TY - JOUR TI - Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish AU - El Maï, Mounir AU - Marzullo, Marta AU - de Castro, Inês Pimenta AU - Ferreira, Miguel Godinho A2 - Valenzano, Dario Riccardo A2 - Tyler, Jessica K A2 - Demaria, Marco VL - 9 PY - 2020 DA - 2020/05/19 SP - e54935 C1 - eLife 2020;9:e54935 DO - 10.7554/eLife.54935 UR - https://doi.org/10.7554/eLife.54935 AB - Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence. KW - telomeres KW - apoptosis KW - senescence KW - p53 KW - AKT KW - aging JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -