The zebrafish (Danio rerio) has proved to be an outstanding animal model system for genetic studies to explore vertebrate diseases as well as development. However, most zebrafish researchers evaluate their mutant animals at the embryonic and larval stages. Thus, mutations which mediate the effects of late-age onset diseases or dysfunctions have not been identified. More primitive model organisms such as Caenorhabditis elegans and Drosophila melanogaster have already been utilized quite successfully for genetic studies of aging, which have identified key evolutionarily conserved genes associated with the aging process. However, these invertebrate models cannot sufficiently identify critical longevity genes that are unique to vertebrates. Therefore it seems obvious that if the zebrafish system, with its the well-established advantages of forward genetics and recently improved reverse genetic technology, could be adapted to study aging, it would present an unparalleled opportunity to advance aging research. A number of theories to explain aging in mammals have been advanced over the years. Theories currently in vogue suggest that aging is the regulated by oxidative or genotoxic stress, telomere metabolism, regulation of caloric restriction and control of metabolic energy rate. Notably these theories are not mutually exclusive. However, compared to mammals, the aging process of zebrafish has gone almost unstudied. We propose to lay a strong foundation for aging studies in the zebrafish. First and foremost, we will perform an intensive search for biological and biochemical aging markers in zebrafish over the course of its entire lifespan (Aim 1). We will then begin to examine the effects treatments thought to regulate aging such as genotoxic stress by ionizing radiation or oxidative stress by hydrogen peroxide on the aging process of zebrafish using the most robust of our markers (Aim 2). These studies should prepare the way for later forward and reverse genetic studies where we will seek premature aging phenotypes or phenotypes resistant to aging and senescence in zebrafish.
|Kishi, Shuji (2014) Using zebrafish models to explore genetic and epigenetic impacts on evolutionary developmental origins of aging. Transl Res 163:123-35|
|Sasaki, Tomoyuki; Kishi, Shuji (2013) Molecular and chemical genetic approaches to developmental origins of aging and disease in zebrafish. Biochim Biophys Acta 1832:1362-70|