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

Chen, Zhi, Xiong, Liling, Jin, Huili, Yu, Jiaxiao, Li, Xin, Fu, Huijia, Wen, Li, Qi, Hongbo, Tong, Chao, Saffery, Richard, Kilby, Mark D. and Baker, Philip N. (2021) Advanced maternal age causes premature placental senescence and malformation via dysregulated α-Klotho expression in trophoblasts. Aging Cell, 20 (7). ISSN 1474-9718

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Abstract

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

Item Type:	Article
Additional Information:	DATA AVAILABILITY STATEMENT: The data and materials described in the manuscript will be available upon reasonable request made to the corresponding authors, and delivery charges and agreement of usage may apply. The RNAseq data reported in this paper have been deposited in a public data depository under accession number HRA000693 and are publicly accessible at http://bigd.big.ac.cn/gsa-human Funding: National Key R&D Program of China. Grant Number: 2018YFC1004103; National Natural Science Foundation of China. Grant Numbers: 81871189, 81520108013, 82071675, 82001580; Chongqing Science and Technology Commission. Grant Number: cstc2017jcyjBX0045
Uncontrolled Keywords:	advanced maternal age,placenta,senescence,trophoblast,a-klotho
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	28 May 2025 13:30
Last Modified:	24 Jun 2025 13:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99330
DOI:	10.1111/acel.13417

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