Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan

利用有益微生物加强肠道屏障完整性，延长寿命和健康寿命

基本信息

批准号：
10659262
负责人：
Jimmy W Crott
金额：
$ 59.24万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659262
关键词：
Ablation Acceleration Address Adherent Culture Affect Age Aging Alzheimer&apos s Disease Anti-Inflammatory Agents Attention Bacteria Bacterial Antigens Bacterial Toxins Bacteroides Blood Circulation Cardiovascular Diseases Cells Chronic Disease Cloning Co-Immunoprecipitations Cognitive Colon Colorectal Cancer Dementia Deterioration Diet Diffusion Disease Drosophila genus Ecosystem Elderly Encephalitis Exclusion Extravasation Functional disorder Genes Goals Health Homologous Gene Human In Vitro Inflammation Inflammatory Intestinal Mucosa Intestinal permeability Intestines Knowledge Life Link Longevity Maintenance Malignant Neoplasms Measures Memory Metabolic syndrome Microbe Mus Mutate Outcome Penetration Persons Physical Function Play Population Process Proteins Recombinants Role TLR4 gene Testing Tight Junctions Translations Up-Regulation Vertebrates Work age related anti aging beneficial microorganism cognitive function commensal bacteria comparative genomics experimental study fly frailty gastrointestinal epithelium genetic manipulation gut bacteria gut inflammation gut microbes gut microbiota healthspan human old age (65+)in vivo innovation intestinal barrier loss of function microbial novel preservation prevent sensor success

项目摘要

Many diseases of old age like colorectal cancer and Alzheimer’s disease, as well as the process of aging itself, have been linked to changes in the composition of microbes in our gut. Moreover, the ability of our gut to exclude toxic microbial components from our bloodstream (so-called gut barrier function) deteriorates with increasing age and results in inflammation which, in-turn, can accelerate aging and promote various chronic diseases. Our long-term goal is to identify bacteria with anti-aging, anti-inflammatory or other beneficial effects on human health and to understand their mechanism of action. So far, we have discovered that Parabacteroides distasonis (Pd), a normal gut bacterium, lowers inflammation and strengthens gut barrier function in mice. Furthermore, Pd increased lifespan and slowed age-relator loss of vigor when fed to fruit flies. The objectives of this application are to determine whether Pd can extend lifespan and healthspan in mice, understand the importance of a protein involved in maintaining gut barrier function called ZO-1, and finally to identify the active factor of Pd and its target molecule. We hypothesize that gut barrier function deteriorates during aging due to loss of ZO-1 expression, resulting in leakage of bacterial toxins into the bloodstream, inflammation and loss of function. Furthermore, specific gut bacteria, such as Pd, can be exploited to prevent or slow age-related gut barrier dysfunction, thereby reducing inflammation and preserving health. The specific aims of the study are to: 1) determine if Pd can increase lifespan and healthspan in mice; 1a) understand how proteins involved in gut barrier maintenance are altered by aging and Pd exposure; 2) determine whether altering ZO-1 expression in the colon affects lifespan and healthspan in mice; 3) identify the active factor of Pd; 3a) identify the mouse target of Pd and 4) determine the mechanism of fruit fly lifespan extension by Pd. The aims of this study will be addressed by conducting several inter-related experiments in cells, mice and fruit flies. Firstly, we will compare the lifespan, gut barrier function, inflammation and various measures of health throughout life, of mice fed diet with or without with added Pd. Next, we will compare the same readouts between mice with normal, deleted and high ZO-1 expression in the intestine. Importantly, mice will be subjected to a battery of tests to assess their frailty and cognitive health – including several measures of memory and brain inflammation that have direct relevance to Alzheimer’s disease and its Related Dementias (ADRD). To identify the active factor of Pd, we will identify additional species of bacteria that are able to increase gut barrier function (via ZO-1) and find the genes they have in common with Pd. These will then be mutated or transferred to other bacteria one by one. Finally, we will delete the pyd gene, the fly version of ZO-1, and compare the lifespan and age-related loss of vigor to normal flies in the presence of absence of Pd. Determining whether Pd can extend lifespan and healthspan in mice, as well as identifying its active factor, will pave the way for this bacterium, or its active factor, to be utilized in therapies to extend the healthy lifespan and establish ZO-1 as a target for such therapies.

许多老年疾病，如结直肠癌和阿尔茨海默病，以及衰老本身的过程，此外，我们的肠道微生物组成的变化也与肠道排除能力有关。我们血液中的有毒微生物成分（所谓的肠道屏障功能）随着细菌的增加而恶化年龄并导致炎症，进而加速衰老并促进各种慢性疾病。长期目标是识别具有抗衰老、抗炎或其他对人类健康有益作用的细菌并了解其作用机制，到目前为止，我们已经发现了 Parabacteroides distasonis (Pd)，一种正常的肠道细菌，可以降低小鼠的炎症并增强肠道屏障功能。当喂给果蝇时，可以延长寿命并减缓与年龄相关的活力丧失。确定 Pd 是否可以延长小鼠的寿命和健康寿命，了解蛋白质的重要性参与维持肠道屏障功能的ZO-1，最终确定了Pd的活性因子及其靶点我们探索了肠道屏障功能在衰老过程中由于 ZO-1 表达缺失而恶化，导致细菌毒素渗入血液、炎症和功能丧失。特定的肠道细菌，例如 Pd，可用于预防或减缓与年龄相关的肠道屏障功能障碍，从而该研究的具体目的是：1) 确定 Pd 是否可以。延长小鼠的寿命和健康寿命；1a) 了解参与肠道屏障维护的蛋白质的作用因衰老和 Pd 暴露而改变；2) 确定结肠中 ZO-1 表达的改变是否会影响寿命和小鼠的健康寿命；3) 识别 Pd 的活性因子；3a) 识别 Pd 的小鼠靶标，4) 确定 Pd 延长果蝇寿命的机制本研究的目的将通过进行来实现。首先，我们将比较细胞、小鼠和果蝇的寿命、肠道屏障。饲喂添加或不添加添加物的饮食的小鼠的功能、炎症和整个生命周期的各种健康指标接下来，我们将比较 ZO-1 表达正常、缺失和高的小鼠之间的相同读数。重要的是，小鼠将接受一系列测试，以评估它们的脆弱性和认知能力。健康——包括与健康直接相关的记忆力和脑部炎症的多项测量阿尔茨海默氏病及其相关痴呆症 (ADRD) 为了确定 Pd 的活性因子，我们将确定 Pd 的活性因子。其他种类的细菌能够增强肠道屏障功能（通过 ZO-1）并找到它们的基因这些与Pd有共同点，然后将它们一一突变或转移到其他细菌上。删除 pyd 基因（ZO-1 的果蝇版本），并将寿命和与年龄相关的活力损失与正常人进行比较确定 Pd 是否可以延长小鼠的寿命和健康寿命。以及鉴定其活性因子，将为该细菌或其活性因子的利用铺平道路延长健康寿命的疗法，并将 ZO-1 作为此类疗法的靶点。