Novel insights into reproductive ageing and menopause from genomics by Arunika Das, Aspasia Destouni

Serge Rozenberg

Human Reproduction, Volume 38, Issue 2, February 2023, Pages

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, the authors 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. They 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, they discuss the potential of genomics studies combined
with epigenetic age acceleration models for providing a predictive toolkit of biomarkers controlling
menopause onset in women. The authors 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.

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