There is an iron law in nature: the larger a species, the longer its members live. That’s why whales outlive elephants, and elephants outlive lions. Very few animals defy this rule. Humans have circumvented it thanks to culture. But there is a small animal that laughs in its face. Given its size, the naked mole-rat (Heterocephalus glaber) shouldn’t live more than two years, yet they often approach 40. What’s more, they age healthily, without typical age-related diseases such as cancer, neurodegenerative disorders, or arthritis. Now, a study published in Science points to four mutations that make their DNA repair system exceptionally efficient.
A team of Chinese scientists, using advanced gene therapy techniques, investigated the cellular aging of the naked mole-rat to try to explain its extreme longevity. The rodent, which lives in colonies of two to three dozen tightly packed individuals in regions surrounding the Horn of Africa, has fascinated scientists for decades. This time, researchers focused on the machinery that repairs DNA.
One of the most serious types of damage is so-called double-strand breaks, in which both strands of the DNA helix lose genetic material. This is a natural occurrence, resulting from the cycle of cell replication and division. To repair such damage, cells use a process called homologous recombination, in which identical or very similar DNA molecules lend genetic fragments to one another. A key player in this process is an enzyme called cGAS.
“The naked mole-rat’s cGAS works in the opposite way to that of humans and mice in regulating repair via homologous recombination,” says Yu Chen, a researcher at Tongji University in Shanghai, China, and the study’s first author, in an email. “Naked mole-rat cells grow more slowly. Therefore, DNA damage could persist for longer in these cells without being repaired, which would eventually lead to sterile inflammation and the onset of aging,” Chen explains.
But the enzymes in these rodents remain active for longer, allowing them to recruit more components that, like mechanics in a workshop, prolong the stability of the genome within each cell’s nucleus. Researchers discovered that what sets these enzymes apart from their human or laboratory mouse counterparts are four mutations in specific amino acids. They found that these mutations promoted “the recruitment of DNA repair factors to damaged sites and improved repair efficiency; this, in the long run, helps improve cellular and tissue aging and extends lifespan,” Chen explains.
To confirm the role of these four mutations, they genetically modified fruit flies (Drosophila melanogaster), the most thoroughly studied insect in laboratories. Some flies were engineered to express the human cGAS enzyme, while others carried the same enzyme but with the four mutations identified in the naked mole-rats. It was as if they had created “superflies”: those with the rodent-modified enzyme showed improved digestive function, greater agility even in old age, increased resistance to infections, and the females maintained their egg-laying capacity as they aged. What’s more: while flies with the human enzyme lived about the same as unmodified flies (around 70 days), those with the naked mole-rat version lived a few weeks longer.
A similar experiment was done with laboratory mice, modified to express either the normal naked mole-rat cGAS enzyme or the version with the four amino acid changes. After two months, mice with the naked mole-rat cGAS showed fewer signs of general aging and cellular senescence. When researchers looked for other rodents with cGAS enzymes that act in the opposite way to those in humans and mice, they found only two species with the same amino acid changes: the gray squirrel and the blind mole-rat. “The gray squirrel and blind mole-rat have a life expectancy of more than 20 years,” Chen concludes.
In a commentary also published in Science, scientists from the University of Rochester who study aging highlight the discovery of the differential role of cGAS enzymes thanks to just four changes, which “ultimately result in higher rates of DNA repair.” One of the authors, Vera Gorbunova, has spent years studying naked mole-rats as a model for aging. In an email, she says: “The lesson we’re learning is that by modifying cGAS or its downstream pathway, we can improve genome stability, reduce inflammation, and promote longevity and health.”
Manel Esteller, a leading expert in aging at the Josep Carreras Leukemia Research Institute, is also interested in the naked mole-rat for its exceptional cancer resistance. “This different final form of the cGAS gene causes it to rapidly repair errors and breaks in genetic material, which delays the aging of its cells and increases longevity,” says Esteller.
The Spanish scientist points out that there must be other factors beyond those discovered by Chen’s group that contribute to the naked mole-rat’s “incredible longevity in extreme living conditions, but the discovery is significant because it shows how evolution shapes our genes to give us a survival advantage depending on our environment.”
Mammals in ant hills
Another recent study reveals all the secrets of the naked mole-rat’s social structure, which resembles that of ants. The environment in which these rodents live is as extraordinary as their molecular biology. It was known that in their colonies only one female reproduces, mating with two or three males, while the rest are sterile. Beyond that, little was known about their social organization. Studying them was difficult because they live tightly packed, on top of one another, in narrow underground chambers. That’s where RFID technology came in.
At the University of Tokyo in Japan, researchers maintain one of the largest collections of captive naked mole-rats — over a hundred individuals spread across five colonies. What they did, as detailed in Science Advances, was implant tiny RFID tags (similar to those used to track products in stores) in the animals. This allowed them to identify each individual at all times. Over the course of a month, they recorded more than 83 million events, which they used to decipher the colony’s organization and social behavior.
The study confirmed the central role of the so-called breeders — the queen and her consorts — whose needs are served by the rest of the colony. Until now, it was thought that non-breeders had no division of labor beyond the fact that the largest and oldest individuals handled defense against predators and rival colonies. But the reality is more complex. Researchers found that some mole-rats specialize in cleaning the chamber where the colony urinates and defecates, others maintain the trash chamber, and another group is dedicated to transportation.
According to the authors, this mammal species exhibits a type of labor division known as temporal polyethism, in which members of the community perform different tasks depending on their age. Bees, ants, and termites are species that operate this way — and now it is known that naked mole-rats do too.
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