The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions

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.

Keywords: ART; DNA damage; aging; atresia; cell signaling; cellular senescence; cytokines; ovarian aging; senolytic drugs; senotherapy.

Figure 1.

Reproductive senescence timeline. Senescent cells accumulate during aging and pathologies. Senescence has beneficial effects during youth to ensure proper embryo development and parturition but has a detrimental impact on uterine, placental and ovarian function later in life.

Figure 2.

Molecular pathways and targets of reproductive senescence. Female reproductive structures undergoing aging and pathological processes associated with stress and damage-induced senescence are depicted. Molecular mechanisms triggering cellular senescence (indicated in blue boxes) are listed in addition to the senotherapeutics that can eliminate senescent cells and/or alleviate their detrimental effects, providing beneficial effects to multiple reproductive tissues (indicated in green boxes). ROS, reactive oxygen species; AGEs, advanced glycation end products; SASP, senescence associated secretory phenotype; NAD+, nicotinamide adenine dinucleotide; NAC, N-acetyl-l-cysteine; CoQ10, coenzyme Q10.