The Effect of Calorie Restriction on Brain Aging

热量限制对大脑衰老的影响

• 批准号: 8704847
• 负责人: Sterling C Johnson
• 金额: $ 41.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704847
• 关键词: 5' -AMP-activated protein kinase; Affect; Age; Aging; Aging-Related Process; Amyloid beta-Protein; Animals; Astrocytes; Atlases; Atrophic; Attenuated; Basal Ganglia; Behavior; Biological Assay; Body Weight; Brain; Brain imaging; Caloric Restriction; Cereals; Characteristics; Cognition; Cognitive; Data; Data Set; Deposition; Disease; Elderly; Energy Metabolism; Exhibits; Funding; Glial Fibrillary Acidic Protein; Glucose; Goals; Health; Healthcare; Hippocampus (Brain); Histology; Homeostasis; Homocysteine; Homocystine; Human; Image; Image Analysis; Immunohistochemistry; In Situ; Insulin; Interleukin-6; Investigation; Iron; Lead; Link; Literature; Macaca mulatta; Magnetic Resonance Imaging; Mammals; Measures; Memory; Metabolic; Metabolism; Methods; Mitochondria; Modality; Modeling; Morphology; Motor; Neurodegenerative Disorders; Outcome; PPAR gamma; Paired Comparison; Plasma; Population; Positron-Emission Tomography; Prefrontal Cortex; Primates; Process; Publishing; Relative (related person); Risk Factors; Running; Scanning; Slice; Sorting - Cell Movement; Speed; Structure; Synapses; Synaptophysin; System; Testing; Time; Tissue Banking; Tissue Banks; Universities; Visual; Wisconsin; abeta accumulation; age effect; age related; aged; aging brain; analog; astrogliosis; base; behavior measurement; behavior test; brain behavior; brain morphology; brain tissue; care burden; cognitive function; cohort; cost; density; executive function; fluorodeoxyglucose positron emission tomography; functional outcomes; glucose metabolism; gray matter; immunoreactivity; in vivo; mTOR protein; mimetics; modifiable risk; multidisciplinary; novel; response; tau Proteins; tau aggregation; tool; touchscreen; white matter; white matter change

DESCRIPTION (provided by applicant): This proposal is to continue our studies of brain aging in rhesus macaques that have been calorically restricted since 1989 or 1994. We will investigate processes and mechanisms that may explain why caloric restriction (CR) exerts a salutary effect on the brain. The key hypothesis is that a metabolic shift occurs due to CR. In this study we will employ a powerful array of investigative tools: MRI to examine longitudinal change in brain morphology, FDG PET to examine glucose metabolic function, detailed cognitive and behavioral testing to examine executive, memory and fine motor dexterity, and on the animals that have died due to natural causes throughout the course of the long-running study, we will examine the brain in fine detail for neuropathologic features and for key indicators of metabolic changes. Aim 1 of this study examines longitudinal change on brain MRI including volumetric changes, and iron deposition changes. In addition we will employ newer scan sequences to obtain greater characterization of white and gray matter. Aim 2 will examine cognitive and motor function using an already existing touch screen response system. Aim 3 examines fine-grained neurohistopathology features including histological characterization of beta amyloid, tau, p-tau, synaptic density, and reactive astrocytes (GFAP). Aim 4 examines the central hypothesis that CR induces an upregulated state of energy metabolism in the brain assessed in vivo with PET FDG and in situ with assays of key metabolic regulators PGC-1a, SIRT1, mTOR, and AMPK. Finally Aim 5 provides an integrative Aim examining associative convergence among the various markers in the study that would lead us to conclude that CR retards the aging process in multiple domains. The significance of this project is quite high since body weight is a modifiable risk factor for disease. In order for CR or CR mimetics to be applied in humans it is critical to understand the effect of CR on the brain in a primate model. In this project we will attain a comprehensive and completely novel set of data on the long-term (18-23 years) effects of CR on the brain and behavior. The powerful combination of the metabolic and structural imaging, cognitive assessment and in-situ brain assays obtained in this multidisciplinary and translational project will lead to better understanding of the mechanisms by which CR affects the brain.

描述（由申请人提供）：该提案是要继续我们对自1989年或1994年以来一直受到热量限制的恒河猕猴中的大脑衰老的研究。我们将研究过程和机制，这些过程和机制可能解释了为什么热量限制（CR）对大脑产生可爱的影响。关键的假设是由于CR发生了代谢转移。在这项研究中，我们将采用强大的调查工具：MRI检查脑形态的纵向变化，FDG PET来检查葡萄糖代谢功能，详细的认知和行为测试，以检查执行，记忆和良好的运动性敏感性，以及由于长期研究的整个过程中的自然原因而导致自然原因导致的动物，我们将对Neurop and neurops neurop and the Neurop and the Neurop and the Neurop consect and neurops chake and neurops进行详细介绍。本研究的目标1检查了大脑MRI的纵向变化，包括体积变化和铁沉积变化。此外，我们将采用较新的扫描序列来获得对白色和灰色物质的更大表征。 AIM 2将使用已经存在的触摸屏响应系统检查认知和运动功能。 AIM 3检查了细粒的神经组织病理学特征，包括β-淀粉样蛋白，TAU，P-TAU，突触密度和反应性星形胶质细胞（GFAP）的组织学表征。 AIM 4研究了CR在体内用PET FDG评估的大脑中的CR上调的能量代谢上调的中心假设，并在原位使用关键代谢调节剂PGC-1A，SIRT1，MTOR和AMPK进行测定。最终，AIM 5提供了一个综合目的，研究了研究中各种标记之间的关联收敛，这将使我们得出结论，CR会阻止多个领域的衰老过程。该项目的重要性很高，因为体重是可改变的疾病风险因素。为了在人类中应用Cr或Cr Mimetics，了解在灵长类动物模型中CR对大脑的影响至关重要。在这个项目中，我们将获得有关CR对大脑和行为的长期影响（18 - 23年）影响的全面且完全新颖的数据。在这个多学科和转化项目中获得的代谢成像，认知评估和原位脑测定的强大组合将使人们更好地理解CR影响大脑的机制。