Zebrafish as Aging Models

Shuji Kishi

Zebrafish (Danio rerio) are well recognized as a powerful model for genetic studies in developmental biology. The zebrafish system has also given insights into several human diseases such as neurodegenerative, hematopoietic and cardiovascular diseases and cancer. The aging process affects these and various other human disorders, and it is important to compare age-related disfunctions at the organismal levels among vertebrates. From the point of view in comparative and evolutionary biology of aging, the aging process of zebrafish remains largely unexplored, and little is known about functional aging and senescence, compared with higher vertebrates including mammals. In our recent studies to assess aging phenotypes in zebrafish, we identified several potential biomarkers of zebrafish aging. In aging zebrafish, we have detected senescence-associated fi-galactosidase activity in skin and oxidized protein accumulation in muscle. In contrast, our initial study showed that lipofuscin granules, which accumulate in postmitotic cells, were not obvious in muscle of zebrafish at fairly advanced age. In agreement with this observation, there were continuously proliferating myocytes in muscle tissues of aged fish. More intriguingly, we found that zebrafish have constitutively abundant telo-merase activity in adult somatic tissues, implicating the unlimited replicative ability of cells throughout their lives. Taken together, some stress-associated markers are up-regulated, and minor histological alterations and lesions are occasionally observed during the aging process of zebrafish. However, our current studies and other evidence of remarkable reproductive and regenerative abilities suggest that zebrafish show very gradual senescence. By using those biological and biochemical aging markers already characterized in normal zebrafish, analyses of transgenic and mutant fish be readily performed for development of zebrafish aging models for age-dependent human diseases and progeroid syndromes. These efforts will help to elucidate the role and molecular mechanisms of common or different pathways of aging among vertebrates from fish to humans and also will contribute to the discovery of possible therapeutic interventions and potential drugs applicable to many age-associated diseases in the future.

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