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<p>Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and senescence. However, the consequences of these events for the organism are not yet understood. Here, we show that <i>sting</i> is responsible for premature aging of telomerase-deficient zebrafish. We generated <i>sting-/- tert-/-</i> double-mutant animals and observed a thorough rescue of <i>tert-/-</i> phenotypes. At the cellular level, lack of cGAS-STING in <i>tert</i> mutants resulted in reduced senescence, increased cell proliferation, and decreased inflammation despite similarly short telomeres. Critically, absence of <i>sting</i> function resulted in dampening of the DNA damage response and reduced p53 levels. At the organism level, <i>sting-/- tert-/-</i> zebrafish regained fertility, showed delayed cachexia, and decreased cancer incidence, resulting in increased healthspan and lifespan of telomerase mutant animals.</p>

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cGAS-STING are responsible for premature aging of telomerase-deficient zebrafish

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月9日

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  • Naz Şerifoğlu,
  • Giulia Allavena,
  • Bruno Lopes-Bastos,
  • Marta Marzullo,
  • Andreia Marques,
  • Pauline Colibert,
  • Pavlos Bousounis,
  • Eirini Trompouki,
  • Miguel Godinho Ferreira

摘要

Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and senescence. However, the consequences of these events for the organism are not yet understood. Here, we show that sting is responsible for premature aging of telomerase-deficient zebrafish. We generated sting-/- tert-/- double-mutant animals and observed a thorough rescue of tert-/- phenotypes. At the cellular level, lack of cGAS-STING in tert mutants resulted in reduced senescence, increased cell proliferation, and decreased inflammation despite similarly short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and reduced p53 levels. At the organism level, sting-/- tert-/- zebrafish regained fertility, showed delayed cachexia, and decreased cancer incidence, resulting in increased healthspan and lifespan of telomerase mutant animals.