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Pré-Publication, Document De Travail Année : 2024

cGAS-STING is responsible for aging of telomerase deficient zebrafish.

Résumé

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 inflammation and senescence. However, the consequences of these events to 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 mutants 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 low inflammation despite similar short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and low p53 levels. At the organism level, sting-/- tert-/- zebrafish regained fertility, delayed cachexia, and cancer incidence, resulting in increased healthspan and lifespan of telomerase mutants.
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Dates et versions

hal-04502630 , version 1 (13-03-2024)

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Naz Serifoglu, Giulia Allavena, Bruno Bastos-Lopes, Marta Marzullo, Pavlos Bousounis, et al.. cGAS-STING is responsible for aging of telomerase deficient zebrafish.. 2024. ⟨hal-04502630⟩
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