Graduation Date
5-2013
Document Type
Master's Thesis
Degree Name
Master of Science
Department or Program
Biological Sciences
Department or Program Chair
Kiowa Bower, Ph.D.
First Reader
Pankah Kapahi, PhD
Second Reader
Mietek Kolipinski, PhD
Abstract
Dietary Restriction (DR) is a robust intervention that is known to extend lifespan and increase spontaneous activity in multiple species. Whether activity increase plays a causal role in mediating the health protective benefits of DR remains unknown. To investigate this relationship, nutritional manipulations and laboratory selection for lifespan were simultaneously applied. Three physiological outputs were used for the screening and characterization of genes that may mediate the effects of DR: starvation resistance, spontaneous activity levels, and lifespan. The physiologic changes that occur are partially mediated by the nutrient sensing TOR pathway and its downstream signaling components, specifically the translational repressor, eukaryotic initiation factor eIF4E binding protein (4E-BP). Overexpression of constitutively active d4E-BP in the muscle tissue of Drosophila melanogaster led to starvation resistance and increased activity in flies fed a nutrient rich diet. However, the associated lifespan extension effect observed in previous studies was not reproduced. This may be due to the use of a different laboratory strain of d4E-BP, of which there are several. Three downstream targets of 4E-BP were identified from screening: Fumble, Nemo, and Nedd2-like Caspase. Both Fumble and Nemo extend lifespan upon DR when inhibited in the muscle tissue. While these candidate genes hold promise for future studies in healthy aging, sources of variation in results must be controlled. In order to truly understand the influence that a specific mutant gene has on lifespan, results need to be clearly interpretable, robust and repeatable. Only then will it be possible to start making conjectures about their relevance to human aging.