The age at which women enter menopause is not only decisive for individual child planning, but also has numerous health consequences. Researchers have now identified 290 gene variants that influence age at the onset of menopause. These mainly include genes that are involved in repairing DNA damage. If the researchers manipulated some of these genes in mice, they were able to extend their reproductive lifespan.
Over the past 150 years, average human life expectancy has increased significantly and is currently around 85 years. By contrast, the age at which women enter menopause has remained largely constant. On average, women between the ages of 47 and 52 experience their last period, but there are also women who go through menopause before the age of 45. Age at the onset of menopause is influenced on the one hand by lifestyle factors such as diet and smoking, and on the other by genetic predisposition.
DNA repair genes affect menopause
A team led by Katherine Ruth from the University of Exeter in Great Britain has now analyzed genomic data from more than 200,000 women who began menopause between the ages of 40 and 60. Ruth and her colleagues investigated which gene variants have an influence on age at the beginning of menopause. They identified 290 variants that are associated with an earlier or later onset of menopause. Only 56 such gene segments were previously known. According to the analyzes, the influence of the individual gene variants on the timing of menopause is between 3.5 weeks and 1.5 years.
“The identified gene locations are involved in a wide range of processes related to DNA damage,” the researchers report. Among other things, these genes ensure that DNA damage is recognized and repaired or that cells with damaged DNA die. In the ovaries, they are active throughout a woman’s life. Co-author Eva Hoffmann from the University of Copenhagen explains: “It is clear that repairing damaged DNA in egg cells is very important in determining the egg supply that women are born with and how quickly they progress of life get lost. A better understanding of the biological processes involved in reproductive aging could lead to improved fertility treatment options. “
Reproductive life span extended in mice
In mice, the researchers tested the effect of two key genes, CHEK1 and CHEK2, on menopause. Both genes are involved in the response to DNA damage, with CHEK1 mainly responsible for repairing the damaged areas, while CHEK2 causes the death of cells with faulty DNA. Using genetic manipulation, the researchers switched off CHEK2 in female mice. “In these females, the egg reserve depleted more slowly, which leads to improved ovarian function at an advanced age,” the authors write. Unlike humans, mice do not have menopause, but the ovarian function of aged animals gave the researchers an indication that CHEK2 apparently causes egg cells to die under normal conditions, thus contributing to an earlier onset of menopause.
Mice without CHEK1 died before birth because the functions that this gene performs are vital. The researchers therefore examined the effects of CHEK1 in mice that had an additional copy of the gene. The result: “Female mice with more CHEK1 protein are born with more egg cells and it takes longer for them to empty naturally, so that the reproductive time is extended,” reports co-author Ignasi Roig from the Autonomous University of Barcelona.
Weighing up the benefits and risks
In addition, the researchers investigated the relationship between a particularly early or late menopause and certain diseases. In doing so, they found, in line with previous studies, that late onset of menopause is associated with better bone health and a lower risk of type 2 diabetes. On the other hand, cancers such as breast and ovarian cancer are more common in women who come later into menopause.
So from a health point of view, could it make sense to delay menopause therapeutically? “How attractive this option is will focus on weighing the benefits and risks, as is the case with hormone replacement therapies today,” writes Krina Zondervan of the University of Oxford in an article accompanying the study, which was also published in the journal Nature.
Family planning advice?
Ruth and her colleagues hope the results will inspire future studies that could lead to new therapies to improve reproductive capacity and maintain fertility. From their point of view, it would be conceivable, for example, to increase the chances of success of artificial inseminations by temporarily preventing the death of egg cells caused by CHEK2. “Treatments that decrease CHEK2 expression could have adverse effects, however, as CHEK2 is a tumor suppressor gene and certain CHEK2 mutations increase the risk of various cancers,” says Zondervan.
The identified gene variants may also be helpful in advising women who want to have children. “We hope that our work will help create new opportunities for women to plan for the future,” says Ruth. “By finding many other genetic causes for the different times of menopause, we can predict which women will enter menopause particularly early.” However, since many other factors play a role in addition to genes, the predictive power is limited. However, this information could support family planning for women who are genetically prone to a particularly early onset of menopause.
Source: Katherine Ruth (University of Exeter, UK) et al., Nature, doi: 10.1038 / s41586-021-03779-7