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

项目摘要/摘要 衰老导致成人大脑中的再生和认知损伤，增加了患痴呆症的易感性。 健康个体的相关神经退行性疾病，如阿尔茨海默病。有证据表明 这种锻炼可以对抗老年大脑中与年龄相关的再生能力和认知能力的下降。这个 通过运动等系统干预逆转大脑衰老的能力可以缓解 易患与年龄相关的神经退行性疾病，满足日益迫切的未得到满足的需求 随着人类人口的老龄化。尽管锻炼有明显的好处，但它在老年人中的应用却受到了阻碍 通过技术障碍，有证据表明，仅身体虚弱或健康状况不佳的感觉就会减少 坚持不懈。因此，找出可获得锻炼益处的治疗方法至关重要。 同时绕过先前存在的限制。我们和其他人之前已经证明，系统性 操作，包括异慢性异种共生(幼年和老年动物的循环系统 加入)和年轻血浆注射，同样增强老年人的成年神经发生和认知 1，3，13.运动所观察到的返老还童的效果反映了年轻的血液循环，提高了 运动可能通过血液因子发挥类似的作用，以发挥其有益的效果。的确， 来自我们实验室的初步数据表明，系统地给药来自于运动 小鼠逆转老年小鼠在成年神经发生和认知方面与年龄相关的损害。该计划的目的是 因此，建议的研究是为了探讨运动诱导的血液因子的复壮和治疗作用。 对衰老的大脑的影响。具体地说，我们的假设是，全身暴露在运动诱导的血液因子中 可持久恢复再生和认知功能，同时改善神经退行性变 表型。我们将用三个具体的目标来测试这个理论：1：描述大脑恢复活力的动力学 在全身暴露于运动诱导的血液因子之后。2：研究运动诱导的作用 血液因子Gpld1在脑老化中的作用。3：确定运动性运动的治疗潜力 阿尔茨海默病小鼠模型中的血液因素。成功完成这些研究将会有 显著的翻译潜力，确定了可以作为小说目标的分子和细胞途径 改善痴呆症相关神经退行性疾病的治疗方法，如阿尔茨海默病。

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.