Graduation Year
2020
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Pankah Kapahi, PhD
Second Reader
Mary B. Sevigny, PhD
Abstract
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.