The age at which women experience their last menstrual period – menopause – is strongly genetically determined. A large international team of scientists has found 290 genes associated with that timing. Many of those genes are essential for repairing DNA damage. Experiments with mice confirmed the role of two of those genes.
This shows that the importance of DNA repair in female fertility is much greater than previously thought. In addition, there is a strong link between these genes and healthy aging. The team, which also includes researchers from Groningen, Utrecht, Amsterdam, Rotterdam and Leiden, published about it in the magazine this Wednesday Nature.
Even in their mother’s womb, girls carry all the eggs they will ever have in their lives. At 24 weeks that is about 7 million eggs; thereafter that number gradually decreases. At birth there are about 2 million left, at the beginning of puberty about 400,000 to 500,000.
About a thousand eggs mature every month. One of them becomes dominant and comes to full maturity, after which it is released and can be fertilized. The rest die. When almost all the eggs are used up, the menopause takes place.
Average age 51
For most women, that time of menopause comes between their 40s and 60s; the average is 51 years. Menopause is in the spotlight because many women experience complaints in the run-up to it (‘the transition’), such as hot flashes, mood swings, fatigue and memory, concentration and sleeping problems.
“But menopause is also medically interesting for many other reasons,” says Joop Laven. He is professor of obstetrics and gynecology at Erasmus MC in Rotterdam and co-author of the study in Nature. “From the menopause, the risk of diabetes and cardiovascular disease suddenly increases sharply and bone density decreases. In general, the later women experience menopause, the healthier they age.”
But the underlying cause was unknown for a long time. It is difficult to investigate: what is cause and effect? And it is obvious that many genes are involved in such a complex system. “In addition, environmental factors also play a major role,” explains Laven, “such as smoking, alcohol consumption, diet, and radiation exposure.”
If a body ages faster, the ovaries also stop working sooner
Joop Laven gynaecologist
Laven and his Rotterdam colleagues are investigating the role of DNA damage in reduced fertility. The egg cells are exposed to harmful external influences for decades, the professor explains. This is partly controlled by your lifestyle, but partly DNA damage is unavoidable: reactive oxygen atoms that are naturally released during metabolism damage the DNA – including that of the eggs waiting to mature in the ovaries. Fortunately, the body can repair much of that damage. “The same DNA repair is important for healthy aging,” says Laven. “Because aging is also the result of DNA damage.”
The Rotterdammers wanted to investigate the relationship between how long a woman is fertile and how healthy she gets old. But in Western society, where almost everyone tightly regulates their family planning with contraception, the duration of female fertility is difficult to study. “That’s why we conducted research with traditionally living Sami in Lapland,” says Laven. “There we saw that the women who lived the oldest had the most children and had gone on to have children the longest.”
100 years old and many children
The link between aging and being fertile for a long time has also emerged from research among so-called centenarians (people over 100 years old) on the Japanese island of Okinawa. Laven: „Female centenarians were six times more likely than average to have a child after age 40.” Here Laven notices something important. For a long time it was believed that menopause causes aging symptoms. “But in fact it’s the other way around,” says Laven. “As a body ages faster, the ovaries also cease to function sooner. Menopause is a symptom of aging – not its cause.”
Laven cites various facts that support this hypothesis, including a large Nijmegen study among women who underwent IVF treatment. Some of them developed pre-enclampsia, also known as preeclampsia. This is a pregnancy complication that is associated with high blood pressure and organ damage, among other things. “That condition indicates a worse condition of the heart and vessels,” says Laven. “If the hypothesis is correct, then those women should also have worse ovaries. And that was indeed the case: their ovaries responded less well to the IVF treatment.”
Laven sees the same connection in girls with cancer. Their ovaries are at a lower level – regardless of any treatment. And he sees it in women who go into menopause early: their hearts and vessels are in relatively poor health. Laven: “At the other end of the spectrum, we see women with polycystic ovarian syndrome (PCOS), who are relatively fertile at a later age.”
PCOS is a condition in which the hormone balance is disrupted and ovulation does not always occur. But women with PCOS seem to have better DNA repair and better maintenance genes. When they go through IVF, their embryos are often of better quality. Laven: “In women with PCOS who undergo IVF between the ages of 40 and 45, only 10 percent have chromosome abnormalities. For women without PCOS in the same age group, that is 90 percent. And pregnancy success is two to three times higher in these PCOS patients.”
Too early for resources
British colleagues investigated for the Naturestudy two of the DNA repair genes found in mice. By switching off or stimulating those genes, they were able to strongly control the fertility of the mice. Can we also do something similar in humans, for example with medicines that link to the relevant genes or proteins? “No, it’s much too early for that,” replies Laven. “To do that, we first need to find out more precisely the relative contribution and function of those 290 genes.”
Laven sees more in drawing up genetic risk profiles, with which doctors can make predictions about the fertility of women. “On the basis of that, you can give women advice on whether or not to postpone pregnancy,” he says. “And about lifestyle. Quitting smoking and losing weight really help when it comes to your fertility. And therefore also for healthy aging.”