Neural Aging and Ab Toxicity Assessments, a Fly Pharmacology-Molecular AD Model Abstract: Human studies have shown that the progressive accumulation of protein aggregates (Aβ42) is key a factor in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). As a result, a significant portion of AD research has since focused on the origin and cytotoxic effects that Aβ42 has on the maintenance, stress responses and functional decline of neurons. However, geroscience studies have highlighted other metabolic, proteolytic, stress response and cell signaling pathways are also closely linked to aging and neurodegenerative processes. It has emerged that AD risk factors include chronic activation of innate immunity (inflammaging) and impaired proteolytic clearance. In addition, AD associated processes like NFkb signaling and APP processing are also involved with neural development and synaptic remodeling. This indicates that a less focus more nuanced geroscience based approach to study AD and potential therapies is required. Our work on gerontology has largely focused on the role of autophagy using an aging Drosophila model. We found that the autophagic capacity of neurons is directly correlated with aggregate formation, stress responses and longevity profiles of Drosophila. Using a fly aging model, we have identified dietary (intermittent fasting, IF) and drug treatment regimens that promote autophagic and neuronal function. This is in part by restoring more youthful gene expression and transcriptional drift variance (TDV) profiles in aged neural tissues. Of particular mechanistic importance was the profound age-related dysregulation of proteolytic components, which was largely suppressed by IF. We developed a second Drosophila model, examining traumatic brain injury (TBI). Using standardized conditions, TBI-treated flies showed conserved pathway changes (autophagy, NFkb), behavioral defects (locomotion, sleep) and molecular alterations known to occur in human trauma patients and in rodent models. We find that aging and the genetic background of adult flies alters TBI responses, as does select drug (J147) or IF treatment. The goal of this application is to take an integrated approach using an AD Drosophila model to examine the impact that in vivo aggregate formation (Aβ42-Arctic) has on the aging or traumatized CNS. The central hypothesis of this proposal is that common protective molecular pathways can be identified using animal models and these unique mechanistic insights can be exploited to develop new therapeutic treatments for complex aging and neurodegenerative disorders. Specific Aim 1 will determine the impact that tissue specific production of Aβ42-Arctic has on the neural aging and TBI dependent phenotypes and longevity profiles of adult Drosophila. In Specific Aim 2, we will use our Drosophila neural aging, trauma and AD models to determine the effectiveness of select diets (IF) and compounds (J147) to delay or suppress ...