While it is established that exercise improves cognition and protects against age-associated neurodegenerative diseases, further research is needed to understand exactly how exercise promotes brain resilience. The Long laboratory has recently identified Lac-Phe, a molecule elevated in the blood during exercise, as a pathway that regulates learning and memory in mice. This new project brings together an innovative, and multidisciplinary partnership between laboratories with expertise in organic chemistry, biochemistry, and neuropathology to understand and harness the Lac-Phe pathway to advance brain resilience. The team will use a variety of mouse models combined with studies in test tubes and in cells to dissect how Lac-Phe regulates cognition and learning. Successful completion of this proposal will pave the way for therapeutics that can capture the benefits of exercise for brain health, brain resilience, and protection against age-associated neurodegenerative disease.