary manipulation; experience; fly; functional decline; genetic analysis; 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; 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（由适用提供）：我们社会中较早的数量的不懈增长以及对与年龄相关疾病的患病率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。尽管包括癌症和痴呆在内的许多疾病的原因和后果正在缓慢地揭示，但与这些疾病状态相关的最重要的危险因素是高级年龄构成的机制。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，我们不仅在谈论延长寿命；了解衰老的基本生物学的进步也将带来巨大的一般健康益处。在过去的十年中，在简单模型系统中，我们对哺乳动物衰老的理解受到了极大的刺激。可以说，当今小鼠中最有效的与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，所有这些途径首先在酿酒酵母，Caenorhabditis elegrans和果蝇中首次鉴定出来。近年来，现代分子遗传学通常使用简单的模型生物，为理解决策的原因和后果提供了明确定义的生物学框架。从规范的感觉系统中进入大脑的信息，并收到内部体内稳态机制，并派遣并派遣到策划外围组织的变化。我们认为，这些“决定”是衰老的重要调节剂。更具体地说，我们的假设是评估内部和外部养分可用性并引发与饥饿和饱腹部等状态相关的身体变化的特定机制在行为和寿命的调节中起着重要作用。利用简单模型系统的神经生物学研究如何响应评估能量状态的物理决策的影响，将为包括人类在内的整个分类单元（包括人类）的长寿影响提供深入的见解。它还将对有关神经元输入如何编排细胞自主和非自治机制的分子细节，以确保复杂的组织中的生存和健康。该提案的创新性质源自果蝇中可用的独特工具，以及关于评估和感官影响对寿命的重要性的新观点，为开发和测试有关细胞对衰老的细胞非自主控制的假设提供了创造性和实验能力，而不是先前考虑过。除了提供一个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，从而减轻与衰老相关的功能下降。