New genes linked to longer reproductive lifespan in women

Date:
August 4, 2021
Source:
University of Exeter
Summary:
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
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.



FULL STORY ==========================================================================
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 ofwhich 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 Auto`noma 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 Auto`noma 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." ========================================================================== Story Source: Materials provided by University_of_Exeter. Note: Content
may be edited for style and length.


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Link to news story: https://www.sciencedaily.com/releases/2021/08/210804123454.htm

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