The Effect of Calorie Restriction on Brain Aging

描述（由申请人提供）：本提案是为了继续我们对恒河猴大脑老化的研究，恒河猴自1989年或1994年以来一直受到热量限制。我们将研究可能解释为什么热量限制（CR）对大脑产生有益影响的过程和机制。关键假设是代谢变化是由于CR而发生的。在本研究中，我们将采用一系列强大的调查工具：MRI检查脑形态的纵向变化，FDG PET检查葡萄糖代谢功能，详细的认知和行为测试来检查执行，记忆和精细运动灵巧性，并且在长期研究过程中由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。本研究目的1探讨脑MRI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，以获得更大的表征白质和灰质。目标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。目的3检查细粒度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）的组织学特征。目的4检验了CR诱导大脑能量代谢上调状态的中心假设，该假设在体内通过PET FDG进行评估，并在原位通过检测关键代谢调节因子PGC-1a、SIRT1、mTOR和AMPK进行评估。最后，目的5提供了一个综合目的，检查研究中各种标记之间的关联收敛，这将使我们得出结论，CR延缓了多个领域的衰老过程。这个项目的意义是相当高的，因为体重是一个可改变的疾病风险因素。为了将CR或CR模拟物应用于人类，了解CR在灵长类动物模型中对大脑的影响至关重要。在这个项目中，我们将获得一套全面的、完全新颖的长期（18-23年）CR对大脑和行为影响的数据。代谢和结构成像、认知评估和原位脑分析在这个多学科和转化项目中获得的强大组合将导致更好地理解CR影响大脑的机制。

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.