Lack of telomerase rescues cancer and shorter lifespan of zebrafish tp53 mutants

Abstract

Abstract Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 that result in apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Zebrafish have restricted telomerase expression and telomeres shorten to critical length during their lifespan. Telomerase deficient zebrafish (tert-/-) is a premature model of aging, that anticipates both short telomeres and aging phenotypes. tert-/- zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to impaired tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia and kyphosis. These cellular defects, tissue impairments and degenerative phenotypes contribute to premature death of tert-/-zebrafish. Mutation in tp53rescues accelerated aging of tert-/-zebrafish by enhancing proliferative capacity and restoring tissue homeostasis. However, the consequences of tp53 mutation at the organism level of tert-/-zebrafish were still undetermined. We show that tp53 mutation extends fertility, reduces aging phenotypes and prolongs life span. However, tp53 mutation does not rescue healthspan of tert-/- zebrafish, as it leads to increased inflammation and higher incidence of spontaneous tumors.