Significance of Telomere and Telomerase in Zebrafish Aging and Senescence

As mentioned above with respect to the telomeric aging markers, the end of chromosomes termed telomeres consists of repeat sequences of TTAGGG, which are conserved in all vertebrates, from fish to humans. Telomerase is essential for maintaining telomere length and chromosome stability in stem cells, germline cells, and cancer cells. The telomerase ribonucleoprotein complex consists of two essential components, a catalytic protein component and an RNA molecule, that provide the template for telomeric repeat synthesis. Telomere shortening and telomerase activation in human somatic cells have been implicated in cell immortalization and cellular senescence. We previously reported that zebrafish have constitutive telomerase activity throughout life (Kishi, 2004; Kishi et al., 2003). To study the role of telomerase and telomere in cellular immortalization and organismal mortality, we assayed telomerase activity and telomere length in primary zebrafish fibroblasts, in spontaneously immortalized cell clones, and in zebrafish embryos and adult tissues. In both primary fibroblasts and spontaneously immortalized clones, telomeres were maintained at stable lengths with telomerase activity during a certain number of passages. During early development in vivo, telomere length was also stably maintained and telomer-ase activity was prominently detectable at all stages, indicating that there is maternal carryover of telomerase before the embryonic gene expression. To determine if telomere shortening occurs with concomitant maintain-ance of telomerase activity throughout life in vivo, we monitored both telomerase and telomere in muscle tissues from zebrafish of many different ages. Telomere length was similar among different ages up to 24-months, whereas stochastic variation of telomere length appeared with more advancing age, as describe already. Differences in telomere lengths among several different tissues from organs in adult zebrafish have not been determined but need to be elucidated, while we know that zebrafish have constitutive telomerase activity in all of the examined tissues throughout their lives. These findings suggest that there is a unique regulation of zebrafish telomerase during development and aging in vivo. In contrast to human tissues, since all zebrafish tissues examined had constitutively active telomerase, there must be some differences in tissue homeostasis via the species-specific telomerase and telomere regulation in situ among vertebrates during evolution. In any case, the presence of telomerase in these tissues may reflect the ease of immortalization of primary fish cells relative to human cells in culture, indeterminate growth, and remarkable regenerative ability throughout life.

It should be noted that telomere shortening may limit the regenerative capacity of cells in vivo by inducing cellular senescence characterized by a permanent growth arrest of cells with critically short telomeres. To examine whether organ regeneration is impaired by telomerase inhibition and telomere shortening in zebrafish in vivo, we monitored caudal fin regeneration after amputation in telomerase-knockdown adult zebrafish. Our study has shown that telomere shortening is caused in regenerated fins and inhibits a subpopulation of cells with critically short telomeres from entering the cell cycle. This subpopulation of regenerated cells with impaired proliferative capacity exhibited induction of SA-^-gal activity. These studies provide experimental evidence for the existence of an in vivo process of premature senescence induced by telomerase knockdown and critical telomere shortening that has functional impact on tissue regeneration in zebrafish.

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