Age‐Associated Senescence of Decidual Macrophages: A Key Mediator of Adverse Pregnancy Outcomes in Advanced Maternal Age

ABSTRACT

Senescence of immune cells can drive senescence of solid organs, and reversing immune cell senescence ameliorates organismal senescence phenotypes. As the second largest subset of decidual immune cells, macrophages play a critical role in pregnancy. However, whether decidual macrophages (DM) exhibit senescence in advanced maternal age (AMA) pregnancies (≥ 35 years old) and their involvement in AMA‐related adverse outcomes remain undefined. This study elucidates the phenotypic and functional characteristics of DM in AMA pregnancies through clinical samples, animal models, and in vitro experiments. It clarifies the mechanisms underlying DM aging and explores novel intervention strategies to reverse DM aging and improve pregnancy outcomes in AMA pregnancies. We found that the presence of DM senescence in AMA pregnancies, manifested by an increased proportion of the pro‐inflammatory phenotype M1, increased expression of senescence markers (P53 and SA‐β‐Gal), and decreased phagocytic capacity—all associated with the development of adverse outcomes in AMA. The mechanistic basis of DM senescence involves two key pathways: on the one hand, low expression of forkhead box O3 causes DM senescence by downregulating mitophagy. On the other hand, elevated IL‐6 in the uterine microenvironment exacerbates senescence. Adoptive transfer of young mouse bone marrow‐derived macrophages significantly rescues embryo resorption rates and placental development in AMA pregnant mice. Overall, our study uncovers novel mechanisms and therapeutic strategies for AMA‐related adverse pregnancy outcomes through a new perspective of uterine macrophage senescence, providing new intervention ideas to improve adverse pregnancy outcomes in AMA.