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Senior Scholar Award in Aging
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Steven N.
Austad,
Ph.D.
University of Idaho
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Genetic Mechanisms of Exceptional Oxidative Damage Resistance in Birds
Evidence that oxidative damage, a by-product of normal metabolism in virtually all animals, is causally involved in the process of aging and the development of degenerative disease has been steadily accumulating for more than forty years. An understanding of the exact nature of this damage to specific cell components and mechanisms by which organisms combat this damage via differential efficacy in the formation of damaging molecules (often called "reactive oxygen species" or ROS's), scavenging of these molecules by specialized enzymes or dietary products, or rapid and efficient repair or replacement of damaged parts is an active area of current aging research. However, all work on these basic mechanisms using animal models, utilize models that age quickly and are therefore demonstrably inefficient at combating oxidative damage. The unique approach of this particular project is to identify genetic mechanisms of oxidative damage resistance in a model bird species, the budgerigar, with exceptional resistance to oxidative damage. Indeed current evidence indicates that birds generally have superior oxidative damage resistance to any other known animal group, superior even to slowly-aging mammals such as humans. The logic of this approach is that by studying how nature has designed such an exquisitely effective system, we will ultimately learn something about how to effectively design interventions to slow aging in humans.
Two sorts of evidence indicate that birds indeed possess exceptional resistance to oxidative damage. First, despite a high metabolic rate, birds are exceptionally long-lived. Mouse-sized birds generally live 20+ years under captive conditions. During that life they process substantially more oxygen per cell than any other known group of organisms. Specifically, some bird species process as much as 5 times the oxygen per cell in a lifetime as humans (Holmes & Austad, 1995). Second, bird cells in culture, survive exposure to a number of ROS-producing agents better than mouse or human cells (Ogburn, et al., 1998).
The research supported by The Ellison Senior Scholar Award will use a multi-pronged approach with multiple collaborators to seek to identify and begin mapping the genes responsible for this resistance. This project will be the first gene mapping project of any organism of specific gerontological interest. Initially, we will seek to identify the chromosomal regions involved in oxidative damage resistance by creating microcell hybrid cell lines, which combine the genome of an oxidative damage-prone species with selected budgerigar genes or chromosomes. Hybrid cells are then exposed to oxidative stress and examined to see whether oxidative damage resistance has been conferred by the presence of specific bird genes. Second, gene expression profiling by three independent techniques (Serial Analysis of Gene Expression, cDNA microarray hybridization, subtractive hybridization) will compare gene expression patterns of cells before and after exposure to ROS-producing agents. By examining closely increased activity of specific gene products, we hope to identify those genes whose activation was causally involved in resistance to the oxidative challenge. Third, we will examine whether the dynamics of telomere length regulation is correlated with exceptional oxidative damage resistance by examining telomere length reulation is correlated with exceptional oxidative damage resistance by examining telomere length dynamics, telomerase activity, and cell proliferation ability in long-lived (budgerigar) versus short-lived (Japanese quail) bird species.
Contact
Dr. Austad.
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