A central challenge in the biology of aging is understanding how specific age-associated pathologies are interconnected with the overall health and longevity of an organism. In recent years, the loss of intestinal barrier function has emerged as a conserved hallmark of aging across evolutionary models. Studies in organisms such as mice and Drosophila have demonstrated that enhancing intestinal barrier integrity can significantly improve lifespan and healthspan. However, critical questions remain regarding the mechanistic links between intestinal barrier dysfunction and aging in distal organs. Notably, the potential role of intestinal barrier decline in brain aging remains largely unexplored.

Using the Drosophila model, my research intends to uncover how intestinal barrier dysfunction directly drives hallmarks of brain aging. Specifically, I intend to demonstrate that targeted disruption of the intestinal barrier—via knockdown of epithelial cell junction components—induces neuroinflammation, mitochondrial dysfunction, proteostasis disruption, impaired autophagy, and altered actin dynamics in brain tissue. Furthermore, I have explored the restorative effects of gut barrier function on reversing these hallmarks of brain aging. To dissect the gut-to-brain signaling mechanisms, my findings reveal that intestinal barrier dysfunction activates JAK-STAT signaling in glial cells of the brain (unpublished data).