Master of Science
Meredith Protas, PhD
Pankah Kapahi, PhD
Mary B. Sevigny, PhD
Dietary restriction (DR) has been demonstrated to be a robust means of extending the healthspan and lifespan, along with improving cognitive performance in various model organisms from yeast to primates, possibly by mediating neuroprotection. We utilized the Drosophila melanogaster model organism to better understand the molecular pathways that enable DR-induced benefits. By performing a genome-wide associated screening of the Drosophila Genetic Reference Panel (DGRP) that catalogues all natural genetic variants, we discovered that Oxidative resistance protein 1 (OXR1) showed the most significant difference in expression between DR and the inverse intervention of ad libitum (AL). Our research found that OXR1 expression within the neural tissues of flies is sensitive to dietary intake resulting in an upregulated expression in flies undergoing DR and down-regulation in flies undergoing AL. Our results also showed that OXR1 knockdown within neuronal tissue prevents DR-induced benefits. OXR1 expression within neural tissue subtypes associated with vision demonstrated a loclozed importance for DR-induced neuroprotection as well as the length of lifespan. Finally, this study has found a connection between DR-mediated effects and the expression of specific metabolites within the fly metabolome, revealing correlations between the expression of certain metabolites at an early age and lifespan. Genetic manipulation of the genes associated with these metabolites further demonstrated the importance toward regulating dietmediated lifespan. These results enhanced our understanding of how diet can influence the molecular pathways that impact neurodegenerative diseases. In doing so, we have identified potential therapeutic targets, such as OXR1.
Brownridge, George W. III, "Neuroprotection against Alzheimer’s and lifespan extension induced by dietary restriction are associated with metabolomic changes and depend on oxidative resistance protein 1 (OXR1)" (2020). Natural Sciences and Mathematics | Biological Sciences Master's Theses. 9.
Available for download on Wednesday, May 31, 2023