Role of exercise-induced blood factors in rejuvenating the aged brain

运动诱发的血液因子在恢复衰老大脑活力中的作用

基本信息

批准号：
10380830
负责人：
SAUL A VILLEDA
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380830
关键词：
Adherence Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animals Behavioral Paradigm Bioluminescence Blood Blood Circulation Brain Cardiovascular system Cognition Cognitive Confocal Microscopy Data Dementia Elderly Enzymes Event Exercise Exposure to Glycosylphosphatidylinositols Health Hippocampus (Brain)Human Immunohistochemistry Impaired cognition Impairment Individual Kinetics Knowledge Learning Link Liver Mass Spectrum Analysis Memory Molecular Mus Neurodegenerative Disorders Parabiosis Pathway interactions Perception Plasma Population Predisposition Proteomics Radial Regenerative capacity Rejuvenation Research Role Running Site-Directed Mutagenesis Testing Therapeutic Therapeutic Effect adult neurogenesis age effect age related age related neurodegeneration aged aging brain aging hippocampus arm cognitive benefits cognitive function conditioned fear fitness frailty improved in vivo insight mouse model neurodegenerative phenotype neurogenesis new therapeutic target overexpression phospholipase D1 regeneration function regenerative systemic intervention theories translational potential water maze

项目摘要

PROJECT SUMMARY/ABSTRACT Aging drives regenerative and cognitive impairments in the adult brain increasing susceptibility to dementia- related neurodegenerative diseases, such as Alzheimer's disease, in healthy individuals. Evidence suggests that exercise can counter age-related decline in regenerative capacity and cognition in the aged brain. The ability to reverse brain aging through systemic interventions such as exercise could enable the mitigation of vulnerability to age-related neurodegenerative diseases, fulfilling an unmet need that is growing more pressing as the human population ages. Despite the evident benefit of exercise, its application is hindered in the elderly by technical barriers, with evidence that perception of physical frailty or poor health alone can decrease adherence. Therefore, it is critical to identify accessible therapeutic approaches that confer benefits of exercise while circumventing pre-existing limitations. We and others have previously shown that systemic manipulations, including heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) and young blood plasma administration, likewise enhance adult neurogenesis and cognition in aged mice1,3,13. The rejuvenating effects observed with exercise mirror those of a youthful circulation, raising the possibility that exercise similarly functions through blood factors to exert its beneficial effects. Indeed, preliminary data from our lab demonstrate that systemic administration of blood plasma derived from exercised mice reverses age-related impairments in adult neurogenesis and cognition in aged mice. The purpose of the proposed study is thus to investigate the rejuvenating and therapeutic effects of exercise-induced blood factors on the aged brain. Specifically, our hypothesis is that systemic exposure to exercise-induced blood factors elicits long lasting rejuvenation of regenerative and cognitive functions, while ameliorating neurodegenerative phenotypes. We will test this theory with Three Specific Aims: 1: Characterize the kinetics of brain rejuvenation following systemic exposure to exercise-induced blood factors. 2: Investigate the role of the exercise-induced blood factor Gpld1 in rejuvenating the aged brain. 3: Determine the therapeutic potential of exercise-induced blood factors in a mouse model of Alzheimer's disease. Successful completion of these studies will have significant translational potential, identifying molecular and cellular pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative diseases such as Alzheimer's disease.

项目概要/摘要衰老会导致成人大脑的再生和认知障碍，增加患痴呆症的风险健康个体中的相关神经退行性疾病，例如阿尔茨海默病。有证据表明运动可以对抗衰老大脑中与年龄相关的再生能力和认知能力下降。这通过运动等系统干预逆转大脑衰老的能力可以减轻易患与年龄相关的神经退行性疾病，满足日益紧迫的未满足需求随着人口老龄化。尽管运动的好处显而易见，但其在老年人中的应用却受到阻碍通过技术障碍，有证据表明，仅对身体虚弱或健康状况不佳的看法就可以减少坚持。因此，确定可赋予运动益处的可行治疗方法至关重要同时规避预先存在的限制。我们和其他人之前已经表明，系统性操作，包括异时性联体共生（其中年轻和年老动物的循环系统加入）和年轻血浆给药，同样增强成人神经发生和老年人认知小鼠1,3,13。通过运动观察到的恢复活力的效果反映了年轻循环的效果，提高了运动有可能通过血液因子发挥类似作用，发挥其有益作用。的确，我们实验室的初步数据表明，对来自运动的血浆进行系统管理小鼠逆转了老年小鼠成年神经发生和认知中与年龄相关的损伤。目的因此，拟议的研究旨在调查运动诱发的血液因子的恢复和治疗效果在衰老的大脑上。具体来说，我们的假设是全身暴露于运动诱发的血液因子引起再生和认知功能的持久恢复，同时改善神经退行性疾病表型。我们将通过三个具体目标来检验这一理论：1：表征大脑再生的动力学全身暴露于运动诱发的血液因子后。 2：研究运动诱发的作用血液因子 Gpld1 使衰老的大脑恢复活力。 3：确定运动诱发的治疗潜力阿尔茨海默病小鼠模型中的血液因子。成功完成这些研究将显着的转化潜力，识别可针对新药物的分子和细胞途径改善与痴呆相关的神经退行性疾病（例如阿尔茨海默病）的疗法。