Novel insights into reproductive ageing and menopause from genomics

The post-reproductive phase or menopause in females is triggered by a physiological timer that depends on a threshold of follicle number in the ovary. Curiously, reproductive senescence appears to be decoupled from chronological age and is instead thought to be a function of physiological ageing. Ovarian ageing is associated with a decrease in oocyte developmental competence, attributed to a concomitant increase in meiotic errors. Although many biological hallmarks of general ageing are well characterized, the precise mechanisms underlying the programmed ageing of the female reproductive system remain elusive. In particular, the molecular pathways linking the external menopause trigger to the internal oocyte chromosome segregation machinery that controls fertility outcomes is unclear. However, recent large scale genomics studies have begun to provide insights into this process. Next-generation sequencing integrated with systems biology offers the advantage of sampling large datasets to uncover molecular pathways associated with a phenotype such as ageing. In this mini-review, we discuss findings from these studies that are crucial for advancing female reproductive senescence research. Targets identified in these studies can inform future animal models for menopause. We present three potential hypotheses for how external pathways governing ovarian ageing can influence meiotic chromosome segregation, with evidence from both animal models and molecular targets revealed from genomics studies. Although still in incipient stages, we discuss the potential of genomics studies combined with epigenetic age acceleration models for providing a predictive toolkit of biomarkers controlling menopause onset in women. We also speculate on future research directions to investigate extending female reproductive lifespan, such as comparative genomics in model systems that lack menopause. Novel genomics insights from such organisms are predicted to provide clues to preserving female fertility.