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

点击翻译按钮获取中文摘要

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.