title: Premature aging in telomerase-deficient zebrafish.
abstract: The study of telomere biology is crucial to the understanding of aging and cancer. In the pursuit of greater knowledge in the field of human telomere biology, the mouse has been used extensively as a model. However, there are fundamental differences between mouse and human cells. Therefore, additional models are required. In light of this, we have characterized telomerase-deficient zebrafish (Danio rerio) as the second vertebrate model for human telomerase-driven diseases. We found that telomerase-deficient zebrafish show p53-dependent premature aging and reduced lifespan in the first generation, as occurs in humans but not in mice, probably reflecting the similar telomere length in fish and humans. Among these aging symptoms, spinal curvature, liver and retina degeneration, and infertility were the most remarkable. Although the second-generation embryos died in early developmental stages, restoration of telomerase activity rescued telomere length and survival, indicating that telomerase dosage is crucial. Importantly, this model also reproduces the disease anticipation observed in humans with dyskeratosis congenita (DC). Thus, telomerase haploinsufficiency leads to anticipation phenomenon in longevity, which is related to telomere shortening and, specifically, with the proportion of short telomeres. Furthermore, p53 was induced by telomere attrition, leading to growth arrest and apoptosis. Importantly, genetic inhibition of p53 rescued the adverse effects of telomere loss, indicating that the molecular mechanisms induced by telomere shortening are conserved from fish to mammals. The partial rescue of telomere length and longevity by restoration of telomerase activity, together with the feasibility of the zebrafish for high-throughput chemical screening, both point to the usefulness of this model for the discovery of new drugs able to reactivate telomerase in individuals with DC.
authors.affiliation: Telomerase, Aging and Cancer Group, Research Unit, Department of Surgery, CIBERehd, University Hospital "Virgen de la Arrixaca", Murcia, Spain.
authors.forename: Monique
authors.initials: M
authors.lastname: Anchelin
authors.forename: Francisca
authors.initials: F
authors.lastname: Alcaraz-Pérez
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Martínez
authors.forename: Manuel
authors.initials: M
authors.lastname: Bernabé-García
authors.forename: Victoriano
authors.initials: V
authors.lastname: Mulero
authors.forename: María L
authors.initials: ML
authors.lastname: Cayuela
mesh_terms: D019588:Aging, Premature / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001947:Breeding; D002869:Chromosome Aberrations; D006801:Humans; D008136:Longevity; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D019098:Telomerase / Q000172:deficiency* / Q000378:metabolism; D016615:Telomere / Q000235:genetics; D059506:Telomere Shortening; D013737:Testis / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D019098:Telomerase