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

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Many age-related diseases (ARD) 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 ARDs. Our long-term goal is to identify bacteria with anti-inflammatory properties, and could therefore promote health, and to understand their mechanism of action. 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-related loss of vigor in fruit flies. The objectives of this application are to determine whether Pd can extend lifespan, preserve vigor and slow cognitive decline relevant to Alzheimer’s disease and/or Alzheimer’s-related dementias (AD/ADRD) during aging in mice and to understand the mechanisms involved. Furthermore, to understand the importance of gut barrier function in the loss of vigor and development of AD/ADRD-related pathologies during aging. We hypothesize that gut barrier function deteriorates during aging due to diminished ZO-1 expression, resulting in leakage of bacterial toxins into the bloodstream, inflammation and loss of vigor and development of AD/ADRD-related pathologies. Furthermore, specific gut bacteria, such as Pd, can prevent or slow age-related gut barrier dysfunction, thereby reducing inflammation, preserving health and preventing AD/ADRD-related pathologies. The specific aims of the study are to: 1) determine if Pd can increase lifespan, preserve vigor and prevent AD/ADRD-related markers 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 intestine affects lifespan, vigor and AD/ADRD-related markers in mice; 3) identify the active factor of Pd; 3a) test whether the ZO-1 upregulating factor of Pd promotes longevity and healthspan and 3b) identify the mouse target of Pd. The aims of this study will be addressed by conducting several inter-related experiments in cell culture, mice and fruit flies. Firstly, we will compare the lifespan, gut barrier function, inflammation and measures of frailty and cognitive health, including several measures of memory and brain inflammation directly relevant to AD/ADRD, between 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. To identify the active factor of Pd, we will identify additional species of bacteria that are able to up-regulate 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. Determining whether Pd can extend lifespan, preserve vigor and prevent AD/ADRD related pathologies 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.