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

项目总结/摘要 衰老导致成人大脑再生和认知障碍，增加了患痴呆症的易感性- 相关的神经退行性疾病，如阿尔茨海默氏病，在健康个体。证据表明 运动可以对抗与年龄相关的老年大脑再生能力和认知能力的下降。的 通过系统性干预（如运动）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。尽管运动的益处显而易见，但它在老年人中的应用受到阻碍 有证据表明，身体虚弱或健康状况不佳的感觉本身就可以减少 坚持。因此，关键是要确定可获得的治疗方法，赋予运动的好处 同时规避了先前存在的限制。我们和其他人以前已经表明， 操作，包括异时共生（其中年轻和年老动物的循环系统 加入）和年轻血浆给药，同样增强老年人的成年神经发生和认知。 小鼠1，3，13.运动观察到的恢复活力的效果反映了年轻时的循环，提高了 运动可能通过血液因子发挥类似的功能，以发挥其有益效果。的确， 来自我们实验室的初步数据表明，来自运动的血浆的全身给药 小鼠逆转老年小鼠中成年神经发生和认知的年龄相关损伤。的目的 因此，本研究拟探讨运动性血液因子的复壮及治疗作用 对老年人的大脑。具体来说，我们的假设是，全身暴露于运动诱导的血液因子， 增强再生和认知功能的持久恢复，同时改善神经退行性疾病 表型我们将测试这个理论与三个具体目标：1：表征动力学的大脑年轻化 在全身暴露于运动诱导的血液因子之后。2：研究运动诱发的 血液因子Gpld 1在使老年大脑年轻化中的作用。3：确定运动诱导的治疗潜力 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有 显著的翻译潜力，鉴定可以靶向新的转录因子的分子和细胞途径。 改善痴呆相关的神经退行性疾病如阿尔茨海默病的疗法。

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.