Human eggs use a minimalist strategy to stay healthy for decades

Human eggs are some of the most patient cells in the body, lying dormant for decades until needed. A study published today in The EMBO Journal shows that the cells deliberately slow the activity of their internal waste disposal systems as they mature, most likely an evolutionary design which keeps metabolism low and damage at bay.

By looking at more than a hundred freshly donated eggs, the largest dataset of its kind, we found a surprisingly minimalist strategy that helps the cells stay pristine for many years."

Dr. Elvan Böke, corresponding author of the study and Group Leader, Centre for Genomic Regulation (CRG), Barcelona

Women are born with one to two million immature eggs, a stock that dwindles to a few hundred by menopause. Each egg must avoid wear-and-tear for up to five decades before it can support a pregnancy. The new study suggests how they manage it.

Protein recycling is essential housekeeping, and lysosomes and proteasomes are the cell's main waste disposal units. But every time these cellular components degrade proteins, they consume energy. This in turn can create reactive oxygen species (ROS), harmful molecules that can damage DNA and membranes. The team did not measure ROS directly, but hypothesise that by tapping the brakes on recycling, the egg keeps ROS production to a minimum while still doing enough housekeeping to survive.

The idea meshes with the group's previous work, published in 2022, which showed that human oocytes deliberately skip a fundamental metabolic reaction to curb ROS production. Taken together, the two studies suggest that human eggs power down in different ways to keep potential damage as low as possible for as long as possible.

The discovery was made possible by collecting over 100 eggs from 21 healthy donors aged 19–34 at Dexeus Mujer, a Barcelona fertility clinic, 70 of which were fertilisation-ready eggs and 30 still-immature oocytes. Using fluorescent probes, they tracked lysosome, proteasome and mitochondrial activity in live cells. All three readouts were roughly 50 percent lower than in the eggs' own surrounding support cells and fell even further as the cells matured.

Live-imaging showed the eggs literally jettisoning lysosomes into the surrounding fluid during the last hours before ovulation. At the same time, mitochondria and proteasomes migrated to the cell's outer rim. "It's a type of spring cleaning we didn't know human eggs were capable of," says first author Dr. Gabriele Zaffagnini.

The research is the largest-scale study of healthy human eggs collected directly from women. Most laboratory research to date has relied on eggs that have been ripened artificially in a dish, yet such in-vitro-matured oocytes often behave abnormally and are linked to poorer IVF results.

The study could lead to new strategies to improve success rates for the millions of IVF cycles attempted worldwide each year. "Fertility patients are routinely advised to take random supplements to improve egg metabolism, but evidence for any benefit for pregnant outcomes is patchy," says Dr. Böke.

"By looking at freshly-donated eggs we've found evidence to suggest the opposite approach, maintaining the egg's naturally quiet metabolism, could be a better idea for preserving quality," she adds.

The team now plans to examine eggs from older donors and failed IVF cycles to see whether throttling the activity of cellular waste disposal units falters with age or disease.