Expectant parents hoping to conceive face a ticking clock: The older potential mothers get, the more their fertility declines. A new study in mice may help explain why. Ovaries accumulate “stiff” tissue as they age, and researchers have found that reducing the amount of this tissue — “softening” the ovaries, as it were — restored fertility in the animals, raising the possibility that the same approach in people can work.
The study “is a major advance,” said ovarian biologist Francesca Duncan of the Northwestern University Feinberg School of Medicine, who was not connected to the research. The results, she says, suggest that treatment for the age-related decline in fertility “is not a pipe dream.”
Female fertility ends at menopause, but it begins to decline around the age of 30. Scientists still don’t know why. One recently discovered suspect is fibrosis, an abnormal proliferation of tough, supportive material known as connective tissue. As we age, fibrosis can stiffen the heart, lungs, liver and, as Duncan and her colleagues revealed in 2016, the ovaries.
Takashi Umehara, then a postdoc at the University of Adelaide, and colleagues wanted to determine whether ovarian fibrosis was responsible for declining fertility. Although female mice do not undergo menopause, their ability to reproduce declines as they age.
The researchers first gave 15-month-old mice (roughly equivalent to humans in their early 50s) an approved drug to reduce fibrosis. These rodents are usually too old to reproduce, but the medication enabled more than half of them to ovulate, the team reports today in Science advances. When the researchers fertilized the resulting eggs in a laboratory dish, apparently healthy embryos developed, indicating that the eggs were healthy.
The mice were past their reproductive age, unlike most patients at fertility clinics. So the scientists also tested the drug on 12-month-old rodents, which are comparable to 35-year-old humans. “That’s where the clinical need is,” says reproductive biologist and study senior author Rebecca Robker, also from the University of Adelaide. Again, the drug provided a reproductive boost, nearly doubling the number of eggs the animals ovulated. The eggs appear to be healthy, giving rise to embryos after in vitro fertilization. However, even younger mice did not benefit from the drug.
Despite these successes, the researchers weren’t sure whether reduced fibrosis drove the improved fertility, Robker says. “We didn’t know if [fibrosis] would be reversible,” she says, because it involves the accumulation of tough collagen strands. But when the scientists examined the animals’ ovaries under the microscope, they found the amount of fibrosis was much lower in both groups of mice that received the drug than in the controls.
Faulty mitochondria, the organelles that provide energy to cells, can promote ovarian fibrosis. As mice and humans age, these structures begin to malfunction, producing fewer of the energy-rich molecules that cells need and generating more destructive metabolic byproducts.
To investigate the role of mitochondria in infertility, Robker and colleagues dosed 14-month-old mice with another drug, BGP-15, that tunes the organelles. Compared to untreated mice of the same age, the rodents ovulated more than twice as many eggs and showed less fibrosis in their ovaries.
The team also tested two other molecules that strengthen mitochondria – metformin, an anti-diabetes drug sometimes prescribed for infertility, and MitoQ, which is often touted as an anti-aging supplement. Both molecules reduced ovarian fibrosis in old mice but did not stimulate ovulation.
Obesity suppresses fertility in humans, but whether ovarian fibrosis is linked to this decline was unknown. The researchers discovered that fibrosis is common in the ovaries of young, obese mice. They also found that BGP-15, metformin and MitoQ reduced fiber build-up and induced ovulation in these animals.
“This is the first evidence linking age-related ovarian fibrosis to a reduction in fertility and shows that reducing it in any way can prolong reproduction,” said Barbara Vanderhyden, an ovarian cancer researcher at the Ottawa Hospital Research Institute who was also not. related to the research. However, she cautions that decreasing fibrosis does not rejuvenate the mice’s ovaries. “It’s helpful, but it’s not a turnaround.”
How fibrosis undermines fertility remains uncertain, but it may stiffen ovarian tissue, Robker says. An egg matures in a cradle known as a follicle, which balloons to about 1 million times its original size before bursting to release the egg. The build-up of connective tissue can trap follicles, preventing them from enlarging and thus stalling egg development. The researchers found that BGP-15 prompts mice to produce an enzyme that dissolves the collagen fibers in connective tissue, which can free the follicles.
Researchers may be able to start clinical trials to test BGP-15 or other fibrosis-fighting molecules. One obstacle is that the ovaries are hidden deep in the abdomen, making it difficult to determine who has developed fibrosis – the condition is usually diagnosed after surgical removal of the ovaries. “We need to find a non-invasive [way],” says Robker.
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