In a recently published study, an international group of scientists has identified nearly 300 gene variations that influence the reproductive lifespan in women. Additionally, in mice, they have successfully manipulated several key genes associated with these variants to extend their reproductive lifespan. The findings—published today in Nature and achieved by a global collaboration involving researchers from more than 180 institutions—substantially increase our knowledge of the reproductive aging process.
“It is clear that repairing damaged DNA in eggs is very important for establishing the pool of eggs women are born with and also for how quickly they are lost throughout life,” explained co-author Eva Hoffmann from the University of Copenhagen. “Improved understanding of the biological processes involved in reproductive aging could lead to improvements in fertility treatment options.”
Their findings identify new genetic variations linked to reproductive lifespan, increasing the number known from 56 to 290. Through analyses of datasets from hundreds of thousands of women from many studies including UK Biobank and 23andMe, the team discovered that many of the genes involved are linked to processes of DNA repair. They also found that many of these genes are active from before birth, when human egg stores are created, but also throughout life as well. Notable examples are genes from two cell cycle checkpoint pathways—CHEK1 and CHEK2 —which regulate a broad variety of DNA repair processes. Knocking out a specific gene (CHEK2) so that it no longer functions, and over-expressing another (CHEK1) to enhance its activity each led to an approximately 25 percent longer reproductive lifespan in mice. The study also looked at women who naturally lack an active CHEK2 gene, and found they reach menopause on average 3.5 years later than women with a normally active gene.
The team also examined the health impacts of having an earlier or later menopause by using an approach that tests the effect of naturally occurring genetic differences. They found that genetically earlier menopause increases the risk of type 2 diabetes and is linked to poorer bone health and increased risk of fractures. However, it decreases the risk of some types of cancer, such as ovarian and breast cancer, that are known to be sensitive to sex hormones which are at higher levels while a woman is still menstruating.