The Effect of Calorie Restriction on Brain Aging

热量限制对大脑衰老的影响

• 批准号: 8383292
• 负责人: Sterling C Johnson
• 金额: $ 46.18万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383292
• 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. PUBLIC HEALTH RELEVANCE: The elderly are the fastest growing segment of the U.S. population and this will only increase as baby boomers began turning 65 in 2011. Thus, functional, cognitive and physical declines associated with brain aging and age-related neuro-diseases will also rise, as will health care burden and costs required to treat these conditions. CR and/or CR-mimetics may be a viable means to prolong healthy brain function if it can be shown to be effective in a primates model of aging (which is the goal of this project), and ultimately in humans.

描述(申请人提供)：这项建议是为了继续我们对恒河猴大脑老化的研究，这些研究自1989或1994年以来一直受到热量限制。我们将研究可能解释卡路里限制(CR)对大脑产生有益影响的过程和机制。关键假设是，由于CR，代谢发生了变化。在这项研究中，我们将使用一系列强大的研究工具：MRI检查大脑形态的纵向变化，FDG PET检查葡萄糖代谢功能，详细的认知和行为测试以检查执行、记忆和精细运动灵活性，以及在整个长期研究过程中，对于自然原因死亡的动物，我们将详细检查大脑的神经病理特征和代谢变化的关键指标。本研究的目的1检查脑MRI上的纵向变化，包括体积变化和铁沉积变化。此外，我们将采用更新的扫描序列来更好地描述白质和灰质。Aim 2将使用现有的触摸屏响应系统来检查认知和运动功能。目的3研究细粒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)的组织学特征。目的4用PET FDG和原位检测关键代谢调节因子PGC-1a、SIRT1、mTOR和AMPK，验证了CR诱导脑内能量代谢状态上调的中心假设。最后，目标5提供了一个综合目标，检验研究中不同标记之间的关联收敛，这将导致我们得出结论，CR在多个领域延缓衰老过程。这个项目的意义相当大，因为体重是疾病的一个可改变的风险因素。为了将CR或CR模拟物应用于人类，在灵长类动物模型中了解CR对大脑的影响是至关重要的。在这个项目中，我们将获得一组关于CR对大脑和行为的长期(18-23年)影响的全面和全新的数据。在这个多学科和翻译项目中获得的代谢和结构成像、认知评估和现场脑分析的强大组合将有助于更好地理解CR影响大脑的机制。 与公共健康相关：老年人是美国人口中增长最快的部分，随着2011年婴儿潮一代开始年满65岁，这一比例只会增加。因此，与大脑老化和与年龄相关的神经疾病相关的功能、认知和身体衰退也将增加，治疗这些疾病所需的医疗负担和费用也将增加。CR和/或CR模拟可能是延长健康大脑功能的可行方法，如果它能在灵长类动物衰老模型中被证明是有效的(这是本项目的目标)，并最终在人类身上。