cGAS-STING are responsible for premature aging of telomerase-deficient zebrafish
Naz Şerifoğlu1, Giulia Allavena1, Bruno Lopes-Bastos1
1Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR7284, INSERM U1081, Université Cote d'Azur, 06107, Nice, France.
Abstract:
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.
Insights
Short telomeres trigger inflammation and aging via the cGAS-STING pathway. Blocking STING in telomerase-deficient zebrafish reversed aging, reduced inflammation, and extended lifespan, revealing STING as a key aging regulator.
Area of Science:
- Molecular Biology
- Genetics
- Immunology
Background:
- Telomere shortening is a hallmark of aging, triggering DNA damage responses and cellular senescence.
- In vitro studies link short telomeres to the cGAS-STING innate immune pathway, causing inflammation and senescence.
- The in vivo consequences of telomere-induced cGAS-STING activation remain largely unknown.
Purpose of the Study:
- To investigate the role of the cGAS-STING pathway in organismal aging due to telomere shortening.
- To determine if STING mediates premature aging phenotypes in telomerase-deficient zebrafish.
- To explore therapeutic potential of targeting STING to ameliorate aging.
Main Methods:
- Generated double-mutant zebrafish lacking both telomerase (tert-/-) and STING (sting-/-).
- Assessed cellular phenotypes including senescence, proliferation, and inflammation in mutant zebrafish.
- Analyzed organismal phenotypes such as fertility, cachexia, cancer incidence, healthspan, and lifespan.
Main Results:
- Absence of STING rescued premature aging phenotypes in telomerase-deficient zebrafish.
- Lack of cGAS-STING signaling reduced cellular senescence and inflammation despite short telomeres.
- STING deficiency dampened DNA damage response and p53 levels.
- Double mutants exhibited restored fertility, delayed cachexia, reduced cancer, and increased lifespan.
Conclusions:
- STING is a critical mediator of premature aging caused by telomere shortening in vivo.
- Targeting the cGAS-STING pathway can mitigate aging phenotypes and extend healthspan/lifespan in telomere-compromised organisms.
- This study highlights the cGAS-STING pathway as a key link between telomere maintenance and organismal aging.
