University of Copenhagen: Researchers identify new genes linked to longer reproductive lifespan in women

Scientists have identified nearly 300 gene variations that influence reproductive lifespan in women. Additionally, in mice, they have successfully manipulated several key genes associated with these variants to increase their reproductive lifespan. Their findings identify potential new targets for fertility treatments in humans, as well as ways to improve the prediction of early menopause.

While life expectancy has increased dramatically over the past 150 years, the age at which women go through natural menopause has remained relatively constant at about 50 years old. Women are born with all the eggs they will ever carry, and these are gradually lost with age. Menopause occurs once most of the eggs have gone, however natural fertility declines roughly ten years before that.

Findings, published today in Nature, identify new genetic variations linked to reproductive lifespan, increasing the number known from 56 to 290. By either knocking out a specific gene or overexpressing another, the researchers were able to prolong the reproductive lifespan in mice by 25 per cent.

‘The average age of Danish women having their first child has risen from 23 to 29 over the past 60 years. This means that more people need fertility treatments such as IVF and 6 percent of children are born after a successful treatment – but these are expensive, stressful and many people need to go through multiple cycles of treatment. Especially because the hormonal treatment does not always work. Our research has identified exciting new targets that could lead to new targets to improve fertility treatment’, says one of four co-leaders of the study, Professor Eva Hoffmann from the DNRF Center for Chromosome Stability, Faculty of Health and Medical Sciences, University of Copenhagen.

About the study
This research has been achieved by a global collaboration involving academics from more than 180 institutions, and jointly led by the University of Exeter, the MRC Epidemiology Unit at the University of Cambridge, the Autonomous University of Barcelona, and the DNRF Center for Chromosome Stability at the University of Copenhagen.

Could help predict early menopause
The genes identified by this work influence the age at natural menopause and can also be used to help predict which women are at highest risk of having menopause at a young age.

‘We can see that genes which play a key role in DNA repair are also linked to reproductive lifespan. We predict, from our findings in mice, that they work in two different ways. When the activity of some genes is higher, females are born with more eggs and they take longer to deplete naturally, thus delaying the age at menopause. For others genes, inhibiting their activity allows eggs to survive longer. We hope our work will help provide new possibilities to help women plan for the future,’ says Eva Hoffmann.

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 a genetically later menopause is protective against type 2 diabetes and is linked to better bone health and lower risk of fractures. However, it increases the risk of some types of cancer, such as ovarian and breast cancer, that are known to be sensitive to sex hormones.

‘This research is incredibly exciting. Although there’s still a long way to go, we think it could open the first step to a new way of improving fertility treatment in women, and it also gives us insights into how to help avoid some health problems that are linked to the timing of menopause.’

Hope to achieve new and better fertility treatments
The team reached their conclusions by studying genetic data from 200,000 women of European ancestry. They discovered that many of the 290 genes are linked to processes of DNA repair. They also found that these genes are active from before birth, when human egg stores are created, and also throughout life. Notable examples are two cell cycle checkpoint genes – CHEK1 and CHEK2 – which regulate a broad variety of DNA repair pathways.

Knocking out CHEK2 so that it no longer functions, and over-expressing CHEK1 to enhance its activity each led to an approximately 25 per cent longer reproductive lifespan in mice.

‘Mouse reproductive physiology differs from humans in key ways, including that mice do not have menopause. However, we 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’, says Eva Hoffmann.

The research team believe these processes are similar enough in mice and humans to offer hope that the discovery could one day lead to new and better fertility treatments.