Advanced maternal age-associated SIRT1 deficiency compromises trophoblast epithelial−mesenchymal transition through an increase in vimentin acetylation

Xiong, Liling, Ye, Xuan, Chen, Zhi, Fu, Huijia, Li, Sisi, Xu, Ping, Yu, Jiaxiao, Wen, Li, Gao, Rufei, Fu, Yong, Qi, Hongbo, Kilby, Mark D., Saffery, Richard, Baker, Philip N. and Tong, Chao (2021) Advanced maternal age-associated SIRT1 deficiency compromises trophoblast epithelial−mesenchymal transition through an increase in vimentin acetylation. Aging Cell, 20 (10). ISSN 1474-9718

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Abstract

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.

Item Type:	Article
Additional Information:	Data Availability Statement: The data and materials described in the manuscript will be available upon reasonable request to the corresponding authors; delivery charges and a material transfer agreement may apply. The proteomics data reported in this paper have been deposited in a public data depository under accession number PXD026574 and are publicly accessible at https://www.iprox.org. Funding Information: This study was funded by the National Key R&D Program of China (2018YFC1004103), the National Natural Science Foundation of China (82171662, 81671488, 81771613, 81701479, 81871189, 82071675, and 82001580), and the Chongqing Commission of Health (2019GDRC012 and 2020MSXM037).
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:	27 May 2025 15:30
Last Modified:	29 May 2025 00:09
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99328
DOI:	10.1111/acel.13491

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