Why do eggs in ovaries last for decades? Long-lived proteins may be key
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Why do eggs in ovaries last for decades? Long-lived proteins may be key
If human ovarian proteins show the same staying power, it would be "mind blowing," experts say
- 1 Jul 2024
- 6:10 PM ET
- ByMitch Leslie
Mammals, including humans, are born with all the oocytes—cells that mature into eggs—they will ever have. But unlike the many short-lived cells in the body, some oocytes are alive and healthy even after more than 4 decades. Now, two new mouse studies uncover a possible reason for this longevity, which preserves fertility well into adulthood. Ovaries, where oocytes are born, harbor proteins that can last almost as long as the animals themselves and could help oocytes endure.
Whether human ovarian proteins show the same staying power isn’t clear. “That would be mind-blowing,” says molecular biologist and geneticist John Labbadia of University College London, who wasn’t connected to either study. “We are talking about proteins that are decades old” potentially contributing to new life.
In humans, a 20-week-old female fetus typically harbors 6 million to 7 million oocytes. Most die, but some 300,000 make it to puberty and about 1000 are alive at menopause around age 50. Oocytes don’t need to live as long in mice, given their shorter life spans, but the animals can reproduce for more than a year, much longer than the average life span of a protein. Cells recycle most of the molecules within a few days.
But not all proteins break down so quickly. Long-lived proteins that last years in rodents and decades in humans have been found in the lens of the eye, the cartilage of joints, the brain, and mitochondria, cells’ power-generating organelles. Scientists also knew of a few persistent proteins in ovaries but not how common they were.
To find out, the two teams behind the new work used similar strategies aimed at determining how long proteins stick around. Both fed female mice chow that contained a heavy version of either carbon or nitrogen. The animals incorporated the hefty element into their proteins—as did their pups in the uterus. Soon after the young were born, the scientists switched them to food containing a lighter, more common form of carbon or nitrogen. Any proteins these second-generation rodents made before the changeover would contain the heavier element, whereas proteins made later would carry the lighter version, enabling the researchers to gauge the proteins’ age.
One group, led by cell biologist Melina Schuh of the Max Planck Institute for Multidisciplinary Sciences, analyzed oocytes from 8-week-old mice, which are in their reproductive prime. About 10% of the proteins in these cells were fashioned while the animals were in utero, they reported last month in Nature Cell Biology.
To determine how quickly these proteins broke down, the researchers again used food-switching to tag proteins in the ovaries of adults up to 15 months old—an advanced age for mice. Mathematical modeling indicated more than 10% of the proteins had a half-life—the time for 50% of the molecules to decay—of more than 100 days, roughly 13% of a mouse’s life span. Many abided in the ovaries for most of the rodents’ lives. Given how long oocytes hang on in mammals, “it makes a lot of sense for the ovary to have these long-lived proteins,” Schuh says.
Ewa Bomba-Warczak, a neuroscientist at the University of Pennsylvania, and colleagues made similar findings, which they described in a paper accepted in eLife. When the researchers analyzed oocytes from 7-month-old mice, they discovered that about 5% of the oocyte proteins were synthesized before or shortly after birth. By the age of 11 months, the rodents still had nearly 10% of that long-lived group.
“They are both well-done, impressive studies from well-respected groups in our field,” says Karen Berkowitz, a reproductive biologist and endocrinologist at the Drexel University College of Medicine.
Both studies also found some proteins are more likely to stick around than others. One that stands out, says neuroscientist Jeffrey Savas of Northwestern University, a co-author of the eLife study, is ZP3, which is important because it’s also the receptor on the egg surface that allows sperm to enter. Mitochondria were also rich in long-lasting proteins. Offspring inherit the organelles from their mother, and durable proteins might ensure that mitochondria are sound when they are passed on via eggs. “The mother gives all the mitochondria to the next generation,” says reproductive biologist Lei Lei of the University of Missouri School of Medicine.”They’d better be good,”
Researchers say the results don’t suggest obvious ways to boost ovarian function. But Yale University School of Medicine reproductive biologist Amanda Kallen says diagnostic tests based on long-lived protein levels could be valuable for patients worried about their fertility. “Even if I can’t stop aging of the ovary, if I can predict who’s going to age faster, I can offer something like egg freezing.”
The gradual disappearance of long-lived proteins from the ovaries may help explain why fertility falls after a certain age. Francesca Duncan, a reproductive biologist at Northwestern and a co-author on the eLife study, says she initially thought the opposite because cells can’t change out long-lived proteins, and they may accumulate so much damage over time that they fail. “I had assumed that if a protein was long-lived, it had to be bad,” Duncan says.
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Mitch Leslie