Advanced maternal age causes premature placental senescence and malformation via dysregulated α-Klotho expression in trophoblasts

Advanced maternal age (AMA) pregnancy is associated with higher risks of adverse perinatal outcomes, which may result from premature senescence of the placenta. alpha-Klotho is a well-known antiaging protein; however, its expression and effect on the placenta in AMA pregnancies have not yet been fully elucidated. The expression patterns of alpha-Klotho in mouse and human placentas from AMA pregnancies were determined by Western blotting and immunohistochemistry (IHC) staining. alpha-Klotho 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 alpha-Klotho in JAR cells were first screened by mRNA sequencing in alpha-Klotho-knockdown and control JAR cells and then validated. alpha-Klotho-deficient mice were generated by injecting klotho-interfering adenovirus (Ad-Klotho) via the tail vein on GD8.5. Ablation of alpha-Klotho 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 alpha-Klotho significantly improved invasion but did not alter the expression of senescence biomarkers. alpha-Klotho-deficient mice exhibited placental malformation and, consequently, lower placental and fetal weights. In conclusion, AMA results in reduced alpha-Klotho 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.

Automated summary

Reduced expression of alpha-Klotho in the placenta of advanced maternal age pregnancies may lead to premature senescence and loss of invasion, ultimately resulting in placental malformation and adverse perinatal outcomes.