Press release from CCS: Researchers identify new genes linked to longer reproductive lifespan in women
PRESS RELEASE: The age at which women go through menopause is critical for fertility and impacts healthy ageing in women, but reproductive ageing has been difficult for scientists to study and insights into the underlying biology are limited. Now, 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 extend their reproductive lifespan.
Their findings, published today in Nature, substantially increase our knowledge of the reproductive ageing process, as well as providing ways to improve the prediction of which women might reach menopause earlier than others.
While life expectancy has increased dramatically over the past 150 years, the age at which most 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 substantially earlier.
Co-author Professor Eva Hoffmann, of the University of Copenhagen, said: “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. Improved understanding of the biological processes involved in reproductive ageing could lead to improvements in fertility treatment options.”
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 Institute of Biotechnology and Biomedicine at the Universitat Autònoma de Barcelona, and the DNRF Center for Chromosome Stability at the University of Copenhagen. Their findings identify new genetic variations linked to reproductive lifespan, increasing the number known from 56 to 290.
The new discoveries were made possible through analyses of datasets from hundreds of thousands of women from many studies including UK Biobank and 23andMe. Data from 23andMe was provided by customers who have opted-in to participate in research. While the large majority are from women of European ancestry, they also examined data on nearly 80,000 women of East Asian ancestry, and found broadly similar results.
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 per cent longer reproductive lifespan in mice. Mouse reproductive physiology differs from humans in key ways, including that mice do not have menopause. However, 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.
Co-author Professor Ignasi Roig, from the Universitat Autònoma de Barcelona, said: “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”.
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.
Co-author Dr Katherine Ruth, of the University of Exeter, said: “We hope 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 timing of menopause, we have shown that we can start to predict which women might have earlier menopause and therefore struggle to get pregnant naturally. And because we are born with our genetic variations, we could offer this advice to young women.”
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 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.
Co-author Dr John Perry, of the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, a senior author on the paper, said: “This research is incredibly exciting. Although there’s still a long way to go, by combining genetic analysis in humans with studies in mice, plus examining when these genes are switched on in human eggs, we now know a lot more about human reproductive ageing. It also gives us insights into how to help avoid some health problems that are linked to the timing of menopause.”
Ruth, K.S. et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature 2021; 04 Aug 2021; DOI: 10.1038/s41586-021-03779-7
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Further information about each institution involved below
The University of Exeter Medical School is part of the University of Exeter’s College of Medicine and Health. Our mission is to improve the health of the South West and beyond, through the development of high quality graduates and world-leading research that has international impact.
As part of a Russell Group university, we combine this world-class research with very high levels of student satisfaction. Exeter has over 19,000 students and is ranked 12th in The Times and Sunday Times Good University Guide 2020.
The University of Exeter Medical School’s Medicine course is in the top 10 in the Complete University Guide 2020.
The College’s Medical Imaging programme is ranked in the top 5 in the Guardian Guide 2020 and the Complete University Guide 2020.
The University of Exeter entered the world top 20 for Biomedical and Health Sciences in the CWTS Leiden Ranking 2019, based on the percentage of publications ranked in the top 10 per cent most cited.
The MRC Epidemiology Unit is a department at the University of Cambridge. It is working to improve the health of people in the UK and around the world. Obesity, type 2 diabetes and related metabolic disorders present a major and growing global public health challenge. These disorders result from a complex interplay between genetic, developmental, behavioural and environmental factors that operate throughout life. The mission of the Unit is to investigate the individual and combined effects of these factors and to develop and evaluate strategies to prevent these diseases and their consequences.
The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. The Medical Research Council is part of UK Research and Innovation.
The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 109 affiliates of the University have won the Nobel Prize.
Founded in 1209, the University comprises 31 autonomous Colleges and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.
The University sits at the heart of the ‘Cambridge cluster’, which employs more than 61,000 people and has in excess of £15 billion in turnover generated annually by the 5,000 knowledge-intensive firms in and around the city. The city publishes 316 patents per 100,000 residents.
The mission of the DNRF is to be a powerful driver of societal development and the improvement of humanity by funding outstanding basic research of the highest international level at the frontiers of all research fields to strengthen the development of Danish research. The Danish National Research Foundation is an independent organization established by the Danish Parliament in 1991. The foundation’s endowment secures its independence and a long-term commitment to the best Danish research. The annual funding amounts to about 470 million DKK on average.
Driven by intellectual creativity and critical thinking since 1479, researchers and students at the University of Copenhagen have expanded horizons and contributed to moving the world forward. With its 5,000 researchers and 37,500 students, the University boasts an international research and study environment and is highly ranked on the leading ranking lists of the world’s best universities.
The University offers researchers and students the opportunity to develop their talent and launches ambitious interdisciplinary initiatives to support its strong academic communities. Through research-based teaching – and by involving them in research – students are equipped to address society’s challenges and needs.
The University of Copenhagen is working towards becoming one of the world’s greenest campus areas, leaving as little environmental and climate footprint as possible. The University facilitates cross-organisation collaboration, liaises with the business community and helps students find relevant programmes and projects in the field of sustainability.
The University also focuses on gender equality and sees diversity as a strength.
The Universitat Autònoma de Barcelona is a young university with a multidisciplinary framework made up of teaching, basic and clinical research, technological platforms, transfer of technology and creation of businesses. It is home to 3,500 lecturers and researchers and over 40,000 students. In the main international rankings, the university positions itself among the top 200 worldwide and the top 100 in Europe, recognised for the quality and innovation of its research, as well as for its academic quality in the fields of social sciences, the humanities, experimental sciences, biosciences, health sciences, engineering and technology.
UK Biobank is a large-scale biomedical database and research resource containing genetic, lifestyle and health information from half a million UK participants.
UK Biobank’s database, which includes blood samples, heart and brain scans and genetic data of the 500,000 volunteer participants, is globally accessible to approved researchers who are undertaking health-related research that’s in the public interest.
UK Biobank recruited 500,000 people aged between 40-69 years in 2006-2010 from across the UK. With their consent, they provided detailed information about their lifestyle, physical measures and had blood, urine and saliva samples collected and stored for future analysis.
UK Biobank’s research resource is a major contributor in the advancement of modern medicine and treatment, enabling better understanding of the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses – including cancer, heart diseases and stroke. Since the UK Biobank resource was opened for research use in April 2012, over 20,000 researchers from +90 countries have been approved to use it and more than 2,000 peer-reviewed papers that used the resource have now been published.
UK Biobank is generously supported by its founding funders the Wellcome Trust and UK Medical Research Council, as well as the British Heart Foundation, Cancer Research UK, Department of Health, Northwest Regional Development Agency and Scottish Government. The organisation has over 150 dedicated members of staff, based in multiple locations across the UK.
You can find out more about UK Biobank at http://www.ukbiobank.ac.uk