William C. Orr, Ph.D.
Ph.D. Wayne State University
Lab: DLSB 315
Lab: DLSB 317
Oxidative Stress and Aging / Model Systems of Aging
My principle research focus lies in the use of transgenic and genetic models to examine mechanisms involved in the aging process, with emphasis on testing the Oxidative Stress Hypothesis of Aging. There are three on-going projects in our laboratory.
The first of these is designed to determine the effects of an increased or a decreased ability of cells to synthesize and regenerate reduced glutathione (GSH) on the aging process in fruit flies. The motivation for this effort lies in the observation that GSH can react with a variety of free radical species and is likely to work in conjunction with superoxide dismutase to provide an important mechanism for the attenuation of oxidative stress. We have generated transgenic flies over-expressing glutamate cysteine ligase and have achieved significant longevity effects (up to 50%) in a long-lived background. In continuing work we are attempting to identify “pace-maker” tissues and temporal windows where longevity effects are conferred and we are determining interactions with other pathways that have been implicated in the aging process.
In a second study we have set out to elucidate the potential role of the thioredoxin peroxidases on oxidative stress, aging and immunity in Drosophila. The thioredoxin peroxidases represent a group of recently identified components of the antioxidative network, which reduce H2O2 and organic peroxides using thioredoxin as an electron source and do so in very specific sub-cellular compartments. Analysis of this gene family has allowed us to reveal elements of both antioxidant function and redox regulation related to longevity and innate immunity.
We have also initiated a study in collaboration with Raj Sohal (USC) designed to reduce mitochondrial superoxide generation by manipulation of cytochrome c oxidase (COX) activity in transgenic flies. Various COX subunit components likely to be limiting for superoxide generation have been identified and we have begun to generate key mutant and transgenic lines.
Radyuk, S.N., Gambini, J., Borras, C., García, E.S., Klichko, V.I., Viña, J. and Orr, W.C. (2012) Age-dependent changes in the transcription profile of long-lived Drosophila over-expressing glutamate cysteine ligase. Mech Ageing Dev. 133(6), 401-413
Sohal, R.S. and Orr, W.C. (2012) The redox stress hypothesis of aging. Free Radic. Biol. Med. 52, 539-555
Radyuk, S.N., Rebrin, I., Klichko, V.I., Sohal, B.H., Michalak, K., Benes, J., Sohal, R.S. and Orr, W.C. (2010) Mitochondrial peroxiredoxins are critical for the maintenance of redox state and the survival of adult Drosophila. Free Radic. Biol. Med. 49(12), 1892-1902.
Radyuk, S. N., Michalak, K., Klichko, V. I., Benes, J. and Orr, W. C. (2010) Peroxiredoxin 5 modulates immune response in Drosophila. Biochim. et Biophys. Acta 1800(11), 1153-1163.
Ren, J.-C., Rebrin, I., Klichko, V., Orr, W.C. and Sohal R.S. (2010) Cytochrome c oxidase loses catalytic activity and structural integrity during the aging process in Drosophila melanogaster. Biochem. Biophys. Res. Commun. 401(1), 64-68.
Radyuk, S. N., Michalak, K., Klichko, V. I., Benes, J., Rebrin, I., Sohal, R. S. and Orr, W. C. (2009) Peroxiredoxin 5 confers protection against oxidative stress and apoptosis and also promotes longevity in Drosophila. Biochem. J. 419(2), 437-445.
Radyuk, S. N., Rebrin, I., Luchak, J. M., Michalak, K., Klichko, V. I., Sohal, R. S., and Orr, W. C. (2009) The catalytic subunit of Drosophila glutamate-cysteine ligase is a nucleocytoplasmic shuttling protein. J. Biol. Chem. 284, 2266-2274.
Legan, S. K., Rebrin, I., Mockett, R. J., Radyuk, S. N., Klichko, V. I., Sohal, R. S., and Orr, W. C. (2008) Overexpression of glucose-6-phosphate dehydrogenase extends the life span of Drosophila melanogaster. J. Biol. Chem. 283(47), 32492-32499.
Sohal, R. S., Toroser, D., Brégere, C. Mockett, R. J. and Orr, W. C. (2008) Age-related decrease in expression of mitochondrial DNA encoded subunits of cytochrome c oxidase in Drosophila melanogaster. Mech Ageing Dev. 129(9), 558-561.
Mockett, R. J., Sohal, R. S., and Orr, W. C. The fruit fly Drosophila melanogaster: roles of oxidative stress in the aging process of Drosophila melanogaster. In: Aging Medicine: Oxidative Stress in Aging: From Model System to Human Diseases. S. Miwa, K.B. Beckman, and F.L. Muller, eds. pp 111-128, Humana Press, Totowa, NJ In Press
Michalak, K, Orr, W. C., and Radyuk, S. N. (2008) Drosophila peroxiredoxin 5 is the second gene in a dicistronic operon. Biochem. Biophys. Res. Commun 368(2), 273-278.
Anderson, P. R., Kirby, K., Orr, W. C., Hilliker, A. J., and Phillips, J. P. (2008) Hydrogen peroxide scavenging rescues frataxin deficiency in a Drosophila model of Friedreich’s ataxia. Proc. Natl. Acad. Sci. USA 105, 611-616.
Toroser, D., Orr, W.C. and Sohal, R.S. (2007) Carbonylation of mitochondrial proteins in Drosophila melanogaster during aging. Biochem. Biophys. Res. Commun. Epub ahead of print.
Radyuk, S.N., Michalak, K, Rebrin, I., Sohal, R.S. and Orr, W.C. (2006) Effects of ectopic expression of Drosophila DNA glycosylases dOgg1 and RpS3 in mitochondria. Free Radic. Biol. Biol. Med. 41(5), 757-764.
Toroser, D., Yarian, C.S., Orr, W.C. and Sohal, R.S. (2006) Mechanisms of gamma-glutamylcysteine ligase regulation. Biochim Biophys Acta 1760 (2), 233-244.
Bayne, A.C., R.J. Mockett, W.C. Orr, and R.S. Sohal. (2005) Enhanced catabolism of mitochondrial superoxide/hydrogen peroxide and aging in transgenic Drosophila. Biochem J., 391 (Pt 2), 277-284.
Ferguson, M., R.J. Mockett, Y. Shen, W.C. Orr, and R.S. Sohal. (2005) Age-associated decline in mitochondrial respiration and electron transport in Drosophila melanogaster. Biochem J 390: 501-11.
Orr, W.C., S.N. Radyuk, L. Prabhudesai, D. Toroser, J.J. Benes, J.M. Luchak, R.J. Mockett, I. Rebrin, J.G. Hubbard, and R.S. Sohal. (2005) Overexpression of glutamate-cysteine ligase extends life span in Drosophila melanogaster. J Biol Chem. 280 (45), 37331-37338.
Cooper, T.M., Mockett, R.J., Sohal, B.H., Sohal, R.S. and Orr, W.C. (2004) Effect of caloric restriction on life span of the housefly, Musca domestica. FASEB J. 18, 1591-1593.
Rebrin, I., Bayne, A.-C.V., Mockett, R.J., Orr, W.C. and Sohal, R.S. (2004) Free amino thiols, glutathione redox state and protein mixed disulfides in aging Drosophila melanogaster. Biochem. J. 382, 131-136.
Radyuk, S.N., Klichko, V.I. and Orr, W.C. (2004) Profiling Cu,Zn-superoxide dismutase in Drosophila melanogaster - a critical regulatory role for intron/exon sequence within the coding domain. Gene. 328, 37-48.
Klichko, V.I., Radyuk, S.N. and Orr, W.C. (2004) Profiling catalase gene expression in Drosophila melanogaster during development and aging. Archives of Insect Biochemistry and Physiology. 56, 34-50.
Orr, W.C., Mockett, R.J., Benes, J.J. and Sohal, R.S. (2003) Effects of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster. J. Biol. Chem. 278(29), 26418-26422.
Radyuk, S.N., Sohal, R.S. and Orr, W.C. (2003) Thioredoxin peroxidases can foster cytoprotection or cell death in response to different stressors-a study of thioredoxin peroxidase under- and over-expression in Drosophila cells. Biochem. J. 371, 743-752.
Orr, W.C. and Sohal, R.S. (2003) Does overexpression of Cu,Zn-SOD extend life span in Drosophila melanogaster? Exper. Gerontol. 38(3), 227-230.
Mockett, R.J., Radyuk, S.N., Benes, J.J., Orr, W.C. and Sohal, R.S. (2003) Phenotypic effects of familial amyotrophic lateral sclerosis mutant SOD alleles in transgenic Drosophila. Proc. Natl. Acad. Sci. USA. 100(1), 301-306.
Mockett, R.J., Bayne, A-C.V., Kwong, L.K., Orr, W.C. and Sohal, R.S. (2003) Ectopic Expression of Catalase in Drosophila Mitochondria Increases Stress Resistance but not Longevity. Free Radic. Biol. Med. 34(2), 207-217.
Sohal, R.S., Mockett, R.J. and Orr, W.C. (2002) Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic. Biol. Med. 33(5), 575-586.
Mockett, R.J., Orr, W.C., and Sohal, R.S (2002) Overexpression of Cu,ZnSOD and MnSOD in transgenic Drosophila. Methods Enzymol. 349, 213-20.
Radyuk, S.N., Klichko, V.I., Spinola, B., Sohal, R.S., and Orr, W.C. (2001) The peroxiredoxin gene family in Drosophila melanogaster. Free Radic. Biol. Med. 31(9), 1090-1100.
Das, N., Levine, R.L., Orr, W.C. and Sohal, R.S. (2001) Selectivity of protein oxidative damage during aging in Drosophila melanogaster. Biochem. J. 360, 209-216.
Mockett, R.J., Orr, W.C., Rahmandar, J.J., Sohal, B.H. and Sohal, R.S. (2001) Antioxidant status and stress resistance in long- and short-lived lines of Drosophila melanogaster. Exp. Geront. 36, 441-43.
Radyuk, S.N., Klichko, V.I. and Orr, W.C. (2000) Catalase expression in Drosophila melanogaster is responsive to ecdysone and exhibits both transcriptional and post-transcriptional regulation. Arch. Insect Biochem. Physiol. 45, 79-93.
Kwong, L.K., Mockett, R.J., Bayne, A.-C.V., Orr, W.C. and Sohal, R.S. (2000) Decreased mitochondrial hydrogen peroxide release in transgenic Drosophila melanogaster expressing intramitochondrial catalase. Arch. Biochem. Biophys. 383(2), 303-308.
Sohal, R.S., Mockett, R.J. and Orr, W.C. (2000) Current issues concerning the role of oxidative stress in aging: a perspective. In Results and Problems in Cell Differentiation, Vol. 29 (The Molecular Genetics of Aging), Springer-Verlag, Berlin, Ed. S. Hekimi, pp. 45-65.
Orr, W.C. and Sohal, R.S. (2000) Oxidative stress as a governing factor in physiological aging. In Antioxidant and Redox Regulation of Genes, Eds. C.K. Sen, H. Sies and P.A. Baeuerle, pp. 517-530, Academic Press, San Diego.
Mockett, R.J., Orr, W.C., Rahmandar, J., Benes, J.J., Radyuk, S.N., Klichko, V.I. and Sohal, R.S. (1999) Overexpression of Mn-containing superoxide dismutase in transgenic Drosophila melanogaster. Arch. Biochem. Biophys. 371(2), 260—269.
Klichko, V.I., Radyuk, S.N. and Orr, W.C. (1999) CuZn-SOD promoter-driven expression in the Drosophila central nervous system. Neurobiol. Aging 20, 537-543.
Mockett, R.J., Sohal, R.S. and Orr, W.C. (1999) Overexpression of glutathione reductase extends survival in transgenic Drosophila melanogaster under hyperoxia but not normoxia. FASEB J. 13, 1733-1742.
Yan, L.-J., Orr, W.C. and Sohal, R.S. (1998) Identification of oxidized proteins based on sodium sulfate-polyacrylamide gel electrophoresis, immunochemical detection, isoelectric focusing and microsequencing. Analytic. Biochem. 263. 67-71.
Sohal, R.S. and Orr, W.C. (1998) Role of oxidative stress in senescence. Aging Clin. Exp. Res. 10, 149-151.
Sohal, R.S. and Orr, W.C. (1998) Oxidative stress may be a causal factor in the aging process. Age 21, 37-38.
Candas, M., Sohal, R.S., Radyuk, S.N., Klichko, V.I. and Orr, W.C. (1997) Molecular organization of the glutathione reductase gene in Drosophila melanogaster. Arch. Biochem. Biophys. 339, 323-334.
Orr, W.C., Orr, E.C., Legan, S.K. and Sohal, R.S. (1996) Molecular Analysis of the Drosophila catalase gene. Arch. Biochem. Biophys. 330, 251-258.
Orr, W.C. (1996) Senescence: in search of causality. Devel. Genet.18, 93-98.
Sohal, R.S., Agarwal, A., Agarwal, S. and Orr, W.C. (1995) Simultaneous overexpression of copper- and zinc-containing superoxide dismutase and catalase retards age-related oxidative damage and increases metabolic potential in Drosophila melanogaster. J. Biol. Chem. 270, 15671-15674.
Sohal, R.S., Sohal, B.H. and Orr, W.C. (1995) Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage and longevity in different species of flies. Free Rad. Biol. & Med. 19, 499-504.
Sohal, R.S. and Orr, W.C. (1995) Is oxidative stress a causal factor in aging? In: Dahlem Workshop Report on Molecular Aspects of Aging (K. Esser & G.M. Martin, eds.), pp. 109-127, John Wylie & Sons, Ltd., Sussex.
Orr, W.C. & Sohal, R.S. (1994) Extension of life span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263, 1128-1130.
Sohal, R.S., Agarwal, S. & Orr, W.C. (1994) Oxidative stress may be a causal factor in senescence. In: Oxidative Processes and Antioxidants: Their Relation to Nutrition and Health Outcomes, 13th Ross Research Conference on Medical Issues (A. Roche, ed.), pp. 6-10, Ross Laboratories, Columbus, Ohio.
Sohal, R.S., Agarwal, S., Dubey, A. & Orr, W.C. (1993) Protein oxidative damage is associated with life expectancy of houseflies. Proc. Natl. Acad. Sci. USA 90, 7255-7259.
Orr, W.C. & Sohal, R.S. (1993) Effects of overexpression of Cu-Zn superoxide dismutase on life span and response to oxidative stress in Drosophila melanogaster. Arch. Biochem. Biophys. 301, 34-40.
Sohal, R.S. & Orr, W.C. Oxidative stress and aging. In: Proceedings of the 8th International Colloquium "Biologie Prospective." 1993. Paris: John Libbey Eurotext.
Orr, W.C., Arnold, L.A. & Sohal, R.S. (1992) Relationship between catalase activity, life span and some parameters associated with antioxidant defenses in Drosophila melanogaster. Mech. Ageing Dev. 63, 287-296.
Sohal, R.S. & Orr, W.C. (1992) Relationship between antioxidants, prooxidants, and the aging process. Ann. N.Y. Acad. Sci. 663, 74-84.
Huang, R.Y. & Orr, W.C. (1992) Broad-complex function during oogenesis in Drosophila. Dev. Gen. 13, 277-288.
Orr, W.C. & Sohal, R.S. (1992) The effects of catalase gene overexpression on life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch. Biochem. Biophys. 297, 35-41.
Orr, E.C., Bewley, G.C. & Orr, W.C. (1990) cDNA and deduced amino acid sequence of Drosophila catalase. Nucl. Acids Res. 18, 3663.
Sohal, R.S., Arnold, L. & Orr, W.C. (1990) Effect of age on superoxide dismutase, catalase, glutathione reductase, inorganic peroxides, TBA-reactive material, GSH/GSSG, NADPH/NADP+ and NADH/NAD+ in Drosophila melanogaster. Mech. Ageing Dev. 56, 223-235.
Mackay, W.J., Orr, W.C. & Bewley, G.C. Genetic and molecular analysis of antioxidant enzymes in Drosophila melanogaster: A correlation between catalase activity levels, life span, and spontaneous mutation rate. In: Molecular Biology of Aging: UCLA Symposium on Molecular and Cellular Biology (eds. Clegg, M. & O'Brien, S.), Vol. 123, pp. 157-170, Alan R. Liss, New York, 1990.
Orr, W.C., Galanopoulos, V.K., Romano, C. & Kafatos, F.C. (1989) A female sterile screen of the Drosophila melanogaster X chromosome using hybrid dysgenesis: Identification and characterization of egg morphology mutants. Genetics 122, 847-858.
Galanopoulos, V.K., Orr, W.C., Szabad, J. & Kafatos, F.C. (1989) Genetic analysis of chorion formation in Drosophila melanogaster. I. The effects of one somatic-specific and seven germ-line specific mutations. Dev. Genet. 10, 87-97.
Kafatos, F.C., Delidakis, C., Orr, W.C., Thireos, G., Komitopoulou, K. & Wong, Y.-C. Studies on the developmentally regulated amplification and expression of Drosophila chorion genes. In: Molecular Developmental Biology (ed. Bogorat, L.), pp. 85-101, Alan R. Liss, New York, 1985.
Kafatos, F.C., Orr, W.C. & Delidakis, C. (1985) Developmentally regulated gene amplification. TIG 1, 301-305.
Orr, W., Komitopoulou, K. & Kafatos, F.C. (1984) Mutants suppressing in trans chorion gene amplification in Drosophila. Proc. Natl. Acad. Sci. USA 81, 3773-3777.
Timberlake, W.E. & Orr, W.C. Steroid hormone regulation of sexual reproduction in Achlya. In: Biological Regulation and Development (ed. Yamamoto, K.), Vol. IIIB, pp. 255-283, Plenum Press, New York, 1984.
Orr, W.C. & Timberlake, W.E. (1982) Clustering of spore-specific genes in Aspergillus nidulans. Proc. Natl. Acad. Sci. USA 79, 5976-5980.
Zimmerman, C., Orr, W.C., Leclerc, R.F., Barnard, E.C. & Timberlake, W.E. (1980) Molecular cloning and selection of genes regulated in Aspergillus development. Cell 21, 709-715.
Rozek, C.E., Orr, W.C. & Timberlake, W.E. (1978) Diversity and abundance of polyadenylated RNA from Achlya ambisexualis. Biochemistry 17, 716-722.
Current Funding from the National Institute of Aging
|“Glutathione, Oxidative Stress and Aging”
Direct Costs: $ 205,000 per year,
Currently one year no cost extension
|4/1/06 – 3/31/11
“Cellular Aging and Oxygen Free Radicals”
Sub-contract: $60,000 Direct Costs per year
4/1/07 – 3/31/12
|“Peroxiredoxins, Immune Signaling and Aging"
Direct Costs: $225,000 per year
|7/1/02 – 6/30/08
||B.A. French Literature, Wayne State University
||Ph.D. Biology / Biochemistry, Wayne State University
||Post-doc, Molecular Biology of Drosophila, Harvard University (with Prof. F. C. Kafatos)
||Assistant Professor, Southern Methodist University
||Associate Professor, Southern Methodist University
||Professor, Southern Methodist University