Female Biological Clock Runs Out as Egg Repair Genes Wane

Scientists have found a possible reason why women lose their fertility in middle age, in a discovery that could pave the way for treatments to extend women’s childbearing years beyond what is naturally possible.

In a series of experiments on eggs from women getting fertility treatments, researchers learned that the function of several DNA repair genes weaken with age. This decline is accelerated in women near the end of their childbearing years, according to the results published in the journal Science Translational Medicine.

The experiments hint at why the female biological clock runs out as women reach their early 40s. The ability to repair DNA inside their egg cells may become impaired, leading to accumulating damage to the eggs that causes them to die off more rapidly, said Kutluk Oktay, senior author on the study and a professor at New York Medical College in Valhalla, New York.

“We found a reason behind age-related infertility, why women become infertile as they become older,” said Oktay, who is also a fertility specialist at the Institute for Fertility Preservation in Rye, New York. “We are saying here is how women’s eggs age.”

The results suggest it may be possible to safely extend a woman’s childbearing years by devising a treatment that preserves the functions of the DNA repair genes inside the eggs. Oktay is beginning to test substances that may accomplish this in his laboratory, he said in a telephone interview. He wouldn’t provide any details.

Such a treatment might be able to extend a woman’s ability to have children into her early 50s, he said.

BRCA1 Gene

The researchers began the work after discovering several years ago that women with the breast-cancer risk gene BRCA1 were less responsive to drugs used to stimulate the ovary to produce eggs in fertility preservation procedures.

“We noticed those women produced fewer eggs than those without the mutations,” said Oktay.

BRCA1 is a DNA repair gene, and the result caused the researchers to examine more broadly the role it and other DNA repair genes play in female age-related fertility decline.

In the new study, the researchers took eggs from 24 women ages 24 to 41. In laboratory experiments, they found that the BRCA1 gene and three other DNA repair genes were much less active in eggs from older women than younger woman, indicating a decreasing ability to repair DNA damage to the eggs that occurs over time.

Women are born with about 1 million egg cells in their ovaries, and the number declines gradually over time, Oktay said. Yet when women reach their late 30s the eggs start to degrade at a much faster rate, for reasons that have long been mysterious. By age 37, a woman has perhaps only 25,000 egg cells left, he said.

‘Compelling Evidence’

The findings “provide compelling evidence for a new mechanism” why a woman’s eggs become dysfunctional with age, wrote David Keefe of the New York University Langone Medical Center and Joshua Johnson of the Yale University School of Medicine in New Haven, Connecticut, in a commentary accompanying the study.

Oktay and his colleagues also indirectly measured egg levels in women with the bad BRCA1 gene, and compared them with a control group of women of the same age without the genetic mutation. The women with the BRCA1 mutation had lower levels of a blood marker that correlates with how many egg cells are left in their ovaries, indicating that the mutation in the DNA repair gene was accelerating the aging of their egg cells.

The finding indicates that women with BRCA1 mutations may lose fertility somewhat earlier and may want to consider having children sooner, perhaps having all the children before age 35 or 36, Oktay said.

Before it's here, it's on the Bloomberg Terminal.