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Advanced Maternal Age-associated SIRT1 Deficiency Compromises Trophoblast Epithelial-Mesenchymal Transition through an Increase in Vimentin Acetylation

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posted on 17.11.2021, 10:21 by Liling Xiong, Xuan Ye, Zhi Chen, Huijia Fu, Sisi Li, Ping Xu, Jiaxiao Yu, Li Wen, Rufei Gao, Yong Fu, Hongbo Qi, Mark D Kilby, Richard Saffery, Philip N Baker, Chao Tong
Advanced maternal age (AMA) pregnancies are rapidly increasing and are associated with aberrant trophoblast cell function, poor placentation, and unfavorable pregnancy outcomes, presumably due to premature placental senescence. SIRT1 is an NAD+-dependent deacetylase with well-known antiaging effects, but its connection with placental senescence is unreported. In this study, human term placentas and first-trimester villi were collected from AMA and normal pregnancies, and a mouse AMA model was established by cross breeding young and aged male and female C57 mice. SIRT1 expression and activity in HTR8/SVneo cells were genetically or pharmacologically manipulated. Trophoblast-specific Sirt1-knockout (KO) mouse placentas were generated by mating Elf5-Cre and Sirt1fl/fl mice. Trophoblast cell mobility was assessed with transwell invasion and wound-healing assays. SIRT1-binding proteins in HTR8/SVneo cells and human placental tissue were identified by mass spectrometry. We identified SIRT1 as the only differentially expressed sirtuin between AMA and normal placentas. It is downregulated in AMA placentas early in the placental life cycle and is barely impacted by paternal age. SIRT1 loss upregulates P53 acetylation and P21 expression and impairs trophoblast invasion and migration. Sirt1-KO mouse placentas exhibit senescence markers and morphological disruption, along with decreased fetal weight. In trophoblasts, SIRT1 interacts with vimentin, regulating its acetylation. In conclusion, SIRT1 promotes trophoblast epithelial−mesenchymal transition (EMT) to enhance invasiveness by modulating vimentin acetylation. AMA placentas are associated with premature senescence during placentation due to SIRT1 loss. Therefore, SIRT1 may be an antiaging therapeutic target for improving placental development and perinatal outcomes in AMA pregnancies.

Funding

National Key R&D Program of China. Grant Number: 2018YFC1004103

National Natural Science Foundation of China. Grant Numbers: 82171662, 81671488, 81771613, 81871189, 82071675, 82001580

the Chongqing Commission of Health. Grant Numbers: 2019GDRC012, 2020MSXM037

History

Citation

AGING CELL, 20 (10), 2021, e13491

Author affiliation

College of Life Sciences, University of Leicester

Version

VoR (Version of Record)

Published in

AGING CELL

Volume

20

Issue

10

Publisher

WILEY

issn

1474-9718

eissn

1474-9726

Acceptance date

19/09/2021

Copyright date

2021

Available date

17/11/2021

Language

English