The Effect of Calorie Restriction on Brain Aging

描述（由申请人提供）：本提案旨在继续我们对自 1989 年或 1994 年以来一直限制热量的恒河猴大脑老化的研究。我们将研究可能解释为什么热量限制 (CR) 对大脑产生有益作用的过程和机制。关键假设是 CR 导致代谢转变。在这项研究中，我们将采用一系列强大的研究工具：MRI来检查大脑形态的纵向变化，FDG PET来检查葡萄糖代谢功能，详细的认知和行为测试来检查执行能力、记忆力和精细运动灵活性，对于在整个长期研究过程中因自然原因死亡的动物，我们将详细检查大脑的神经病理学特征和代谢变化的关键指标。本研究的目标 1 检查脑 MRI 的纵向变化，包括体积变化和铁沉积变化。此外，我们将采用更新的扫描序列来获得白质和灰质的更多特征。目标 2 将使用现有的触摸屏响应系统检查认知和运动功能。目标 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。目标 4 检验了一个中心假设，即 CR 会诱导大脑能量代谢状态上调，并通过 PET FDG 进行体内评估，并通过关键代谢调节因子 PGC-1a、SIRT1、mTOR 和 AMPK 进行原位检测。最后，目标 5 提供了一个综合目标，检查研究中各种标记之间的关联收敛性，这将使我们得出结论，CR 在多个领域延缓了衰老过程。该项目的意义非常重大，因为体重是疾病的一个可改变的危险因素。为了将 CR 或 CR 模拟物应用于人类，了解 CR 对灵长类动物模型中大脑的影响至关重要。在这个项目中，我们将获得一组全面且全新的数据，了解 CR 对大脑和行为的长期（18-23 年）影响。在这个多学科和转化项目中获得的代谢和结构成像、认知评估和原位大脑检测的强大结合将有助于更好地理解 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.