孕妇年龄是影响孕妇妊娠成功的最重要因素之一。子宫老化是老年女性妊娠失败的主要原因。然而，子宫衰老如何影响子宫容受性和蜕膜化尚不清楚。在这项研究中，使用自然衰老的一岁雌性小鼠来研究母亲年龄对妊娠早期胚胎着床的影响。在我们的研究中，我们发现老年小鼠的子宫容受性异常。衰老的小鼠子宫表明核 LAMIN A 减少，而 PRELAMIN A 和 PROGERIN 增加。在老年小鼠子宫中，细胞质部分中的双链DNA（dsDNA）显着增加。 PROGERIN 在小鼠子宫上皮细胞和上皮类器官中过度表达会导致核 DNA 泄漏和子宫容受性受损。衰老小鼠子宫中DNase I、DNase II和TREX1明显减少。使用外源 DNA 或 STING 激动剂治疗可显着下调子宫容受性标志物并激活 cGAS-STING 通路。老年小鼠的子宫雌激素（E2）浓度显着增加。去势小鼠经高水平E2处理后，PROGERIN和细胞质DNA显着增加，cGAS-STING通路激活。 CD14在老化子宫中显着增加。宫内注射CD14会抑制胚胎着床。对培养的上皮细胞或上皮类器官进行体外 CD14 处理会降低子宫容受性。 STING 抑制剂可以部分挽救老年小鼠的子宫异常。总之，老年小鼠子宫中子宫 PROGERIN 的增加导致细胞质 DNA 积累和 cGAS-STING 通路激活。衰老子宫中的 CD14 分泌会损害子宫容受性。© 2024 作者。衰老细胞由解剖学会和约翰·威利出版

Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E2) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E2, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.