BRC-BIO: Interplay Between Intestinal Barrier Function, Aging, and Neurodegeneration

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The world population is aging, with the number of people over 65 more than doubling to 1.57 billion by 2050, making a concomitant elevation in numerous age-related pathologies, including neurodegenerative diseases such as Alzheimer’s Disease, highly likely. Because of this, a clearer understanding of the pathophysiological changes accompanying aging, and the discovery of novel therapeutics to assist in aging phenotypes, are essential. Recent advances have implicated perturbations in the gut as being closely linked to aging and mortality, with intestinal barrier dysfunction associated with age-related health decline in numerous organisms, including humans. This research will investigate the microbiota-gut-brain axis, the term used to describe communication between commensal bacteria in the gut, gut health, and neurons, to understand if the intestinal barrier dysfunction associated with aging may play a role in the aging pathologies observed in the brain and other tissues, such as muscle. Fundamental details about how communication from the gut may impact aging in tissue outside the gut are poorly understood. Insight into the cellular and molecular changes accompanying the aging gut, how these changes may impact and accelerate aging in the brain and muscle, and whether strengthening the intestinal barrier can reverse or delay aging phenotypes, are, therefore, crucial emerging areas of research. This research will be conducted by a diverse group of undergraduate students, thereby increasing the number of students participating in robust research and gaining experiences leading to more effective scientific communication and the possible pursuit of biological research in future careers. Aging is a process marked by a continuous decline in multiple physiological functions, including the intestinal barrier function, which is tightly linked to longevity in Drosophila melanogaster and other organisms. Previous experiments have revealed that altered expression of occluding junctions in the guts of fruit flies can lead to various hallmarks of aging, including modulation of intestinal homeostasis, variations in microbial dynamics, changes in immune activity, and alterations in lifespan. Loss of a specific occluding junction, Snakeskin (Ssk), leads to rapid and reversible intestinal barrier dysfunction, altered gut morphology, dysbiosis, and a dramatically reduced lifespan. Remarkably, restoration of Ssk expression in flies showing intestinal barrier dysfunction rescues each of these phenotypes previously linked to aging. Intestinal up-regulation of Ssk protects against microbial translocation, improves intestinal barrier function during aging, limits dysbiosis, and extends lifespan. These findings indicate that intestinal occluding junctions may represent prolongevity targets in mammals, in addition to their possible roles in intestinal dysfunction, aging, and disease. This project will investigate the impact of the gut on tissue outside of the gut and address communication between the gut and the brain and muscles in disease models. Current work utilizes cellular and molecular biological methodologies to build upon current knowledge to address crucial questions at the intersection between microbial dysbiosis, epithelial integrity, inflammation, protein aggregation, neurodegeneration, and disease, with the ultimate goal of discovering novel therapies that may enhance barrier function, healthspan, and lifespan.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.