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Traditionally regarded as a central organ involved in regulating aging, the small intestine (SI) communicates with remote organs. However, the mechanisms underlying its role in CFs senescence remain undefined. We aimed to clarify whether the SI epithelium-derived exosomes (SI-exos) and their contained microRNAs could regulate CFs senescence and participate in deteriorating cardiac fibrosis during aging. Systemic administration of aged SI-exos exerted deleterious effects on the hearts of young recipient mice, as evidenced by exacerbated cardiac aging, inflammation, fibrosis, and the resulting poorer cardiac function. In vitro studies revealed that aged SI-exos could induce the activation and senescence of young CFs, while treatment with young SI-exos mitigated the activation and senescence of aged CFs. Mechanistic investigation identified that miR-223-3p was a common molecule significantly increased both in aged SI-exos and aged serum-exos. Incubation of young CFs with miR-223-3p mimics exacerbated cellular activation and senescence by cooperatively suppressing target genes: RASA1 and KLF15. In contrast, miR-223-3p inhibitor could rescue D-gal-induced CFs activation and senescence. Overexpression of RASA1 or KLF15 significantly rescued miR-223-3p-induced CFs activation and senescence. Summarily, our findings demonstrate for the first time that miR-223-3p enrichment in aged SI-exos, and its suppression of RASA1 and KLF15 in CFs, is a novel potential mechanism exacerbating cardiac aging and fibrosis. Targeting miR-223-3p mediated pathological communication between the aged SI epithelium, and CFs might be an effective strategy for cardioprotection during aging.<\/jats:p>","DOI":"10.1093\/gerona\/glaf183","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T11:55:22Z","timestamp":1755172522000},"source":"Crossref","is-referenced-by-count":4,"title":["Exosomes from small intestinal epithelium mediate cardiac fibrosis during aging"],"prefix":"10.1093","volume":"80","author":[{"given":"Yijun","family":"He","sequence":"first","affiliation":[{"name":"Division of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University , Nanjing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanbei","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University , 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