Circulatory Rejuvenating Factors for the Brain

描述（由申请人提供）：人类的认知功能在50-60岁左右开始基本上在所有领域都下降，除了少数存活到很老的人之外，神经变性和痴呆似乎是不可避免的。只有人类寿命一小部分的老鼠 显示出类似的认知能力下降，表明特定的生物过程，而不是时间， 是大脑老化的罪魁祸首虽然人类中与年龄相关的认知功能障碍和痴呆症是明显不同的实体，并影响不同的大脑区域，但衰老的大脑显示出具有大多数神经退行性疾病特征的分子和细胞变化，包括突触丢失，功能障碍性自噬，炎症增加和蛋白质聚集。值得注意的是，衰老的大脑仍然具有可塑性，运动或饮食变化可以增加人类和动物的认知功能，动物大脑显示出与衰老相关的一些上述生物学变化的逆转。利用异时共生，我们最近表明，血液传播的因素存在于全身环境中可以抑制或促进成年神经发生在一个年龄依赖性的方式在小鼠。因此，将老年小鼠暴露于年轻的全身性环境或年轻小鼠的血浆增加了神经发生、突触可塑性，并改善了情境恐惧条件反射和空间学习和记忆。初步的蛋白质组学研究表明，在年老的“返老还童”小鼠中，几种具有干细胞活性的蛋白质增加，这支持了年轻血液可能含有具有再生能力的有益因子水平增加的观点。在本申请中，我们打算 测试这一假设，即在年轻的小鼠血液传播的蛋白质因子足以增加成年 神经发生和再生旧的大脑，一个集中的蛋白质组学筛选将使我们能够确定最有效的这些因素。我们的研究追求创新的概念，即大脑老化和认知功能障碍至少部分地受到循环环境因素的控制，并且这些因素足以使老化的大脑恢复活力。

DESCRIPTION (provided by applicant): Cognitive function in humans declines in essentially all domains starting around age 50-60, and neurodegeneration and dementia seem to be inevitable in all but a few who survive to very old age. Mice with a fraction of the human lifespan show similar cognitive deterioration indicating that specific biological processes rather than time alone are responsible for brain aging. While age-related cognitive dysfunction and dementia in humans are clearly distinct entities and affect different brain regions, the aging brain shows the telltale molecular and cellular changes that characterize most neurodegenerative diseases including synaptic loss, dysfunctional autophagy, increased inflammation, and protein aggregation. Remarkably, the aging brain remains plastic and exercise or dietary changes can increase cognitive function in humans and animals, with animal brains showing a reversal of some of the aforementioned biological changes associated with aging. Using heterochronic parabiosis we showed recently that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing an old mouse to a young systemic environment or to plasma from young mice increased neurogenesis, synaptic plasticity, and improved contextual fear conditioning and spatial learning and memory. Preliminary proteomic studies show several proteins with stem cell activity increase in old "rejuvenated" mice supporting the notion that young blood may contain increased levels of beneficial factors with regenerative capacity. In this application we intend to test the hypothesis that blood-borne protein factors in young mice are sufficient to increase adult neurogenesis and regenerate the old brain, and that a focused proteomic screen will allow us to identify the most potent such factors. Our studies pursue the innovative concept that brain aging and cognitive dysfunction is at least in part under control of factors from the circulatory environment and that such factors are sufficient to rejuvenate the aging brain.