Date on Senior Honors Thesis

5-2023

Document Type

Senior Honors Thesis

Degree Name

B.S.

Department

Biology

Author's Keywords

Drosophila melanogaster; Werner Syndrome; Dietary Restriction; physiology; lifespan; aging

Abstract

Werner syndrome (WS) is an autosomal recessive disorder that results in premature aging and occurs in 1 in 1,000,0000 to 1 in 10,000,000 people. In humans, WS is the result of mutations that render the WRN gene, that contains a helicase and an exonuclease domain, non-functional. Currently, there is no cure for WS in humans, making dietary and lifestyle interventions attractive for increasing the quality and longevity of lives. Diet restriction (DR) has been shown to extend the lifespan of several model organisms, including Drosophila melanogaster, making it a strong candidate for WS treatment. In this thesis, mutant flies for the gene WRNexo, homologous to the exonuclease domain of WRN in humans, were used to examine the effect of DR on lifespan and the DR mediated physiological, and behavioral characteristics of starvation, oxidative stress, and sleep/activity. Serial yeast dilution medias (1%, 5%, and 20% yeast w/v), were used to evaluate the effects of DR on WS lifespan and physiological and behavior characteristics. Surprisingly, it was found that DR did not extend the lifespan of WS flies and even had a detrimental effect in females, but early life yeast supplementation was shown to partially rescue the early life mortality observed. DR was also observed to have a sex-dependent effect on WS flies that results in a reduced resistance to both starvation and oxidative stress while creating more sleep/activity disruption. Deleterious effects of DR on lifespan, physiological, and behavioral characteristics, suggest that the WRN protein is necessary for longevity benefits traditionally observed in DR as well as the WRN protein having a function in metabolic control. Future studies could identify and evaluate the mechanisms that control the effects of DR on the WRNexoΔ mutants.

Lay Summary

Werner syndrome is a rare genetic disease that results in the premature death of the patients. This genetic disease is caused by mutations in the WRN gene that cause the gene to be nonfunctional. Currently there is no cure for this disease in humans, which makes dietary and lifestyle interventions attractive options for increasing life expectancy. Dietary restriction is a process where calories or nutrients are limited in the diet and has been shown to reverse the signs of aging and extend lifespan in several animal models, including flies.

In this thesis, a fly model of Werner syndrome, WRNexoΔ, was used to evaluate the effects of dietary restriction on Werner syndrome. It was initially thought that dietary restriction could be a possible lifestyle intervention for patients, but DR was not found to increase the lifespan of the Werner syndrome model flies and even had a negative effect on the lifespan. Additionally, dietary restriction mediated physiological characteristics such as starvation, oxidative stress, and sleep/locomotion showed disruption in Werner syndrome model flies. Dietary restriction negatively impacting Werner syndrome model flies indicates that WRN protein has a function in metabolic control outside of its currently known function.

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