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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要衰老是一个不可阻挡的、多因素的过程，在这个过程中，生物体失去健康和维持生命的能力。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，阿尔茨海默病和其他与年龄相关的疾病导致的认知衰退将迅速扩大。痴呆症是衰老过程中最令人衰弱的问题之一，它剥夺了数百万人的日常功能，除了独立之外，更健康的老龄化和独立也可能价值数万亿美元。随着年龄的增长，我们的细胞并不是我们身体中唯一能带来无法量化的社会和情感益处的东西。微生物组是栖息在我们胃肠道中的数万亿微生物的集合。器官系统中，微生物组也会随着年龄而变化，失去多样性并获得有害物种。人们普遍认为微生物组在新陈代谢、消化和肥胖中发挥着重要作用，但最近它还与大脑中的疾病过程有关，例如自闭症和抑郁症。连接中枢神经系统和肠神经系统以介导肠道到大脑的信号传导，其消融已被证实此外，研究还表明，对粪便微生物组进行检测会引起大鼠的认知缺陷。在最初的实验中，我将年老小鼠的移植物（FMT）移植到年轻的无菌小鼠体内会导致认知缺陷。研究表明，通过将年轻和年老小鼠共同饲养来被动转移微生物组会诱导认知能力在幼龄小鼠中没有发现这种效应，但在无菌饲养或抗生素处理的小鼠中未观察到这种效应。通过 FMT 繁殖到来自年长粪便供体的年轻无菌小鼠中消融或抑制传入迷走神经。神经元也会诱发认知缺陷，而低剂量辣椒素或激素激活的迷走神经刺激逆转与衰老微生物组相关的缺陷因此，我认为衰老微生物组会损害。为了探索这一点，我将首先使用细菌测序来探索这一点。识别老化微生物组中足以诱发认知缺陷的细菌种类（目标 1）。将确定学习和记忆需要肠道到大脑信号传导的哪些组成部分（目标 2）。最后，我将通过全脑神经激活图谱来描述衰老微生物组的影响这些研究将深入了解未充分研究的衰老机制。并可能确定对抗与年龄相关的认知能力下降的新目标。大量的初步数据并拥有实现这些目标所需的工具和技能。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：Virginia Lee 博士（因神经退行性疾病研究而享誉国际）和 Christoph 博士 Thaiss，一位微生物组专家，最大限度地提高了我在本提案期间接受的培训。将使我成为衰老和神经退行性疾病领域未来医学科学家的领导者。