Eggs survive for decades without aging.Now scientists may know why

MeFemale mammals, the evolutionary gambits of high stakes, are born with a limited amount of immature eggs. Propagation of future generations depends on this spare egg cell, the “primitive oocyte,” to stay alive and out of the way of molecules that cause harmful mutations. Therefore, it is possible to produce mature eggs that can produce healthy eggs. descendants.

Such a feat should not be possible.

To stay alive, cells must produce energy. However, the organelles that do that, mitochondria, are not 100% efficient. They leak electrons, which are scooped up by lone oxygen molecules and supercharge them to the “free radicals” of DNA bashing, lipid ripping. Scientists have long been confused about how oocytes, the largest cells in the human body and rich in mitochondria, maintain their original cellular state for up to 50 years.

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That was the question Elvan Böke tried to answer when he founded the Institute for Egg Mother Cell Biology and Cell Dormantism at the Genome Regulatory Center in Barcelona in 2017. After many years of painstaking experiments combining live imaging and proteomics, she and her colleagues found that oocytes wear other types of tissue, the basic metabolic reactions that occur in all other cells of the human body. Suffering from skipping.

Their work, Published in Nature on WednesdayIs the first time scientists have observed animal cells using alternative metabolic pathways that avoid the production of destructive free radicals. Researchers say the findings not only open new avenues for treating infertility, but may also provide a blueprint for improving the longevity of other types of human cells. I did.

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“This is very compelling data,” said Christopher Hine, an aging researcher at the Learner Institute at Cleveland Clinic who was not involved in the new study. “They were able to answer questions that were long believed to be unanswerable.”

We tend to think of aging as occurring when people orbit the sun for the 60th or 70th time. However, when born with female reproductive organs (ovaries, fallopian tubes, uterus), these tissues begin to age in the 30th year of life. Around the age of 35, oocytes suddenly begin to decline.

The way primordial oocytes have been dormant for 30 years, undamaged, and why these cells suddenly begin to deteriorate after 5 years are important issues surrounding female age-related infertility. “This treatise sheds new light on the whole process,” said John Aitken, a reproductive biologist at Newcastle University in Australia.

In the 1980s, Aitken discovered free radicals that attack sperm DNA, the main cause of male infertility. Bake’s group has shown that oocytes are not protected from free radicals in much of their early life, as many scientists believe, but instead, carefully reconstruct metabolism. In the first place, it avoids the production of these toxic molecules.

Mitochondria power cells by receiving 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 it happens 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 the gatekeeper of this process,” Böke told STAT by email. So she was surprised to find that the mitochondrial gene that produces complex I was turned off in a study of human and frog oocytes. Parasitic mistletoe is the only other multicellular organism known to exist without it.

By skipping Complex I, primordial oocytes can eliminate the main cause of electron leakage and eliminate free radical damage while maintaining ultra-low energy states such as standby mode.

“The safeguards built here are more robust than many other systems such as the heart and liver, demonstrating the importance of protecting reproduction,” said the Swiss Ecole Polytechnique Federal. Said Johann Owerks, a molecular biologist studying aging. “Excellent functional oocytes enable reproduction, which is the most important act of our existence from an evolutionary point of view, because it allows the species to survive.”

However, as a trade-off, this strategy seems to be feasible for humans for only about 35 years. However, being able to mechanically know what was happening, fertility doctors tested the levels of the oocyte complex I subunit in unexplained infertility women and this quiescence. He said he could see if early exit from the state was causing the problem. This finding also points the way to possible treatments.

“If inhibition of complex I drives these oocytes to stay safe in a quiescent state, interventions that inhibit complex I activity may help prolong reproductive lifespan.” Hine says.

One example of a drug that targets complex I is metformin. Approved as a treatment for diabetes in the 1990s and since then prescribed to millions of people around the world, metformin has long been linked to longer and healthier lifespans. Researchers who compared the health status of people taking medications to those taking other diabetes medications found that people taking metformin were less likely to develop cancer and suffer from age-related dementia. We have found that it is unlikely and generally tends to live longer.

This latest study confirms whether diabetic women taking metformin have improved ovarian reserve compared to women taking other medications or not taking any medications at all. It suggests that it may be worth digging into these epidemiological datasets to do so. Study in mouse It has also been shown that metformin can delay ovarian aging.

This latest study also highlights the long-overlooked potential of studying reproductive organs such as the ovaries and oocytes as a model system for aging.

“If we can determine how these genes are selectively silenced in oocytes, there may be applications of this know-how in other cell types,” Auwerx said. “This is a major challenge for the future and has long-term clinical implications.”

Scientists have been trying for decades to elucidate the biological processes that underlie aging, but most federal research funding has been directed towards understanding diseases such as Alzheimer’s disease. rice field. In contrast, reproductive aging has long been an academic backwater. Most recently, researchers have begun to take an interest as public health agencies are tracking an increase in the average age at which Americans begin to give birth (from 21 in 1970 to 27 in 2014).

“It’s a dramatic short-term social change,” Hine said. “Therefore, we need to catch up with this area and invest more resources. It has been ignored for too long.”