The cGMP-signaling axis in intestinal aging.

Along with the aging of our population comes important socioeconomic costs due to the numerous healthcare concerns of the elderly. Changes in the aging gastrointestinal tract underlie the high incidence of regional diseases such as chronic constipation and colorectal cancer in the elderly. In addition, intestinal barrier dysfunction that increases with age has been implicated as a central driver of inflammaging that underlies a plethora of other pathologies that contribute to morbidity in the elderly population. The processes driving intestinal aging are poorly understood and there is an urgent need to identify pathways mediating intestinal aging in order to develop therapeutic interventions. A large body of published and preliminary data underscores the critical role of cGMP signaling in intestinal health. Defective cGMP signaling in the mouse intestine mimics key aspects of the aging phenotype, and while reduced cGMP signaling is well-documented in aging vascular and urogenital tissues, it has not previously been studied in the aging intestine. Our goal is to understand the role of cGMP-signaling in the aging gut-epithelium in order to develop prevention and treatment strategies to reduce the impact of intestinal diseases on the elderly. Our central hypothesis is that cGMP signaling becomes dysregulated in the intestinal epithelium during aging, and this predisposes elderly individuals to diseases such as constipation, colon cancer, and others resulting from barrier dysfunction- promoted inflammaging. Our objectives are (1) to characterize the expression and function of cGMP signaling components in the intestinal epithelium of mice during aging, and (2) to determine the extent to which intestinal organoids are appropriate avatars of the “aged” gut phenotype. These objectives will be accomplished in the following aims. Aim 1. Test the hypothesis that cGMP signaling is reduced and can be therapeutically targeted in intestinal epithelium of aged mice. Aim 2. Test the hypothesis that intestinal organoids are suitable avatars for cGMP signaling in the gut of aged mice. Our project’s scientific impact is potentially paradigm-shifting new information about the cGMP-signaling axis during gut aging, and how it contributes to intestinal disorders in the elderly. By testing the suitability of intestinal organoids as avatars of the aged epithelium, our results will set the stage for future studies of cGMP signaling in the aging human intestine, and provide a model to interrogate the underlying mechanisms of gut aging. Importantly, our results will also determine proof of principle for the ability of FDA- approved drugs that target cGMP signaling to treat elderly patients with intestinal cGMP dysfunction.