Microbiome Contributions to Age-Associated Cognitive Decline

项目总结/摘要 衰老是一个不可阻挡的多因素过程，在这个过程中，生物体失去健康和维持能力， 体内平衡随着现代医学的进步和地球仪生活水平的提高， 因此老化，将迅速扩大。阿尔茨海默病和其他与年龄相关的疾病导致的认知能力下降 痴呆症是衰老最令人衰弱的方面之一，剥夺了数百万人的日常功能， 独立更健康的老龄化和独立性可能价值数万亿美元， 无法量化的社会和情感利益。随着年龄的增长，我们的细胞并不是我们体内唯一的东西， 年龄微生物组是居住在我们胃肠道中的数万亿微生物的集合。像 在器官系统中，微生物组也会随着年龄的增长而变化，失去多样性并获得有害物种。是 人们普遍认为微生物组在新陈代谢、消化和肥胖中起着重要作用，但最近 它还与大脑中的疾病过程有关，如自闭症和抑郁症。迷走神经 连接中枢和肠神经系统，以介导肠到脑的信号传导， 会导致大鼠认知缺陷此外，还表明执行粪便微生物组 从老年小鼠到年轻无菌小鼠的FMT移植（FMT）诱导认知缺陷。在最初的实验中，我 已经表明，通过共同饲养年轻和年老的小鼠来被动转移微生物组会诱导认知能力， 幼鼠的缺陷。这种效应在共同饲养的无菌小鼠或驱虫小鼠中没有观察到， 在FMT后从老年粪便供体复制到年轻的无菌小鼠中。抑制迷走神经传入的 神经元也诱导认知缺陷，而迷走神经刺激与低剂量辣椒素或激素激活 逆转与老年微生物组相关的缺陷。因此，我认为老年微生物组损害了 通过抑制肠道到大脑的信号传导来提高认知能力。为了探索这一点，我将首先使用细菌测序， 鉴定老年微生物组中足以诱导认知缺陷的细菌种类（目标1）。接下来我 将确定哪些肠道到大脑的信号传导成分是学习和记忆所必需的（目标2）。 最后，我将通过神经元激活的全脑映射来描述老年微生物组的影响。 在记忆编码（目标3）。这些研究将提供深入了解欠研究的衰老机制 并有可能发现新的靶点来对抗与年龄相关的认知能力下降。我收集了大量 我们需要大量的初步数据，并拥有实现这些目标所需的工具和技能。体制 宾夕法尼亚大学的支持和资源，沿着我的专业知识和指导 赞助商，弗吉尼亚李博士，她在神经退行性疾病的研究国际知名，和克里斯托弗博士 Thaiss是一位微生物专家，他最大限度地提高了我成功的机会。我在这次求婚中接受的培训 将使我成为未来衰老和神经退行性疾病领域的领导者，成为一名医学科学家。

PROJECT SUMMARY/ABSTRACT Aging is an inexorable, multifactorial process in which organisms lose fitness and ability to maintain homeostasis. With advances in modern medicine and standards of living across the globe, life expectancy, and thus aging, is set to expand rapidly. Cognitive decline due to Alzheimer’s disease and other age-associated dementias is one of the most debilitating aspects of aging, robbing millions of people of everyday function and independence. Healthier aging and independence are potentially worth trillions of dollars in addition to unquantifiable social and emotional benefits. As we get older, our cells are not the only thing in our body that age. The microbiome is the collection of trillions of microorganisms that inhabit our gastrointestinal tract. Like organ systems, the microbiome also changes with age, losing diversity and gaining deleterious species. It is widely accepted that the microbiome plays an important role in metabolism, digestion, and obesity, but recently it has also been linked to disease processes in the brain, such as autism and depression. The vagus nerve connects the central and enteric nervous systems to mediate gut-to-brain signaling, and its ablation has been shown to induce cognitive deficits in rats. Additionally, it has also been shown that performing fecal microbiome transplants (FMT) from old mice into young germ-free mice induces cognitive deficits. In initial experiments, I have shown that passive transfer of the microbiome by cohousing young and old mice induces cognitive deficits in young mice. This effect is not seen in cohoused germ-free or antibiotics-treated mice and is reproduced upon FMT into young germ-free mice from old stool donors. Ablating or inhibiting afferent vagal neurons also induces a cognitive deficit, while vagal stimulation with low dose capsaicin or hormonal activation reverses deficits associated with the aged microbiome. Thus, I propose that the aged microbiome impairs cognition through inhibition of gut-to-brain signaling. To explore this, I will first use bacterial sequencing to identify bacterial species in the aged microbiome that are sufficient to induce cognitive deficits (Aim 1). Next, I will determine which components of gut-to-brain signaling are required for learning and memory (Aim 2). Finally, I will characterize the effects of the aged microbiome with brain-wide mapping of neuronal activation during memory encoding (Aim 3). These studies will provide insight into understudied mechanisms of aging and potentially identify new targets to combat age-associated cognitive decline. I have collected a significant amount of preliminary data and possess the tools and skills required to pursue these aims. The institutional support and resources of the University of Pennsylvania, along with the expertise and mentorship of my sponsors, Dr. Virginia Lee, internationally renowned for her research in neurodegeneration, and Dr. Christoph Thaiss, a microbiome expert, maximize my chances at success. The training I will receive during this proposal will position me to be a future leader in aging and neurodegeneration as a physician-scientist.