Allavena, G.; Rossiello, F.; Idilli, A. I.; Mione, M.; di Fagagna, F. d.; Ferreira, M. G.; Lopes-Bastos, B.

Telomerase activity is restricted in somatic cells, resulting in progressive telomere shortening. Telomere erosion eventually activates the DNA damage response (DDR), inducing cell-cycle arrest and cellular senescence or apoptosis. We previously reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which are critical mediators of DDR activation. Blocking tncRNAs with telomeric antisense oligonucleotides (tASOs) suppresses in vivo DDR signaling and its downstream effects. Here, we show that tASO-mediated inhibition of telomeric DDR in second-generation tert-/- zebrafish embryos with critically short telomeres leads to improved developmental outcomes and rescues premature aging phenotypes, including enhanced survival. Notably, a single tASO treatment administered at the one-cell stage of first-generation tert-/- embryos leads to enhanced fertility observed in 6-month-old adults. Overall, these findings demonstrate that tASO-based inhibition of telomeric DDR is sufficient to effectively rescue premature aging phenotypes in zebrafish.