Universität zu Köln

Ballhysa, Eugen ORCID: 0000-0002-9715-8685 (2025). Deciphering the role of cGAS/STING signaling in vivo using the short-lived turquoise killifish Nothobranchius furzeri. PhD thesis, Universität zu Köln.

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Abstract

The cGAS/STING pathway is a central innate immune signaling pathway whose chronic activation has been implicated in multiple age-related pathologies, yet its impact on life span itself is unknown. Here we engineered knockouts of pathway components in the killifish Nothobranchius furzeri, and assessed their impact on physiology and aging. In vitro, loss of killifish cGAS and STING mitigated DNA damage-induced senescence in cultured primary fibroblasts, while cGAS loss uniquely triggered low levels of basal DNA damage. In vivo, cGAS knockout unexpectedly led to transcriptional signatures indicative of low-grade inflammation. It also attenuated changes in gene expression in response to DNA damage in young animals and age-related changes in the transcriptome of old animals, suggesting dampening of senescence and aging. Necroscopy indicated that STING KO appeared to have less infection rates and that tissue pathology tended to be milder overall in both mutants, though some tissues showed a trend for enhanced sterile macrophage infiltration. Our observation of cGAS-specific effects related to the DNA damage response and ageing transcriptome hint towards functions separate from canonical cGAS/STING pathway. Despite the attenuated aging signatures, however, longevity of cGAS or STING mutants was not significantly different from that of wild type. Our findings reveal a potential tradeoff, where inhibiting the cGAS/STING pathway alleviates age-related signatures, but increases sterile inflammation, offsetting potential beneficial effects on lifespan.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Ballhysa, Eugen eugen.ballhysa@age.mpg.de orcid.org/0000-0002-9715-8685 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-782515
Date:	12 May 2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Natural sciences and mathematics
Uncontrolled Keywords:	Keywords Language Inflammaging English Killifish English cGAS/STING English
Date of oral exam:	19 March 2025
Referee:	Name Academic Title Antebi, Adam Professor
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78251