The role of cellular senescence in ageing of the placenta.

Aberrant placental ageing is implicated in a high percentage of birth complications, stillbirths and neonatal deaths. Understanding how this complex organ is established and maintained for the 9-10 months of pregnancy and then how and why it undergoes the physiological changes that result in labour at term is therefore of enormous clinical importance. In this review, we assess the evidence that placental ageing results from cellular senescence, a state of terminal proliferation arrest accompanied by characteristic morphological and metabolic changes including a shift to a pro-inflammatory phenotype. We discuss how senescence both contributes to placental formation during cytotrophoblast fusion, and to the changes necessary for labour onset, such as cervical remodelling and increased sterile inflammatory signalling. Based on evidence from human clinical studies and experimental interventions in mice, we assess possible biochemical pathways that may drive senescence, and speculate on how aberrant senescence in the placenta may contribute to pre-eclampsia, pre-term birth and stillbirth.