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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，如结肠直肠癌和阿尔茨海默病，以及衰老本身的过程，