Project Summary Aging is the major risk factor for Alzheimer’s disease (AD), with changes in the aging nervous system contributing to AD pathology. The major goal of this proposal is to develop novel approaches to counteract neuronal aging phenotypes, prolong healthy lifespan and delay the onset and progression of Alzheimer’s disease. In recent years, loss of intestinal barrier function has emerged as an evolutionarily conserved pathophysiological hallmark of aging. Importantly, studies in model organisms, including mice and Drosophila, have revealed that directly targeting intestinal barrier integrity can mediate healthy lifespan at the organismal level. However, fundamental questions remain regarding the relationships between intestinal barrier dysfunction and aging of distal organ systems. Indeed, little is known regarding the causal relationships between intestinal barrier dysfunction, neuronal aging and AD. Alterations in the actin filament network have been implicated in Alzheimer’s disease and related dementias, but the role of neuronal actin dynamics in aging and lifespan determination has not been characterized. In preliminary work, we have discovered that aging and age-onset intestinal barrier dysfunction are associated with the accumulation of filamentous actin (F-actin) and actin-rich rods in aged brains. Furthermore, we have discovered that targeted, neuron-specific interventions that reduce the hyper stabilization of F-actin in the aging brain, improve cellular markers of aging and dramatically prolong healthy lifespan. These findings provide an important first step towards understanding the mechanistic interplay between neuronal actin dynamics, AD-related neurotoxicity and organismal health during aging. Here, we propose to build upon these groundbreaking findings by exploring three broad questions: 1) What are the mechanistic relationships between intestinal barrier dysfunction and actin dynamics in the aging brain? 2) Can modulating neuronal actin dynamics in aged animals improve neuronal function, healthy longevity and/or counteract AD pathogenesis? 3) What are the mechanistic relationships between actin dynamics in the aging brain and other cellular hallmarks of aging; loss of proteostasis and mitochondrial dysfunction? The work described herein will bring about fundamental knowledge towards our understanding of the mechanisms of aging and AD-related pathology. Our findings may also lead to novel therapeutic approaches to counteract aging, AD and related dementias.