View Program - 63rd Annual Drosophila Research Conference

Intestinal barrier function is tightly linked to longevity in Drosophila melanogaster and other organisms. We have previously shown 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 following oral infection with pathogenic bacteria. Furthermore, intestinal up-regulation of Ssk improves intestinal barrier function during aging, limits dysbiosis, and extends lifespan. Additionally, perturbing barrier function in the gut has non-cell-autonomous impacts, including alterations in the brain and muscle. Moreover, these analyses add more information about the impact of the gut on tissue outside the gut and begin to address communication between the gut and the brain and muscles in disease models. 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. They also attempt to gain a better understanding of the impact of intestinal dysfunction on cells outside of the gut.

Impacts of Intestinal Occluding Junction Modulation on Non-Cell Autonomous Hallmarks of Aging