Aging and Mutation Load in Transgenic Medaka Fish

City Of Hope/Beckman Research Institute, Duarte CA

Investigators

Abstract

Medaka fish (Oryzias latipes) transgenic for the Big Blue mutation detection system are an excellent model for direct in vivo analysis of age and mutation load (mutation frequency and pattern) with consideration of associated parameters such as tissue type and certain environmental conditions, including temperature. This system provides a novel model for comparison of aspects of mutagenesis in the mouse with those in a non-mammalian vertebrate. The central hypothesis is that the mutational process as it relates to aging is broadly similar among all vertebrates implying that previous observations made regarding spontaneous mutation frequency and pattern with aging in the mouse will be observed in a non-mammalian vertebrate, the medaka. In addition, medaka fish provide a new vertebrate model of aging with distinct differences from mammalian models and the popular invertebrate models of aging (C. elegans and D. melanogaster). It is expected that temperature is a major determinant of longevity in fish. The rationale for use of a fish model in aging research is that the evolutionary conservation of spontaneous mutations from fish to mouse can likely by extrapolated to humans given the closer evolutionary relationship between rodents and humans (i.e., the evolutionary distance between fish and mouse (about 450 megayears) is greater than mouse and human (about 65 megayears)). The objective for the project is to determine the mutations load in a somatic tissue and the germline in young and old fish maintained at three different temperatures. It is anticipated that the findings will provide preliminary data regarding mutation load in old age with tissue type and temperature. The pilot data will be important for planning future experiments. Prior to this proposal, it was not possible to compare the various parameters (i.e., age, tissue type and temperature) affecting spontaneous mutagenesis in distantly related vertebrate species.