Prospective Basic Studies of Aging and Senescence in Zebrafish

The potential maximum lifespan of zebrafish is more than five years (Gerhard et al., 2002), though the differences among strains as well as betwen genders need to be clarified. Thus, while searching for late age-onset disease models and long-lived mutants is extremely important and worthwhile trying, it will be tough and tedious work because of current paucity of baseline information on zebrafish aging. On the other hand, we have been planning to isolate zebrafish mutants like progeroid syndromes in humans as described above. Genetic manipulations of several genes related to pathophysiolo-gical aging symptoms into zebrafish embryos have the potential to unveil some important aspects of the molecular mechanisms of senescence through the use of easier traceable developmental stages. Without performing lengthy lifespan analyses and long-term studies of age-associated alterations and lesions in the animal, it may be possible to pick up predictable late-age onset phenotypes in early developmental stages. Although an ''antagonistic pleiotropy'' theory of aging is needed concerning phenomena early- versus late-in-life, antagonistically pleiotropic genes and processes that benefit organisms turn out to be detrimental immediately after stress rather than later in life. Based on the fact that senescence induced by stress exposure is recognized as ''stress-induced premature senescence'' at cellular levels in the cell culture system (Toussaint et al., 2000), probably it is amenable at organismal levels in animal model systems. During mouse embryogenesis, the absence of the BRCA1 full-length isoform causes embryonic senescence that is carried out by p53 (Cao et al., 2003). Usually, p53, the clearest example of an antagonistically pleiotropic gene product, has early-life benefit suppressing cancer development, but has late-life detrimental cost compromising tissue functions with age. However, once BRCA1 is disrupted, p53 turns out to be harmful to embryonic survival by inducing senescence during development. Thus, DNA-damaging stress as well as BRCA1 deficiency triggers p53-dependent stress-induced premature senescence in cells and in organisms. Moreover, embryonic senescence in p63-deficient mice as well as accelerated aging phenotypes in conditional p63-disrupted adult mice have been most recently reported in the literature (Keyes et al., 2005). These lines of recent evidence strongly support the notion that it is possible to assess biological aging phenomena in model organisms without having to perform more time-consuming chronological aging studies.

Importantly, nematodes and fruitflies have no cancer or other abnormal growth during aging, in contrast to their common occurrence in vertebrates from fish to humans with advancing age. Having relevance to these phenomena with regard to cell growth characteristics, nematodes with a constant number of cells lack somatic cell replacement, whereas insects such as the fruitfly have limited but detectable cell proliferation in some adult tissues. On the other hand, mammalian tissues contain different proportions of the cells that are continuously replaced in adults but are of great importance to outcomes of organismal aging through replicative senescence of critical cells. However, humans possess only a limited capacity to restore their missing or injured body parts. Therefore, stimulating regenerative capability may circumvent some tissue deterioration in aging humans. Adult zebrafish have been shown to possess a remarkable capacity for regeneration. Zebrafish regenerate almost all tissues and organs such as fins, spinal cord, retina, and heart. By dissecting molecular mechanisms of zebrafish regeneration, it may be possible to illuminate novel factors that can stimulate a regenerative response in higher vertebrates. Thus, research of regeneration in zebrafish during the aging process will contribute to aging medicine as well as to regenerative medicine in humans.

With respect to amenability of genetic manipulations through forward genetic and reverse genetic approaches, robust zebrafish genetics will obviously hold the key to success. However, zebrafish have a relatively long generation time and fairly long lifespan compared with those of nematodes and flies, which slows down experiments that require breeding and analyzing offspring as well as longitudinal aging studies. Nevertheless, zebrafish are one of the most genetically pliable/tractable (visually traceable) and biologically attractive animal models. Presumably, specific gene expression and its function and a role of tissue-specific stem and progenitor cells in aging will be actively and progressively investigated in zebrafish, closely connected with regeneration studies.

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