Extending recent advances in healthy aging to include the brain is one of the top challenges in medicine today. Currently, one in ten people over 65 years of age has Alzheimer's Disease, 32% of those over 85, with an associated healthcare burden of nearly $260 billion per year. These numbers are expected to rise dramatically over the next decade as people continue to live longer and longer. Yet there is currently no prospect for rapid improvement in this emerging healthcare crisis. Although the symptoms and bioindicators of dementia are becoming clearer, a means of treating the root cause of the disease remains completely unknown. This proposal takes a radically different approach to attacking this problem by searching for mutations that help keep young brains stay healthier longer rather than trying to treat the disease after it has already progressed. This will be accomplished using novel genome editing approach to engineer high-throughput screens in the model nematode C. elegans so as to identify mutations that allow individuals to maintain proper neuronal function and learning-ability late in life. The most innovative feature of this approach is that we will focus on neurological and behavioral function of male C. elegans, which have heretofore been largely ignored in aging research. The major contribution of this research will be the generation of unique collection of strains that that contain mutations that help promote enhanced neuronal function late in life. Specifically, we aim to (1) use our knowledge of the C. elegans sex determination system to create very large male-only populations and to then use these populations to screen for mutations that lead to enhanced behavior function late in life, and (2) create a new paradigm for investigating late-life associative learning of mate attraction in males. This project will use innovative microfluidic approaches to generate and assay the behavioral components, as well as developing unique genetic resources that will allow the molecular pathways responsible for the maintenance of neuronal health throughout aging.