Microbiome Contributions to Age-Associated Cognitive Decline

微生物组对年龄相关认知能力下降的影响

• 批准号: 10605551
• 负责人: Timothy Cox
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605551
• 关键词: Ablation; Affect; Afferent Neurons; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Antibiotic Therapy; Antibiotics; Bacteria; Behavior; Brain; Brain Stem; Brain region; Capsaicin; Cell Nucleus; Cells; Central Nervous System; Cholecystokinin; Chronic; Cognition; Cognitive deficits; Collection; Communication; Complex; Data; Dementia; Digestion; Disease; Dose; Economics; Emotional; Enteric Nervous System; Exhibits; Feces; Future; Gastrointestinal tract structure; Genes; Genetic; Germ-Free; Hippocampus; Histology; Homeostasis; Hormonal; Impaired cognition; Impairment; Injections; Institution; International; Learning; Life Expectancy; Link; Living Standards; Maps; Medial; Mediating; Memory; Memory Loss; Mental Depression; Mentorship; Metabolism; Modern Medicine; Mus; Nerve Degeneration; Neurologic; Neurons; Neurotoxins; Nodose Ganglion; Obesity; Organism; Pathogenicity; Pathway interactions; Pennsylvania; Performance; Persons; Phenotype; Physicians; Play; Positioning Attribute; Process; Public Health; Rattus; Reproducibility; Research; Ribosomal DNA; Role; Sampling; Scientist; Seminal; Sensory; Signal Transduction; Stimulus; Synapses; System; Tamoxifen; Testing; Time; Training; University resources; Vagus nerve structure; Virginia; age effect; age related; aged; aging population; autism spectrum disorder; body system; burden of illness; cognitive testing; combat; comparison control; cost; designer receptors exclusively activated by designer drugs; effective therapy; experience; experimental study; fecal transplantation; fitness; germ free condition; glucagon-like peptide 1; gut microbiome; gut-brain axis; insight; memory encoding; metagenomic sequencing; microbiome; microbiome analysis; microbiome components; microbiome composition; microbiome sequencing; microorganism; neural circuit; novel; novel therapeutics; object recognition; prevent; resilience; response; skills; social; success; therapeutic target; tool

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.

项目摘要/摘要 衰老是一个不可驱动的多因素过程，其中生物会失去适应性和维护能力 稳态。随着全球现代医学和生活水平的进步，预期寿命和 因此，老化将迅速扩展。由于阿尔茨海默氏病和其他年龄相关的认知能力下降 痴呆症是衰老中最令人沮丧的方面之一，每天抢夺数百万的人， 独立。除了更健康的衰老和独立性外，还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的微生物的集合。喜欢 器官系统，微生物组也随着年龄的增长而变化，失去多样性并获得有害物种。这是 广泛认为，微生物组在代谢，消化和肥胖症中起着重要作用，但最近 它也与大脑中的疾病过程有关，例如自闭症和抑郁症。迷走神经 连接中央和肠道神经系统以介导肠道到脑信号，其消融一直是 证明会诱导大鼠的认知缺陷。此外，还显示出执行粪便微生物组 从旧小鼠到无菌小鼠的移植（FMT）会影响认知缺陷。在最初的实验中，我 已经表明，通过共同的年轻小鼠和老鼠对微生物组的被动转移会影响认知 年轻小鼠的缺陷。这种效果在无菌或抗生素处理的小鼠中没有看到 在FMT中复制到老粪便供体的无菌小鼠中。减轻或抑制传入迷走神经 神经元还会诱导认知缺陷，而剂量低辣椒素或激素激活的迷走神经刺激 逆转定义与老化的微生物组相关。那我建议老化的微生物组会损害 通过抑制肠道信号传导的认知。为了探讨这一点，我将首先使用细菌测序 鉴定老年微生物组中的细菌物种足以诱导认知缺陷（AIM 1）。接下来，我 将确定学习和记忆需要哪些肠道到脑信号的组成部分（AIM 2）。 最后，我将通过神经元激活的大脑映射来表征老化的微生物组的影响 在内存编码期间（AIM 3）。这些研究将洞悉了解衰老的机制 并有可能确定与年龄相关认知能力下降的新目标。我收集了一个重要的 初步数据的数量，并拥有追求这些目标所需的工具和技能。机构 宾夕法尼亚大学的支持和资源，以及我的专业知识和心态 赞助商弗吉尼亚·李（Virginia Lee）博士因其在神经变性方面的研究而闻名，克里斯托夫博士 这是一名微生物组专家，最大程度地提高了我成功的机会。我将在此提案中接受的培训 将把我作为身体科学家的未来衰老和神经变性领域的领导者。