tp53mut rescues the premature infertility of the telomerase deficient zebrafish. (A) quantification of tert −/− male fertility at 6 months of age (n_WT = 7, n_tert−/− = 7, n_tp53mut = 7, n_{tert−/− tp53mut} = 7) (B) quantification of tert −/− male fertility at 9 months of age (n_WT = 6, n_tert−/− = 7, n_tp53mut = 5, n_{tert−/− tp53mut} = 4 (C) quantification of tert −/− male fertility at 12 months of age (n_WT = 6, n_tert−/− = 5, n_tp53mut = 5, n_{tert−/− tp53mut} = 6). Each value in the graphic represents the mean of a minimum and maximum number of eggs of 5–7 crosses. Statistical tests were performed using a one-way ANOVA, **** p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05.

tp53 rescues early incidence of tert −/− cachexia and kyphosis. (A) representative images of 12-month-old zebrafish of different genotypes. Bar represents 1 cm. (B) quantification of aging phenotypes in adult zebrafish (n_WT = 28, n_tert−/− = 17, n_tp53mut = 12, n_{tert−/− tp53mut} = 25). (C) quantification of weight in adult zebrafish (n_WT = 28, n_tert−/− = 17, n_tp53mut = 12, n_{tert−/− tp53mut} = 25). Statistical tests were performed using a one-way ANOVA, **** p < 0.0001, *p < 0.05.

tp53 does not rescue chronic inflammation of the telomerase-deficient zebrafish. (A) RT-qPCR analysis of isg15 in head kidney (n_WT = 6, n_tert−/− = 6, n_p53−/− = 6, n_{tert−/− tp53mut} = 6). (B) RT-qPCR analysis of ifn-i in head kidney (n_WT = 6, n_tert−/− = 6, n_p53−/− = 6, n_{tert−/− tp53mut} = 6). (C) RT-qPCR analysis of mmp15a in head kidney (n_WT = 6, n_tert−/− = 6, n_p53−/− = 6, n_{tert−/− tp53mut} = 6). Statistical tests were performed using a one-way ANOVA, **p < 0.01, *p < 0.05.

Absence of telomerase reduces earlier and higher tumor incidence of tp53mut. (A) quantification of spontaneous tumors through macroscopic analysis (n_WT = 44, n_tert−/− = 40, n_p53−/− = 36, n_{tert−/− tp53mut} = 40). Log-rank test was performed to determine statistical differences between the different groups. ***p < 0.001, **p < 0.01. Loss of telomerase also modifies the tumour profile of tp53mut. (B) Example of haematoxylin and eosin (HE) staining of a soft tissue sarcoma (arrows, upper panel) and an intestinal adenocarcinoma (arrow, lower panel). Sarcoma of tp53mut expanded to the abdominal cavity, infiltrating adipose tissue, pancreas, liver and intestine and was histologically consistent with malignant peripheral nerve sheath tumor (MPNST). The carcinoma of tert −/− expanded and effaced the intestinal mucosa and submucosa (asterisk), corresponding to a loosely cellular, unencapsulated, poorly circumscribed neoplasm composed of polygonal cells arranged in poorly cohesive cords (black arrowhead). Original magnification, 5x (bar 500 μm) and 20x (bar 100 μm). (C) quantification of spontaneous tumors through histological analysis in 12 months old fish (n_WT = 25, n_tert−/− = 59, n_p53−/− = 22, n_{tert−/− tp53mut} = 21). Number of tumors were not significantly different between mutants (Chi-square test).

Lack of telomerase rescues the lifespan of tp53 deficient zebrafish. quantification of survival of zebrafish from 6 to 30 months after birth. Median lifespans tp53mut: 14 months, tert −/−: 15.5 months, WT and tert −/− tp53mut: 20.5 months (n_WT = 33, n_tert−/− = 28, n_p53−/− = 34, n_{tert−/− tp53mut} = 29). Log-rank test was performed to determine statistical differences between the different groups. ***p < 0.001, *p < 0.05.