Superoxide Dismutases and Ionic Manganese in Aging

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DESCRIPTION (provided by applicant): The long-term goal of this research is to understand at the molecular level, the link between oxidative stress, metal metabolism and aging. The proposed research utilizes a multi-cellular higher organism, the nematode C. elegans (worms), as a model system to investigate the importance of the antioxidant enzyme, superoxide dismutase (SOD), in oxidative stress and aging. "Oxidative stress" is a term that is used to describe a cellular condition when there is an excess of free radicals in comparison to antioxidants and has been linked to many human diseases as well as aging. Superoxide dismutases are the class of enzymes that provide antioxidant defense against superoxide radicals. Also it is this enzyme (in the copper, zinc form) that when mutated in humans causes the debilitating neurodegenerative disorder commonly known as Lou Gehrig's disease. Almost all aerobic organisms including humans have SODs. C. elegans unlike most organisms have 5 SODs, 3 containing copper and zinc and 2 others containing manganese, at the active site. The first aim of this study is to use various SOD deleted worms to examine for any phenotypic differences in comparison to the wild-type worms. The lack of some forms of SOD in model organisms have been linked with reduced life-span. The ultimate goal of this specific aim is to understand the functions of various forms of SODs in C. elegans. Oxidative stress is one of the factors responsible for aging and since metals and oxidative stress are implicated in various neurodegenerative disorders we propose to study how altered levels of certain metals can have an impact on oxidative stress and life-span. Our main focus is on manganese, as there is accumulating evidence in unicellular organisms suggesting that manganese in vivo can complex to ligands such as phosphate or lactate and provide defense against oxygen radicals. The true role of ionic manganese is not clearly understood yet as it is also documented to be toxic causing Parkinsonian-like syndrome. The second specific aim is devoted to figuring out if manganese ions have any antioxidant properties similar to enzymes such as SOD. Manganese availability in the diet of the worms will be altered and free radical levels, oxidative damage, internal metal levels, and life-span in the worms will be monitored to further our understanding of the roles played by manganese ions in vivo.