Open Access Dissertation
Date of Award
Robert A. Arking
The protein deacetylase Sir2 has been shown to increase lifespan in a variety of organisms, possibly through its ability to engender the effects of dietary restriction. The Drosophila nicotinamidase DNAAM increases lifespan in a Sir2 dependant manner, and may play a role in oxidative stress resistance. Oxidative damage that accumulates in cells during normal aging contributes to a variety of diseases and pathologies, and can result in an increase in age specific mortality. Accordingly, the oxidative stress theory of aging predicts that organisms with an increased tolerance to oxidative damage will have an increased longevity, while organisms with decreased tolerance will exhibit early mortality. Evidence is mounting, however, that many genetic manipulations that promote resistance to oxidative stress do not correlate with an increase in lifespan. Furthermore, many biochemical and genetic pathways involved in lifespan regulation do not have any known role in oxidative stress response. Here we report theoxidative stress responses of adult Drosophila that over-express Sir2 or the nicotinamidase DNAAM. Both of these gene manipulations are known to increase adult lifespan; however only Sir2 endows strong, reproducible resistance to two different forms of oxidative stress. Sir2 is required for normal oxidative stress resistance, as mutant animals have virtually no tolerance to dietary paraquat and a reduced tolerance to hydrogen peroxide. In order to determine the efficacy of our experimental system, we tested two inert genes, GFP and LacZ, for the effects of over-expression on oxidative stress response. Interestingly, in male flies, small but significant increases in paraquat resistance could be observed when inert genes were expressed. This data highlights an important contribution of background genetics and/or expression system artifacts in eliciting stress response phenotypes. Thus, more comprehensive methodologies for controlling gene expression experiments should be required to confirm small effects on stress response and lifespan. Taken together our data suggests that a correlation between oxidative stress and increased longevity may be gene or gene-pathway dependant, and that pathways independent of oxidative stress response can contribute to increased lifespan.
Miller, Gregory, "Drosophila Nicotinamidase And Sir2 In Longevity Regulation And Oxidative Stress Response, And The Implications For Aging Theory" (2010). Wayne State University Dissertations. Paper 177.