Abstract

BACKGROUND

Advanced maternal age is associated with decreased oocyte quantity and quality as well as uterine and placental dysfunctions. These changes lead to infertility, pregnancy complications and birth defects in the offspring. As the mean age of giving birth is increasing worldwide, prevention of age-associated infertility and pregnancy complications, along with the more frequent use of ART, become extremely important. Currently, significant research is being conducted to unravel the mechanisms underlying female reproductive aging. Among the potential mechanisms involved, recent evidence has suggested a contributing role for cellular senescence, a cellular state of irreversible growth arrest characterized by a hypersecretory and pro-inflammatory phenotype. Elucidating the role of senescence in female reproductive aging holds the potential for developing novel and less invasive therapeutic measures to prevent or even reverse female reproductive aging and increase offspring wellbeing.

OBJECTIVE AND RATIONALE

The review will summarize the positive and negative implications of cellular senescence in the pathophysiology of the female reproductive organs during aging and critically explore the use of novel senotherapeutics aiming to reverse and/or eliminate their detrimental effects. The focus will be on major senescence mechanisms of the ovaries, the uterus, and the placenta, as well as the potential and risks of using senotherapies that have been discovered in recent years.

SEARCH METHODS

Data for this review were identified by searches of MEDLINE, PubMed and Google Scholar. References from relevant articles using the search terms ‘Cellular Senescence’, ‘Aging’, ‘Gestational age’, ‘Maternal Age’, ‘Anti-aging’, ‘Uterus’, ‘Pregnancy’, ‘Fertility’, ‘Infertility’, ‘Reproduction’, ‘Implant’, ‘Senolytic’, ‘Senostatic’, ‘Senotherapy’ and ‘Senotherapeutic’ where selected. A total of 182 articles published in English between 2005 and 2020 were included, 27 of which focus on potential senotherapies for reproductive aging. Exclusion criteria were inclusion of the terms ‘male’ and ‘plants’.

OUTCOMES

Aging is a major determinant of reproductive wellbeing. Cellular senescence is a basic aging mechanism, which can be exploited for therapeutic interventions. Within the last decade, several new strategies for the development and repurposing of drugs targeting senescent cells have emerged, such as modulators of the anti-inflammatory response, oxidative stress, DNA damage, and mitochondria and protein dysfunctions. Several studies of female reproductive aging and senotherapies have been discussed that show promising results for future interventions.

WIDER IMPLICATIONS

In most countries of the Organization for Economic Co-operation and Development, the average age at which women give birth is above 30 years. Currently, in countries such as the Netherlands, Australia, Spain, Finland, Germany and the UK, birth rates among 30- to 34-year-olds are now higher than in any other age groups. This review will provide new knowledge and scientific advancement on the senescence mechanisms during female reproductive aging, and benefit fundamental and clinical scientists and professionals in the areas of reproduction, cancer, immunobiology and fibrosis.

中文翻译：

---

细胞衰老在女性生殖衰老中的作用和治疗干预的潜力

摘要

背景

高龄产妇与卵母细胞数量和质量下降以及子宫和胎盘功能障碍有关。这些变化会导致后代不育、妊娠并发症和出生缺陷。随着全球平均分娩年龄的增加，预防与年龄相关的不孕症和妊娠并发症以及更频繁地使用抗逆转录病毒疗法变得极为重要。目前，正在进行大量研究以揭示女性生殖衰老的机制。在所涉及的潜在机制中，最近的证据表明细胞衰老具有促进作用，细胞衰老是一种以高分泌和促炎表型为特征的不可逆生长停滞的细胞状态。

目标和理由

该综述将总结细胞衰老对衰老过程中女性生殖器官病理生理学的积极和消极影响，并批判性地探索旨在逆​​转和/或消除其有害影响的新型 senotherapeutics 的用途。重点将放在卵巢、子宫和胎盘的主要衰老机制，以及使用近年来发现的衰老疗法的潜力和风险上。

搜索方法

本次审查的数据是通过搜索 MEDLINE、PubMed 和 Google Scholar 确定的。使用搜索词“细胞衰老”、“衰老”、“孕龄”、“孕龄”、“抗衰老”、“子宫”、“怀孕”、“生育力”、“不孕症”、“ Reproduction”、“Implant”、“Senolytic”、“Senostatic”、“Senotherapy”和“Senotherapeutic”（如果选择）。共纳入 2005 年至 2020 年间以英文发表的 182 篇文章，其中 27 篇关注潜在的生殖衰老疗法。排除标准是包含术语“男性”和“植物”。

结果

衰老是生殖健康的主要决定因素。细胞衰老是一种基本的衰老机制，可用于治疗干预。在过去十年中，出现了几种针对衰老细胞的药物开发和再利用的新策略，例如抗炎反应调节剂、氧化应激、DNA 损伤以及线粒体和蛋白质功能障碍。已经讨论了几项关于女性生殖衰老和衰老疗法的研究，这些研究显示了未来干预的有希望的结果。

更广泛的影响

在经济合作与发展组织的大多数国家，妇女的平均生育年龄在 30 岁以上。目前，在荷兰、澳大利亚、西班牙、芬兰、德国和英国等国家，30 至 34 岁人群的出生率现在高于任何其他年龄组。本综述将为女性生殖衰老过程中的衰老机制提供新的知识和科学进展，并使生殖、癌症、免疫生物学和纤维化领域的基础和临床科学家和专业人员受益。