Potential Model Systems for Premature Aging Syndromes in Zebrafish

There are no perfect models for human aging, but zebrafish are vertebrates, and therefore are more closely related to human than commonly used invertebrate models. They are more likely to be similar to humans in many biological and biomedical traits such as genes, developmental processes, anatomy, physiology, behaviors, and diseases. This is an obvious advantage because invertebrate animals do not share these traits with humans. The invertebrates are more extensively used in identifications and comparisons of fundamental aging mechanisms, likely conserved in entire organisms rather than biologically complex traits in pathophysiology at the cellular and biochemical levels of organization where zebrafish share many features with humans.

Most premature aging models in vertebrates are derived from mutant and genetically manipulated mice. Zebrafish will probably become an alternative model for study of premature aging to recapitulate some of the human progeroid syndromes, such as ataxia telengiectasia (A-T), Fanconi anemia (FA), dyskeratosis congenita (DC), and Hutchinson-Gilford progeria syndrome (HGPS), because we have known that the molecular structures and functions of the genes and proteins responsible for these diseases are highly conserved between zebrafish and humans.

Functional aberrations of ATM protein cause a genetic disease A-T. We have recently demonstrated that zebrafish ATM (zATM) is functionally conserved at least in part because zebrafish embryos with disrupted ATM showed radiation hypersensitivity as observed in A-T patients and ATM-knockout mice (Imamura and Kishi, 2005). Since multiple aging/senescence-associated markers are readily monitored, it is worthwhile trying to identify premature senescence phenotypes in ATM-deficient zebrafish embryos as a representative model. Moreover, once a stable model system of zebrafish for human progeroid syndromes including A-T is established, it will become a powerful tool for characterizing molecular functions in the signal transduction pathway and using chemical genetic approaches for drug screening.

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