The age at which women go through menopause is essential for establishing the duration of their fertility and for healthy aging. Even so, the reproductive aging of women has been difficult for scientists to study and knowledge about the underlying biology is still quite limited today.
An international team of scientists from more than 180 institutions co-led by researchers from the University of Exeter, the University of Cambridge, the University of Copenhagen and the Autonomous University of Barcelona (UAB) has identified nearly 300 gene variants that influence the reproductive life of women. Researchers have also successfully manipulated key genes associated with these variants in mice that have increased their reproductive life.
The results of this study, published this week in the journal Nature, substantially increase knowledge about the reproductive aging process, as well as providing ways to improve the prediction of women who could reach menopause earlier than others.
Despite the fact that life expectancy has increased dramatically in the last 150 years, the age at which most women go through the menopause naturally it has remained relatively constant over the past 50 years or so. Women are born with all the eggs they will have throughout their lives, and these are progressively lost with age, which is known as reproductive aging. Thus, menopause occurs once most of these eggs have disappeared, despite the fact that natural fertility decreases substantially earlier.
The age at which most women go through menopause naturally has remained relatively constant at about 50 years
Professor Eva Hoffmann, team leader at the University of Copenhagen, remarked: “It is evident that repair damaged DNA in the ovules is very important to establish the set of eggs with which women are born and also because of the speed with which they are lost throughout life. A better understanding of the biological processes involved in reproductive aging could lead to improvements in fertility treatment options. ”
This research has managed to identify new genetic variations related to reproductive life, increasing the known number from 56 to 290 variations.
The new discoveries have been made possible by analyzing data sets of hundreds of thousands of women from many studies, including the UK Biobank and 23andMe. The data for the latter was provided by clients who opted to participate in the research. Although the vast majority are from women of European descent, they also examined data on nearly 80,000 women of East Asian descent and found broadly similar results.
The team found that many of the genes involved are related to DNA repair processes. They also found that many of these genes are active from before birth, when the egg pool is created in humans, but also throughout adult life.
A notable example is the two-way cell cycle control genes – CHEK1 and CHEK2 – that regulate a wide variety of DNA repair processes. Eliminating a specific gene (CHEK2) to stop working and overexpressing another (CHEK1) to increase its activity, caused a approximate 25% increase in the length of reproductive life in mices. Notably, the reproductive physiology of the mouse differs from that of humans in several ways, including the fact that mice are not menopausal.
Females with more CHEK1 production were born with more eggs and therefore they took longer to deplete naturally, thus lengthening reproductive life
However, the study also looked at the onset of menopause in women who do not naturally have the CHEK2 gene active and found that women reach menopause, on average, 3.5 years later than women with a normally active gene.
Ignasi roig, head of the team at the UAB Institute of Biotechnology and Biomedicine, highlights: “We saw that two of the genes that produce proteins necessary for DNA repair (CHEK1 and CHEK2) work in the opposite way. Females with more CHEK1 production were born with more eggs and therefore took longer to deplete naturally, thus lengthening reproductive life. This suggests that CHEK1 gene activity protects eggs. In contrast, when we removed the CHEK2 gene, females were born with the same number of eggs, but these took longer to deplete. This suggests that the activation of CHEK2 can cause the death of ovules during the adult life of the mice ”.
The genes identified in this work influence the age of natural menopause and can also be used to help predict which women are most at risk for early menopause. The co-author of the work, Katherine Ruth, from the University of Exeter, commented: “We hope that our work will help provide new possibilities to help women plan for the future. By finding many more of the genetic causes of variability in the onset of menopause, we have shown that we can begin to predict which women might have a early menopause and therefore fight to get pregnant naturally. And since we are born with these genetic variations, we could offer this advice to young women“.
We hope that our work will help provide new possibilities to help women plan for the future.
The team also looked at the health impact of an earlier or later menopause. They found that a previous menopause increases the risk of type 2 diabetes and it is linked to poorer bone health and an increased risk of fractures. However, a previous menopause lowers the risk of some cancers, such as ovarian and breast cancers, which are known to be sensitive to sex hormones.
John perry, head of the team of the Epidemiology Unit of the Medical Research Council (MRC) of the University of Cambridge, said: “This research is incredibly exciting. Although there is still a long way to go, thanks to the research combining genetic analysis in In humans, mouse studies, and analysis of when these genes are turned on in human eggs, we now know much more about the mechanisms that regulate reproductive aging in women. health related to menopause “.
Ruth, KS et al. “Genetic insights into biological mechanisms governing human ovarian aging”. Nature
Rights: Creative Commons.