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In a high-stakes evolutionary gambit, female mammals are born with a finite supply of immature eggs. Propagating future generations depends on this reserve of pre-egg cells, or “primordial oocytes,” staying alive and out of the way of harmful, mutation-causing molecules — sometimes for decades — so they can give rise to mature eggs capable of producing healthy offspring.

Such a feat should be impossible.

To stay alive, cells have to produce energy. But mitochondria, the organelles that do that, aren’t 100% efficient. They leak electrons, which get scooped up by lone oxygen molecules, supercharging them into DNA-bashing, lipid-ripping “free radicals.” Scientists have long been stumped by how oocytes — the largest cell in the human body and the richest in mitochondria — persist in maintaining pristine cellular conditions for up to 50 years.

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It was a question Elvan Böke set out to answer when she established the Oocyte Biology and Cellular Dormancy Lab at the Centre for Genomic Regulation in Barcelona in 2017. After years of painstaking experiments combining live imaging and proteomics, she and her colleagues discovered that oocytes avoid the wear and tear other kinds of tissues suffer by skipping a fundamental metabolic reaction that takes place in every other cell in the human body.

Their work, published Wednesday in Nature, marks the first time scientists have observed animal cells using an alternative metabolic pathway that avoids generating destructive free radicals. Researchers said the discovery could open up new avenues for treating infertility as well as providing a blueprint for improving the longevity of other types of human cells.

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“It’s extremely compelling data,” said Christopher Hine, an aging researcher at the Cleveland Clinic’s Lerner Research Institute who was not involved in the new study. “They’ve been able to answer questions that were long believed to be unanswerable.”

We tend to think of aging as something that happens to people around the time they clock their 60th or 70th trip around the sun. But if you’re born with female reproductive organs — ovaries, fallopian tubes, a uterus — those tissues start aging once you enter your third decade of life. Around age 35, oocytes suddenly begin to decline.

How primordial oocytes stay dormant and undamaged for three decades and why these cells suddenly start to deteriorate five years later are key questions that surround age-related infertility in women. “This paper sheds new light on this entire process,” said John Aitken, a reproductive biologist at the University of Newcastle Australia.

In the 1980s, Aitken uncovered a major cause of male infertility — free radicals attacking sperm DNA. Böke’s group demonstrated that for much of their early lives, oocytes are not protected from free radicals, as many scientists believed, but instead avoid generating these toxic molecules in the first place by a careful restructuring of their metabolism.

Mitochondria power the cell by taking electrons and using them to make a cellular fuel called ATP, through a process known as oxidative phosphorylation. It doesn’t happen all at once, but in a series of linked steps involving five protein complexes. Complex I is the largest of these molecular machines and the first to accept electrons.

“It’s considered to be the gatekeeper of this process,” Böke told STAT via email. So she was surprised to find that in studies of human and frog oocytes, the mitochondrial genes that produce Complex I were turned off. Only one other multicellular organism is known to be able to exist without it — the parasitic mistletoe.

By skipping Complex I, primordial oocytes are able to maintain a super-low energy state, kind of like standby mode, while removing a major source of electron leakage, and therefore damage from free radicals.

“The safeguards built here are more robust than those in many other systems, like the heart or liver, a testament to the importance of conserving reproduction,” said Johan Auwerx, a molecular biologist who studies metabolism and aging at École Polytechnique Fédérale in Switzerland. “Excellent functional oocytes allow reproduction, which is the most important act of our existence, from an evolutionary perspective, since it allows the continuation of the species.”

The trade-off though, is that this strategy only seems to be viable for about 35 years in humans. But now that they have a window into what’s happening mechanistically, Böke said fertility doctors could start testing for levels of Complex I subunits in oocytes of women with unexplained infertility to see whether an early exit from this quiescent state is causing the problem. The discovery also points the way toward possible treatments.

“If inhibition of Complex I is what drives these oocytes to stay safe in a quiescent state, then interventions that inhibit activity of Complex I may help extend reproductive lifespan,” said Hine.

One example of a drug that targets Complex I is metformin. Approved in the 1990s for treating diabetes, and since then prescribed to millions of people around the world, metformin has long been linked to longer, healthier lifespans. Researchers comparing the health of people on the drug to those taking other diabetes medications found that metformin-takers tended to get cancer less frequently, were less likely to suffer from age-related dementia, and, in general, just lived longer.

This latest research suggests there might be value in digging back through those epidemiological datasets to see if women with diabetes who take metformin have improved ovarian reserves compared to those who either take other medications or no drugs at all. Studies in mice have also indicated that metformin can delay ovarian aging.

This latest research also highlights the long-overlooked potential of studying reproductive organs like ovaries and oocytes as model systems for aging.

“If we can determine how these genes are selectively silenced in the oocyte, then there may be applications for this know-how in other cell types,” said Auwerx. “This is a major task for the future, with long-ranging clinical implications.”

While scientists have been trying to unravel the biological processes that underlie aging for decades, most federal research dollars have been funneled toward understanding ailments such as Alzheimer’s disease. Reproductive aging, by contrast, has long been an academic backwater. Only recently, as public health agencies have tracked an upward tick in the average age at which Americans start having kids — from 21 in 1970 to 27 in 2014 — have researchers begun to take an interest.

“That’s a drastic societal change in a short period of time,” said Hine. “So we need to catch up and put more resources into this field. It’s been neglected for too long.”

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