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.

项目摘要 我们社会中较早的数量不断增长，以及对流行率的影响 与年龄有关的疾病将在未来二十年内产生与经济和健康有关的巨大后果。 尽管许多疾病的原因和后果，包括癌症和痴呆症，正在缓慢地 揭露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。这是一个重要的问题，因为影响的单一干预措施 衰老的机制有望改善或消除多种病理和疾病。我们是 因此，不仅在谈论延长寿命；了解衰老的基本生物学的进步 也将具有巨大的一般健康益处。我们对哺乳动物衰老的理解已经 在过去的十年中，通过简单模型系统中的研究大大刺激了。可以说，今天最有效 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 其中最初是在酿酒酵母，秀丽隐杆线虫和果蝇的葡萄球菌中发现的。 近年来，经常使用果蝇等简单模型生物的分子神经科学已提供 一个定义明确的框架，用于剖析融合行为的原因和后果。稳态 在此过程中，驱动器与奖励的经验以及神经元和神经元一样的影响 影响觅食，交配和许多其他行为的动机，也影响整个整个细胞途径 身体，甚至那些被认为主要是细胞自主的人。我们有证据表明电路和中立 编码喂养动机的国家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启动生理的特定机制 与饥饿和饱腹感相关的变化在行为调制中起着重要作用 和寿命。 利用简单模型系统的神经生物学来研究生理决策的影响 以评估的能源状态为响应，将产生对养分对养分的广泛影响的见解 包括人类在内的整个分类单元的寿命。它还将提供对有关的分子细节的理解 神经元输入如何编排细胞自主和非自治机制来确保生存和 复杂生物体的健康。该提议的创新性质，它来自独特的 果蝇中可用的适当工具以及关于评估重要性的新颖观点 以及寿命上的动机神经回路，为发展和 关于先前尚未考虑的关于衰老的非自治控制的测试假设。在 除了提供发现衰老基本机制的机会，我们的工作还可能导致 改善人类衰老相关的功能下降的创造性干预策略。