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We used the aneurysmal <jats:italic>Fibulin-4<\/jats:italic><jats:sup><jats:italic>R\/R<\/jats:italic><\/jats:sup> mouse model to further unravel the underlying mechanisms of aneurysm formation. RNA sequencing of 3-month-old <jats:italic>Fibulin-4<\/jats:italic><jats:sup><jats:italic>R\/R<\/jats:italic><\/jats:sup> aortas revealed significant upregulation of senescence-associated secretory phenotype (SASP) factors and key senescence factors, indicating the involvement of senescence. Analysis of aorta histology and of vascular smooth muscle cells (VSMCs) in vitro confirmed the senescent phenotype of <jats:italic>Fibulin-4<\/jats:italic><jats:sup><jats:italic>R\/R<\/jats:italic><\/jats:sup> VSMCs by revealing increased SA-\u03b2-gal, p21, and p16 staining, increased IL-6 secretion, increased presence of DNA damage foci and increased nuclei size. Additionally, we found that p21 luminescence was increased in the dilated aorta of <jats:italic>Fibulin-4<\/jats:italic><jats:sup><jats:italic>R\/R<\/jats:italic><\/jats:sup>|p21-luciferase mice. Our studies identify a cellular aging cascade in Fibulin-4 aneurysmal disease, by revealing that <jats:italic>Fibulin-4<\/jats:italic><jats:sup><jats:italic>R\/R<\/jats:italic><\/jats:sup> aortic VSMCs have a pronounced SASP and a senescent phenotype that may underlie aortic wall degeneration. Additionally, we demonstrated the therapeutic effect of JAK\/STAT and TGF-\u03b2 pathway inhibition, as well as senolytic treatment on <jats:italic>Fibulin-4<\/jats:italic><jats:sup><jats:italic>R\/R<\/jats:italic><\/jats:sup> VSMCs in vitro. These findings can contribute to improved therapeutic options for aneurysmal disease aimed at reducing senescent cells.<\/jats:p>","DOI":"10.1038\/s41514-024-00154-4","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T10:02:42Z","timestamp":1718877762000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice"],"prefix":"10.1038","volume":"10","author":[{"given":"Sanne J. 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