Zebrafish Aging and Senescence Research for Drug Discovery and Geriatric Medicine

Zebrafish have become a widely used model organism because of their fecundity, their morphological and physiological similarity to mammals, the existence of many genomic tools, and the ease with which large-scale and phenotype-based screens can be performed. Because of these attributes, zebrafish may provide opportunities to accelerate the process of drug discovery (Goldsmith, 2004; Yeh and Crews, 2003; Zon and Peterson, 2005). By combining the scale and throughput of in vitro screens with the physiological complexity of animal studies, the zebrafish system promises to contribute to several aspects of the drug development process, including identification of the molecular target, recapitulation of the disease, lead compound discovery and toxicology testing (Hill et al., 2005; Parng, 2005). At present, assessment of toxicity often occurs independently from efforts to discover lead compounds and improve their potency. High-throughput zebrafish toxicity assays combine many of the advantages of in vitro and in vivo toxicity models, making it possible to assess toxicity much earlier in the drug development process.

Moreover, large-scale genetic and MO-based screens allow unbiased discovery of genes that cause a desired phenotype (Dodd et al., 2004; Rubinstein, 2003). Zebrafish screens for genetic or epigenetic perturbations that suppress a disease phenotype can be used to discover novel therapeutic targets. These attributes might also enhance the efficiency of several steps in the drug development process for aging and age-associated diseases.

Historically, numerous drugs have been discovered by observing phenotypic changes in whole animals exposed to small molecules, but these discoveries have often been serendipitous and are usually arduous. However, if we can utilize zebrafish through the power of functional genomics and phenomics, the genome-wide study of gene dispensability by quantitative analysis of phenotypes can be performed as a large-scale and systematic screen in zebrafish to identify small molecules that can suppress multiple disease phenotypes (Love et al., 2004; MacRae and Peterson, 2003; Pichler et al., 2003). This apparently has the potential to contribute so enormously in the search for drugs against complex diseases that zebrafish aging can truly become a paradigm in gerontology diseases and geriatric medicine when we adopt zebrafish aging as a paradigm of gerontology.

Many genetic or environmental manipulations that alter lifespan in model organisms also alter survival following acute stresses such as oxidative damage, genotoxic stress, and thermal stress. Thus, in flies and worms, mutations that enhance lifespan also increase resistance to oxidative stress. This is also true for most of the small number of mutations that increase lifespan in mice. In lower organisms, this coupling of stress responses and aging mechanisms has proved a useful tool in identifying new genes that affect the aging process without the need for performing lengthy lifespan analyses. Therefore, it is quite possible that this approach may also be applied to the identification of zebrafish aging mutants and pharmacological agents that slow the aging process or extend lifespan through enhanced resistance to oxygen radicals or other stresses. To facilitate high-throughput mutant and drug screens in zebrafish aging, we have developed SA-^-gal-based colormetric and fluorometric quantitation assays to monitor a marker of premature senescence in zebrafish embryos. We have first verified that the signal intensity of SA-^-gal is dramatically increased both in aging fish and in embryos exposed to stress. We are further validating the assay by demonstrating that known signaling molecules and genetic mutations, which would be expected to modulate oxidative stress response or telomere metabolism, are linked to SA-^-gal induction in embryos. Screening for potential aging mutants in zebrafish is also in progress. In these screens, chemical/radiation-induced oxidative/genotoxic stress is used to identify mutant fish, which either enhance or suppress activity of the SA-^-gal depending on the sensitizing regimen. We have already isolated several candidate mutants that show enhanced response to stress. Our novel approach of mutant analysis in zebrafish has the potential to accelerate the identification of new aging mutants and to contribute to future drug discovery for pharmaceutical interventions in geriatric medicine.

Finally, although this chapter has not dealt with aging histopathology in zebrafish, traditional histopathological analysis is important for assessing aging phenotypes in animals versus humans. We previously reported some age-dependent histological and/or pathologic alterations in a few selected organs of zebrafish at fairly advanced age (Kishi et al., 2003). However, we still need to extensively examine aging tissues and organs. We also need to investigate the possible relationship of age-related functional impairments of organs as a cause of exponentially increasing mortality in aging zebrafish.

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