The age of menopause in women is linked to fertility and healthy aging, yet reproductive aging has long posed challenges for scientific research.Now, scientists have identified nearly 300 genetic variants influencing female reproductive lifespan. Furthermore, in mice, they have successfully manipulated several key genes associated with these variants to extend reproductive longevity. The research paper, published in the recent issue of Nature, significantly advances our understanding of the reproductive aging process and aids in predicting which women may enter menopause earlier than others.
Although human life expectancy has increased significantly over the past 150 years, the natural age of menopause for most women has remained around 50. All the eggs a woman is born with gradually diminish with age. Once most of these eggs are depleted, menopause occurs. However, the actual decline in natural fertility begins much earlier than menopause.
This study identified new genetic mutations associated with human reproductive lifespan, expanding the known list from 56 to 290. The research team analyzed datasets from hundreds of thousands of women across multiple studies, including the UK Biobank and the genetic sequencing company 23andMe. While the majority of participants were of European ancestry, they also examined data from nearly 80,000 women of East Asian ancestry and found broadly consistent results.
The team discovered that many genes involved in reproductive lifespan are linked to DNA repair processes. They also found that numerous these genes are active before birth—even before the ovaries form—and remain active throughout life.
Notably, two cell cycle checkpoint pathway genes—CHEK1 and CHEK2—regulate various DNA repair processes.Knocking out one CHEK2 gene to render it nonfunctional, or overexpressing CHEK1 to enhance its activity, both extended reproductive lifespan in mice by approximately 25%.
The study also examined women born with inactive CHEK2 genes, finding they entered menopause an average of 3.5 years later than those with normal gene activity.
The study found that female mice with higher levels of the CHEK1 gene produced more eggs at birth, took longer to naturally deplete their egg supply, and exhibited extended reproductive lifespan. However, while CHEK2 has a similar effect of prolonging egg viability, knocking out this gene may cause egg death in adult mice. Therefore, overexpressing the CHEK1 gene is the preferred approach for extending reproductive lifespan.
This research demonstrates that scientists can now begin predicting which women may experience earlier menopause, making natural conception difficult. Given that genetic variations exist from birth, this study also offers fertility-related guidance for young women. (Intern reporter Zhang Jiaxin)