The main purpose of the proposed studies is to test the validity of the oxidative stress hypothesis of aging, which postulates that the age-associated loss of functional capacity is substantially due to the accrual of molecular oxidative damage. The focus of this study is to investigate one of the main predictions of this hypothesis, namely that variations in the level of oxidative stress, induced by experimental alterations in antioxidative defenses, should correspondingly affect the rate of aging. Specifically, this study will determine the effects of an increased or a decreased ability of cells to synthesize and regenerate reduced glutathione (GSH) on the aging process of Drosophila melanogaster. GSH can react with a variety of free radical species and, in conjunction with superoxide dismutase, provide the main mechanism or the attenuation of oxidative stress. Flies that have an increased ability to synthesize and regenerate GSH will be created by the transgenic overexpression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in GSH synthesis) and glucose-6-phosphate dehydrogenase (which generates NADPH, required for reduction of oxidized glutathione to GSH), respectively. In contrast, flies with a decreased ability to synthesize and regenerate GSH will be obtained by isolating mutant alleles of these genes. The effects of over-and under-expression of these genes on life span and a variety of biochemical/physiological alterations, related to the aging process, will be determined. Subsequently, the effects of co-overexpression of these genes with other antioxidative genes (e. Cu,Zn-superoxide dismutase and catalase) on the aging process of the flies will be determined. Results should (i) provide a direct test of the role of the genes, involved in the maintenance of GSH, in the aging process, (ii) permit further assessment of the validity of the oxidative stress hypothesis of aging, and (iii) aid in the design of similar studies in mammals.
| Orr, William C; Radyuk, Svetlana N; Sohal, Rajindar S (2013) Involvement of redox state in the aging of Drosophila melanogaster. Antioxid Redox Signal 19:788-803 |
| Radyuk, Svetlana N; Klichko, Vladimir I; Michalak, Katarzyna et al. (2013) The effect of peroxiredoxin 4 on fly physiology is a complex interplay of antioxidant and signaling functions. FASEB J 27:1426-38 |
| Radyuk, Svetlana N; Gambini, Juan; Borras, Consuelo et al. (2012) Age-dependent changes in the transcription profile of long-lived Drosophila over-expressing glutamate cysteine ligase. Mech Ageing Dev 133:401-13 |
| Sohal, Rajindar S; Orr, William C (2012) The redox stress hypothesis of aging. Free Radic Biol Med 52:539-555 |
| Radyuk, Svetlana N; Rebrin, Igor; Klichko, Vladimir I et al. (2010) Mitochondrial peroxiredoxins are critical for the maintenance of redox state and the survival of adult Drosophila. Free Radic Biol Med 49:1892-902 |
| Radyuk, Svetlana N; Rebrin, Igor; Luchak, James M et al. (2009) The catalytic subunit of Drosophila glutamate-cysteine ligase is a nucleocytoplasmic shuttling protein. J Biol Chem 284:2266-74 |
| Legan, Susan K; Rebrin, Igor; Mockett, Robin J et al. (2008) Overexpression of glucose-6-phosphate dehydrogenase extends the life span of Drosophila melanogaster. J Biol Chem 283:32492-9 |
| Toroser, Dikran; Yarian, Connie S; Orr, William C et al. (2006) Mechanisms of gamma-glutamylcysteine ligase regulation. Biochim Biophys Acta 1760:233-44 |
| Orr, William C; Radyuk, Svetlana N; Prabhudesai, Leena et al. (2005) Overexpression of glutamate-cysteine ligase extends life span in Drosophila melanogaster. J Biol Chem 280:37331-8 |
| Rebrin, Igor; Bayne, Anne-Cecile V; Mockett, Robin J et al. (2004) Free aminothiols, glutathione redox state and protein mixed disulphides in aging Drosophila melanogaster. Biochem J 382:131-6 |
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