Newly Discovered Genes Help in Delaying Menopausal Age in Women

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Highlights:

• Menopause is the natural and permanent cessation of menstrual cycles (periods) in women between the ages of 40 and 55
• The age at which a woman attains menopause is a significant factor to predict fertility and other health impacts among them
• Almost 290 genetic variations are recognized to influence the reproductive lifespan (menopausal age) in women, noticeable ones being CHEK1 and CHEK2 genes
• Over-expression of CHEK1 and reduced function of CHEK2 genes lead to a 25% longer reproductive lifespan

Longer reproductive lifespans in women are found to be linked to new genes according to the scientists at the University of Exeter, as published in the journal Nature.

‘Genetic variants are found to affect the biological age at menopause. Detailed understanding of reproductive aging in women is crucial for interpreting fertility and other health impacts among women.’

These genetic variants impact the biological or natural age at menopause. The menopausal age in women is important for fertility which also impacts healthy aging in women. However, a precise understanding of reproductive aging has been inadequate until now.

What is Menopause?

Menopause is defined as the natural biological state of permanent cessation of menstrual cycles (periods) in women between the ages of 40 and 55. It is caused by reduced levels of a female hormone - estrogen that is produced by the ovaries (female reproductive organ).

Women, by birth have all the eggs (ovum) they will ever carry. These eggs are gradually lost with age. Hence menopause is the condition where almost all the eggs are lost due to hormonal variations that substantially reduce natural fertility.

Around 4% of women experience early menopause before the age of 45 or 40 due to primary ovarian insufficiency (POI).

Genetic Influence upon Fertility

Although a dramatic increase in the overall life expectancy of humans over the past 150 years is witnessed, the menopausal age of the women has remained constant.

"It is clear that repairing damaged DNA in eggs is very important for establishing the pools of eggs women are born with and also for how quickly they are lost throughout life. Improved understanding of the biological processes involved in reproductive ageing could lead to improvements in fertility treatment options," says Co-author Professor Eva Hoffmann, of the University of Copenhagen.

The COVID-19 pandemic has resulted in the peak drop in childbirth that has never occurred in more than a century as per the data from the Centers for Disease Control and Prevention. Several other factors are also associated with the delay in having children, which incorporates financial and career considerations.

Data on Genes and Menopause

The global collaboration from academics of more than 180 institutions went a mile longer to analyze the datasets from hundreds of thousands of women from many studies, including UK Biobank and 23andMe (300,000 female).

The large majority of women were of European ancestry, and nearly 80,000 women were of East Asian ancestry. However, their results were found to be broadly similar.

The study team identified 290 gene variations (from 56 known earlier) that influence the reproductive lifespan in women.

DNA Repair and Reproduction - The Detailed Understanding

The study discovered that the processes of DNA repair are driven by many of the genes. Interestingly most of these genes remain active even before birth, when the human egg stores are created, and also throughout life.

The prominent genes known to regulate a broad variety of DNA repair processes are from two cell cycle checkpoint pathways - CHEK1 and CHEK2.

When a specific gene - CHEK2 was knocked out (no longer functional), and the other gene CHEK1 was over-expressed (enhanced activity), there was a 25% longer reproductive lifespan in mice.

The Correlation Gap

Although they successfully manipulated several key genes in mice models that further extend their reproductive lifespan, the reproductive physiology of mice greatly differs from humans.

One of the prime differences is that the female mice do not have menopause. However, the data were also correlated with the women who naturally lack an active CHEK2 gene. It was found that in the absence of CHEK2, menopause was attained 3.5 years later on an average when compared to women with a normally active gene.

"We saw that two of the genes which produce proteins involved in repairing damaged DNA work in opposite ways with respect to reproduction in mice. Female mice with more of the CHEK1 protein are born with more eggs and they take longer to deplete naturally, so reproductive lifespan is extended. However, while the second gene, CHEK2, has a similar effect, allowing eggs to survive longer, but in this case the gene has been knocked out so that no protein is produced suggesting that CHEK2 activation may cause egg death in adult mice", says Co-author Professor Ignasi Roig, from the Universitat Aut�noma de Barcelona.

Translational Approach

The data obtained from mice models can help in the identification of the exact timing when these genes are switched on in human eggs by correlating with the genetic analysis. This shows the influence of the genes on natural menopause.

Hence, one can easily predict the group of women who belong to the highest risk of having earlier menopause (at a young age) which in turn provokes a struggle to get pregnant naturally.

The data also revealed other health impacts of earlier or later menopause. Genetically earlier menopause was found to increase the risk of type 2 diabetes, fractures, and poor bone health. The good news is that menopause also decreases the risk of ovarian and breast cancer.

The authors affirm that the results collected in the study would help formulate new opportunities for fertility treatment. Identifying the risk group may even help in offering future guidance for early pregnancy among these women.

Facts On Menopause

• Physical activity and nutrition may play a role in the timing of menopause for all women.
• Common symptoms like hot flashes, night sweats, depression, and sleep disturbances may serve as contributing risk factors to cardiovascular diseases, especially in women who enter menopause at an earlier age.
• Women who drink little to moderate amounts of alcohol may have a later onset of menopause.
• Smoking cigarette predisposes women to earlier menopause about a year earlier, when compared to non-smokers.
• Data indicate that only 7.2% of women in menopause meet physical activity guidelines, and fewer than 20% of those women consistently maintain a healthy diet.

References:

1. New genes linked to longer reproductive lifespan in women - (https:www.sciencedaily.com/releases/2021/08/210804123454.htm)
2. Genomic analysis identifies variants that can predict the timing of menopause - (https:www.nature.com/articles/d41586-021-01710-8)
3. Researchers identify new genes linked to longer reproductive lifespan in women - (https:dg.dk/en/press-release-from-ccs-researchers-identify-new-genes-linked-to-longer-reproductive-lifespan-in-women/)
4. What Is Menopause? - (https:www.nia.nih.gov/health/what-menopause)
5. Menopause - Symptoms & Causes - (https:www.mayoclinic.org/diseases-conditions/menopause/symptoms-causes/syc-20353397#:~:text=Menopause%20is%20the%20time%20that,is%20a%20natural%20biological%20process)

Source: Medindia

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