Most organisms experience progressive declines in physiological function as they age. A number of studies in a variety of species support a strong link between oxidative damage, age-related functional declines and life span determination. Here, manipulating the expression levels of superoxide dismutase (SOD) isoenzymes SOD1 and SOD2, resulted in altered functional senescence and survival characteristics in Drosophila. Overexpression of cytosolic Sod1 using the yeast GAL4/UAS system conferred a 30-34% increase in mean life span and resulted in an attenuated senescence of odor avoidance behavior in aging flies. Tissue-specific Sod1 overexpression selectively in the nervous system or muscle failed to reproduce these delayed aging phenotypes suggesting that Sod1 overexpression in these tissues alone was not primarily responsible for the aging effects observed. Graded reduction of mitochondrially localized Sod2 expression in a series of Sod2 mutants led to progressive reductions in life span, accelerated age-related functional declines, mitochondrial oxidative damage and neuronal cell death. Tissue-specific Sod2 knock-down using RNA interference revealed that muscle is a key tissue underlying the accelerated age-related functional decline and mortality observed upon loss of SOD2. Sod2 knock-down in the musculature caused a degenerative phenotype consisting of a dramatic reduction in muscle mitochondrial content and ATP levels, elevated cell death and progressive locomotor dysfunction which culminated in early-onset mortality. Collectively, these studies highlight the important role of SOD enzymes in protecting against the impact of oxidative damage on senescence and survival. These findings also lend further support to the oxidative damage hypothesis of aging.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-2588 |
| Date | 28 April 2008 |
| Creators | Martin, Ian |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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