Study Unlocks Clues to Naked Mole-Rats’ Exceptional Fertility

A new study sheds light on unique processes that bestow naked mole-rats with what seems like eternal fertility, findings that could eventually point to new therapies for people.

Naked mole-rats are the longest-lived rodent, with a maximum life span of more than 37 years. They are highly resistant to cancer, don’t feel pain like other mammals, live in underground colonies – and unlike most female mammals, including humans and mice, don’t experience a drop in fertility as they age.

For most mammals, including humans and mice, females are born with a finite number of egg cells, which are produced in utero via a process called oogenesis. Because this limited supply of egg cells depletes over time – some are released during ovulation, but most simply die – fertility declines with age.

A new study, published Feb. 22 in Nature Communications, suggests that naked mole-rats have exceptionally large numbers of egg cells compared to mice, and that death rates of these cells were lower than in mice. For example, at 8 days old, naked mole-rat females had on average 1.5 million egg cells, about 95 times more than mice of the same age.

Most remarkably, the study found that oogenesis – the process by which egg cells are produced – happens postnatally in naked mole-rats. Egg precursor cells were actively dividing in 3-month-old animals, and these precursors were found in 10-year-old animals, suggesting that oogenesis could continue throughout their lives.

“This finding is extraordinary,” said senior author Dr. Ned Place, professor in the College of Veterinary Medicine. “It challenges the dogma that was established nearly 70 years ago, which stated female mammals are endowed with a finite number of eggs before or shortly after birth, without any additions being made to the ovarian reserve thereafter.”

In contrast, naked mole-rat queens can breed right through old age, suggesting the rodents have special processes to preserve their ovarian reserve and avoid waning fertility.

The researchers compared ovaries from naked mole-rats and mice across different stages of development. Despite their similar sizes, mice live four years at most and start to show a drop in fertility by nine months, whereas naked mole-rats have a life expectancy of 30 years or more.

Naked mole-rats live in colonies of several dozen to hundreds of individuals. Like bees and ants, colony members divvy up tasks, including providing defense, digging tunnels, caring for young and collecting food. Only the single dominant female in a colony can breed, and she suppresses reproduction in other females to maintain her queenly status.

“Unlike bees or ants, a female naked mole-rat is not born a queen,” said lead author Dr. Miguel Brieño-Enríquez, assistant professor at Magee-Womens Research Institute and the University of PittsburghSchool of Medicine’s Department of Obstetrics, Gynecology and Reproductive Sciences. “When the queen dies or is removed from the colony, a subordinate female becomes reproductively activated and takes her place. Any girl can become a queen.”

To learn more about this process, the researchers removed 3-year-old females from the colony to prompt reproductive activation and compared these new queens with subordinate females. They found that non-breeding subordinates had egg precursor cells in their ovaries, but the cells started dividing only after a transition to queen.

“This is important because if we can figure out how they’re able to do this, we might be able to develop new drug targets or techniques to help human health,” said Brieño-Enríquez. “Even though humans are living longer, menopause still happens at the same age. We hope to use what we are learning from the naked mole-rat to protect ovary function later in life and prolong fertility.”

“But the ovary is more than just a baby factory,” he continued. “Ovary health influences cancer risk, heart health and even lifespan. Better understanding of the ovary could help us find ways to improve overall health.”

Other Cornell authors contributing to the study are: Paula Cohen, professor of genetics and associate vice provost for life sciences; Ashley McGrath ’19; Dr. Alexandra M. Prado, D.V.M. ’21; Jacob Sinopoli ’19; and Kate Wagner ’20. Other co-authors are: Mariela Faykoo-Martinez, Michael D. Wilson and Melissa M. Holmes, all of the University of Toronto; Meagan Goben, Patrick T. Walsh and Samia H. Lopa, all of Pittsburgh; and Diana J. Laird of the University of California, San Francisco.

This research was funded by the National Institutes of Health, the Natural Sciences and Engineering Research Council of Canada, the Ontario Early Researcher Award, the W.M. Keck Foundation Award, the Empire State Stem Cell Fund and the Magee-Auxiliary Woman Scholar endowment.

Publication: Miguel Angel Brieño-Enríquez, et al., Postnatal oogenesis leads to an exceptionally large ovarian reserve in naked mole-rats, Nature Communications (2023) DOI: 10.1038/s41467-023-36284-8

Original Story Source: Cornell University