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 衰老是一个不可阻挡的、多因素的过程，在这个过程中，生物体失去了健康和维持的能力 动态平衡。随着现代医学的进步和全球生活水平的提高，预期寿命和 因此，老龄化势必迅速扩大。阿尔茨海默病和其他与年龄相关的认知能力下降 痴呆症是衰老最令人虚弱的方面之一，剥夺了数百万人的日常功能和 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身体中唯一 年龄。微生物群是生活在我们胃肠道中的数万亿个微生物的集合。喜欢 除了器官系统，微生物群也会随着年龄的增长而变化，失去多样性，获得有害物种。它是 微生物群在新陈代谢、消化和肥胖中起着重要作用，这一点被广泛接受，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 连接中枢和肠道神经系统以调节肠道到大脑的信号，其消融已经被 被证明会导致大鼠的认知缺陷。此外，也有研究表明，执行粪便微生物组 从老年小鼠移植到年轻无菌小鼠会导致认知障碍。在最初的实验中，我 已经表明，通过共居幼鼠和老年鼠来被动转移微生物组可以诱导认知 幼鼠的缺陷。这种影响在共居的无菌或抗生素治疗的小鼠中看不到，而且 在FMT后从老年粪便捐赠者那里复制成年轻的无菌小鼠。消融或抑制传入迷走神经 神经元也会导致认知障碍，而小剂量辣椒素或荷尔蒙刺激迷走神经 逆转与衰老微生物群相关的缺陷。因此，我认为衰老的微生物群损害了 通过抑制肠道到大脑的信号来进行认知。为了探索这一点，我将首先使用细菌测序来 确定老化微生物群中足以导致认知缺陷的细菌种类(目标1)。接下来，我 将确定学习和记忆所需的肠道到大脑信号的哪些组成部分(目标2)。 最后，我将用全脑神经元激活图来描述衰老微生物组的影响。 在记忆编码期间(目标3)。这些研究将提供对衰老机制研究不足的洞察。 并有可能确定新的目标来对抗与年龄相关的认知能力下降。我收集了一份意义重大的 拥有大量的初步数据，并拥有实现这些目标所需的工具和技能。体制上的 宾夕法尼亚大学的支持和资源，以及我的专业知识和指导 赞助商是因在神经变性方面的研究而享誉国际的弗吉尼亚·李博士和克里斯托弗博士 泰斯，一位微生物组专家，让我的成功机会最大化。在此提案期间我将接受的培训 将使我成为未来衰老和神经退行性变领域的领导者，成为一名内科科学家。