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疾病的流行的影响将在未来二十年产生巨大的经济和健康相关后果。许多疾病，包括癌症和痴呆症，正在慢慢被揭开，作为与这些疾病状态相关的最重要危险因素的高龄机制相对未知，这是一个重要的问题，因为预期会影响衰老机制的单一干预措施。改善因此，我们不仅仅是在谈论延长寿命；在过去的十年中，我们对衰老的基本生物学的理解也将产生巨大的普遍健康益处。可以说，当今针对小鼠的最有效的衰老相关干预措施是针对沉默调节蛋白基因以及 TOR 和胰岛素/IGF 信号通路，所有这些都是首先在酿酒酵母中发现的。近年来，现代分子遗传学通常使用简单的模型生物，为理解从典型感觉系统和内部进入大脑的信息的原因和后果提供了明确的生物学框架。稳态机制被接收、整合和调度，以协调周围组织的变化。更具体地说，我们的假设是评估内部和外部的特定机制。营养可用性和启动与饥饿和饱腹感等状态相关的生理变化在行为和寿命的调节中发挥着重要作用，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策的影响。深入了解营养物质对包括人类在内的整个分类群的寿命的广泛影响，它还将提供对神经输入如何协调细胞自主和非自主机制以确保生存和健康的分子细节的理解。该提案的创新性源于果蝇中可用的独特合适的工具，以及关于评估和感觉对寿命影响的重要性的新颖视角，为开发和测试有关细胞的假设提供了创造力和实验能力。除了提供发现衰老基本机制的机会之外，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。