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The expression patterns of \u03b1\u2010Klotho in mouse and human placentas from AMA pregnancies were determined by Western blotting and immunohistochemistry (IHC) staining. \u03b1\u2010Klotho expression in JAR cells was manipulated to investigate its role in trophoblastic senescence, and transwell assays were performed to assess trophoblast invasion. The downstream genes regulated by \u03b1\u2010Klotho in JAR cells were first screened by mRNA sequencing in \u03b1\u2010Klotho\u2010knockdown and control JAR cells and then validated. \u03b1\u2010Klotho\u2010deficient mice were generated by injecting <jats:italic>klotho<\/jats:italic>\u2010interfering adenovirus (Ad\u2010Klotho) via the tail vein on GD8.5. Ablation of \u03b1\u2010Klotho resulted in not only a senescent phenotype and loss of invasiveness in JAR cells but also a reduction in the transcription of cell adhesion molecule (CAM) genes. Overexpression of \u03b1\u2010Klotho significantly improved invasion but did not alter the expression of senescence biomarkers. \u03b1\u2010Klotho\u2010deficient mice exhibited placental malformation and, consequently, lower placental and fetal weights. In conclusion, AMA results in reduced \u03b1\u2010Klotho expression in placental trophoblasts, therefore leading to premature senescence and loss of invasion (possibly through the downregulation of CAMs), both of which ultimately result in placental malformation and adverse perinatal outcomes.<\/jats:p>","DOI":"10.1111\/acel.13417","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T13:26:22Z","timestamp":1623245182000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Advanced maternal age causes premature placental senescence and malformation via dysregulated \u03b1\u2010Klotho expression in trophoblasts"],"prefix":"10.1111","volume":"20","author":[{"given":"Zhi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Obstetrics The First Affiliated Hospital of Chongqing Medical University Chongqing China"},{"name":"State Key Laboratory of Maternal and Fetal 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