A study reveals the keys to the rodent’s extraordinary ability to live ten times longer than it should, without cancer or age-related degenerative diseases. Applied to flies, they obtained “superflies”.
There is an iron law in nature: the larger the size of a species, the longer its members live. That is why whales surpass elephants in life expectancy and elephants surpass lions. Very few animals do not follow this law. Humans have circumvented it thanks to culture. But there is one small animal that laughs at it. Due to its size, the spiny mouse (Heterocephalus glaber) should not live more than two years, but it usually reaches forty. In addition, it ages healthily, without age-related diseases such as cancer, neurodegenerative diseases or osteoarthritis. Now, research published in Science points to four mutations that make its DNA repair a perfect machine.
A group of Chinese scientists, using advanced gene therapy techniques, investigated the ageing process at the cellular level in the mouse to try to explain its extreme longevity. The rodent, which lives in colonies of two or three dozen individuals huddled together in the regions surrounding the Horn of Africa, has fascinated science for decades. On this occasion, the researchers focused on the machinery for repairing DNA. One of the most serious types of damage it can suffer is what are known as double-strand breaks (the double helix) in the DNA. In such cases, both strands lose genetic material. This is a natural occurrence, resulting from the cycle of replication and cell division. To repair this damage, cells resort to homologous recombination, in which identical or very similar DNA molecules lend genetic fragments. In this process, the activation of an enzyme called cGAS is essential.
‘Ratpip’s cGAS works in the opposite way to that of humans and mice in regulating homologous recombination repair,’ says Yu Chen, a researcher at Tongji University in Shanghai (China) and first author of the study, in an email. “The mouse cells have slower growth rates. Therefore, DNA damage can persist longer in these cells without being repaired, which would eventually lead to sterile inflammation and the onset of ageing,” Chen points out. Among naked mole rats, there is a marked division of labour, previously seen only in eusocial insects such as ants or bees. In the image, one of these rodents in a zoo.
But the enzymes in these rodents remain active for longer, allowing them to recruit more elements that, like mechanics in a workshop, can prolong the stability of the genome within the nucleus of each cell. The researchers found that what differentiates these enzymes from their human or laboratory mouse counterparts are four mutations in four amino acids. They observed that these mutations promoted ‘the recruitment of DNA repair factors to damaged sites and improved repair efficiency; in the long term, this helps to improve cellular and tissue ageing and prolong lifespan,’ explains Chen.
To confirm the role of these four mutations, they genetically modified specimens of the fruit fly (Drosophila melanogaster), the most studied insect in laboratories and about which almost everything is known. Some flies were manipulated to express the human cGAS enzyme, while others had the same enzyme but with the four mutations identified in mice. They almost created superflies: those with rodent material improved their digestive system, showed greater agility even at advanced ages, also showed greater resistance to infections, and the females maintained their ability to lay eggs as they aged. What’s more, while the flies with human genetic material lived as long as the unmodified ones (about 70 days), those carrying the mouse genetics lived a few weeks longer.
They did something similar with laboratory mice, modified to express enzymes from normal mice or with alterations in the four amino acids they identified. After two months, they observed that mice with the bald mouse’s cGAS showed fewer signs of general ageing and cellular senescence in particular. When they looked for other rodents that have these enzymes with the reverse mechanism, the researchers found that only two other species have these amino acid changes in their cellular machinery: the grey squirrel and the blind mole rat. ‘The grey squirrel and the blind mole rat have a life expectancy of over 20 years,’ Chen concludes.
In a commentary also published in Science, scientists at the University of Rochester (United States) who study ageing highlight the discovery of the differential role of cGAS enzymes thanks to just four changes that ‘ultimately result in higher rates of DNA repair’. One of the signatories of this article is Vera Gorbunova, who has been studying mice for years as a model for studying the causes of ageing. In an email, she says: ‘The lesson we have learned is that by modifying cGAS or its downstream pathway, we can improve genome stability, reduce inflammation and promote longevity and health.’
Manel Esteller is another leading expert in the study of ageing, in his case at the Josep Carreras Leukaemia Research Institute. The mouse also interests them because of its exceptional resistance to cancer. ‘This different final form of the cGAS gene causes it to induce rapid repair of errors and breaks in genetic material, which slows down the ageing of its cells and increases its longevity,’ notes Esteller. The Catalan scientist points out that there must be other factors besides the one discovered by Chen’s group that contribute to the ‘incredible longevity of the mouse 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 anthills
Another recently published study reveals all the secrets of the social structure of the naked mole rat, which lives in colonies very similar to those of ants. This is because the environment in which these rodents — also known as naked mole rats — live is as special as their molecular biology. It was known that in their colonies only one of the females reproduces, mating with two or three males. The rest are sterile. But little else was known about their social structure and organisation. The fact that they live huddled together in narrow underground cavities did not facilitate the study of mole rat society. And then RFID technology came along. The University of Tokyo (Japan) has one of the largest collections of mole rats in captivity, with over a hundred distributed across five colonies. What they did, as detailed in Science Advances, was to implant a tiny RFID tag (like those found on many products to trigger alarms) into each animal. This allowed them to be identified at any time.
Until now, it was believed that there was no division of labour among the non-breeders, apart from the fact that the largest and oldest were responsible for defending the colony against predators and rival groups. But it’s not that simple. It has been discovered that while some rats seem to specialise in cleaning the chamber where they urinate and defecate, others are responsible for waste, while there is a group dedicated to transport. According to the authors, this species of mammal has a division of tasks known as temporal polyethism, in which members of the community perform different tasks according to their age. Bees, ants and termites are species that function in this way. And now we know that field mice do too.
