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Aging Cell

Title:		Advanced Maternal Age-associated SIRT1 Deficiency Compromises Trophoblast Epithelial-Mesenchymal Transition through an Increase in Vimentin Acetylation
Author(s):		Xiong L; Ye X; Chen Z; Fu H; Li S; Xu P; Yu J; Wen L; Gao R; Fu Y; Qi H; Kilby MD; Saffery R; Baker PN; Tong C;
Address:		"Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. Ministry of Education-International Collaborative Laboratory of Reproduction and Development, Chongqing, China. State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China. Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China. Institute of Metabolism and System Research, University of Birmingham, Edgbaston, UK. Cancer, Disease and Developmental Epigenetics, Murdoch Children's Research Institute, Parkville, Victoria, Australia. College of Life Sciences, University of Leicester, Leicester, UK"
Journal Title:		Aging Cell
Year:		2021
Volume:		20211003
Issue:		10
Page Number:		e13491 -
DOI:		10.1111/acel.13491
ISSN/ISBN:		1474-9726 (Electronic) 1474-9718 (Print) 1474-9718 (Linking)
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 Sirt1(fl/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"
Keywords:		Acetylation Aged Animals Epithelial-Mesenchymal Transition/*immunology Female Humans Maternal Age Mice Pregnancy Sirtuin 1/*metabolism Trophoblasts/*metabolism Vimentin/*adverse effects Sirt1 advanced maternal age epithelial-mesenchymal transition placent;
Notes:		"MedlineXiong, 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 Tong, Chao eng Research Support, Non-U.S. Gov't England 2021/10/05 Aging Cell. 2021 Oct; 20(10):e13491. doi: 10.1111/acel.13491. Epub 2021 Oct 3"