2006 AFAR Research Grant: Couch Potato Aging in Drosophila

Please give a brief summary of your AFAR research project.
The proposed research will investigate the role of the recently identified gene for reproductive diapause, couch potato (cpo), on the process of aging in the model organism Drosophila melanogaster. It was previously determined that reproductive diapause maps exclusively to cpo, and that a reduction in cpo expression is associated with the ability to express diapause. The first aim of the research program is to examine the impact of cpo expression level on lifespan, rates of aging, and correlated traits. In natural populations of Drosophila melanogaster, it has also been shown that variation for the diapause phenotype is a major predictor of lifespan and aging associated traits. The second aim of the research is to test the functional significance of naturally occurring cpo variants on aging traits.

What problems are you addressing and what specific questions will your research seek to answer?
The general problems we are seeking to address are:

• to what extent are lifespan and aging determined by the genetic makeup of an individual?
• what are the pathways involved in the determination of lifespan?
• what is the functional significance of allelic variation at identified candidate genes for aging?
• how does lifespan evolve in natural populations?
• does lifespan evolve by the direct action of evolutionary forces on the trait itself, or does it change indirectly by the action of forces on correlated traits?

The specific questions addressed by the proposed research relate to the specific role of a newly identified candidate gene for aging, couch potato, on lifespan and correlated traits in Drosophila.

What aspects of your project are most interesting from a scientific point of view?
The aspect of the project that is most interesting from a scientific perspective is the identification and characterization of a gene that has such major and widespread effects on life histories. The propensity to express diapause explains a significant amount of the variance for traits such as lifespan, reproductive output, lipid content, stress resistance, and development time. That this extensive variation results from functional variation at a single gene is remarkable. Determining the mechanisms of cpo effect and outlining the genetic interactions with other identified aging pathways will also be of great interest.

What are the implications of your research for age-related diseases and disorders?
From the mapping results, the cpo alleles from the diapause-capable lines were characterized by a substantial deletion of the polyglutamine run in one of the cpo exons. In other systems, such truncation of OPA or polyglutamine regions impacts protein stability and accumulation; this has been linked to the rate of progression of various neurodegenerative diseases. When cpo is overexpressed in Drosophila lines in which a human transgene for a neurodegenerative disease is present, the rate of degeneration is accelerated. Diapause-capable flies are characterized by hypomorphic activity at cpo, which is associated not only with extended lifespan but also increased resistance to all tested stressors and a general reduction in the rate of senescence. Thus, it has been hypothesized that hypomorphic activity at cpo may result in delay in the onset and progression of neurodegeneration. Because cpo has such widespread effects on aging and on age-dependent traits, this research may be of significance to the study of diseases or disorders that are age-dependent.

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