Grant: Operating Grant: Geroscience Demonstration Grants

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. In the inherited forms of disease, the disease-causing mutation is present from birth and yet disease onset occurs multiple decades later. This indicates that these mutations are well-tolerated in younger individuals. Based on this observation, we hypothesized that changes that take place during normal aging make the cells in the brain (and elsewhere) susceptible to the disease-causing mutations. If so, then delaying some of these age-related changes may be beneficial in disease treatment. To test this idea, we used a simple model organism, the worm C. elegans, which has been used extensively to identify genes that modulate aging. We found that targeting molecular pathways that have been shown to modulate aging is neuroprotective in C. elegans models of Parkinson's disease and Huntington's disease. These experiments provide support for our idea that delaying changes that take place during aging will be beneficial in treating neurodegenerative disease. The current proposal will build upon these exciting preliminary studies by (1) identifying common downstream factors that contribute to longevity in different long-lived genetic mutants, (2) exploring the mechanisms by which these mutations extend longevity, and (3) examining the effect of modulating these aging pathways in animal models of neurodegenerative disease. Overall this work will advance our understanding of the aging process and apply that knowledge to the development of novel treatments for neurodegenerative disease.