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

Liling Xiong,Philip N Baker,Sisi Li,Li Wen,Chao Tong,Hongbo Qi,Ping Xu,Jiaxiao Yu,Huijia Fu,Xuan Ye,Richard Saffery,Zhi Chen,Yong Fu,Mark D Kilby,Rufei Gao

doi:10.1111/acel.13491

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.

Highlights

Maternal age has increased steadily over the past decades; the number of births to women in their early 40s rose by 2% from 2017 to 2018 in the UK, and the rate has risen almost continuously since 1985 (Martin et al, 2019)
These results show that the Advanced maternal age (AMA) placenta has SIRT1 deficiency beginning at the early stage of pregnancy, which may contribute to premature senescence and maldevelopment
Cellular senescence is characterized by irreversible growth arrest and altered function (Campisi & d'Adda di Fagagna, 2007) and can be divided into two types: replicative senescence, a permanent state of cell growth arrest that occurs after a limited number of cell divisions owing to telomere attrition, and premature senescence, a term used to describe a senescence-like state that can occur from aberrant oncogene expression

Summary

| INTRODUCTION

Maternal age has increased steadily over the past decades; the number of births to women in their early 40s rose by 2% from 2017 to 2018 in the UK, and the rate has risen almost continuously since 1985 (Martin et al, 2019). Limited evidence shows that SIRT1 is anti-inflammatory in trophoblasts of the human placenta (Lappas et al, 2011); SIRT2 is reported to be restricted to syncytiotrophoblasts, and its downregulation may induce necroptosis in the PE placenta (Hannan et al, 2017). These observations suggest potential crucial roles for sirtuins in the placenta, their roles in placental senescence remain largely unknown. Cytotrophoblasts (CTBs) derived from the trophectoderm of the blastocyst after implantation function as precursor cells of the human placenta and form the placental villous structure. We aimed to explore the role of sirtuins in AMA-associated placental senescence, as well as the underlying mechanism that involves EMT

| RESULTS

| DISCUSSION

Findings

| Ethics statement