Female fecundity declines in a nonlinear manner with age during the reproductive years, even as ovulatory cycles continue, which reduces female fertility, disrupts metabolic homeostasis, and eventually induces various chronic diseases. Despite this, the aging-related cellular and molecular changes in human ovaries that occur during these reproductive years have not been elucidated. Here, single-cell RNA sequencing (scRNA-seq) of human ovaries is performed from different childbearing ages and reveals that the activation of the pyroptosis pathway increased with age, mainly in macrophages. The enrichment of pyroptotic macrophages leads to a switch from a tissue-resident macrophage (TRM)-involve immunoregulatory microenvironment in young ovaries to a pyroptotic monocyte-derived macrophage (MDM)-involved proinflammatory microenvironment in middle-aged ovaries. This remolded ovarian immuno-microenvironment further promotes stromal cell senescence and accelerated reproductive decline. This hypothesis is validated in a series of cell and animal experiments using GSDMD-KO mice. In conclusion, the work expands the current understanding of the ovarian aging process by illustrating a pyroptotic macrophage-involved immune mechanism, which has important implications for the development of novel strategies to delay senescence and promote reproductive health.
Keywords: aging; cell death; developmental trajectory; immune cells; intercellular communication; macrophage; ovary; pyroptosis; senescence; single-cell RNA sequencing.
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.