Studying naked mole rats could help develop new anti-aging strategies
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Naked mole rats live up to 37 years, much longer than other rodents their size. What is the secret to their longevity? Among other factors, this could be due to a variant of an immune protein that stimulates DNA repair.
The discovery could lead to therapies that extend human lifespan, says Zhiyong Mao of Tongji University in Shanghai, China. It’s also another piece of evidence that supports the idea that the accumulation of mutations – that is, the inability to repair damaged DNA – is one of the main causes of aging.
The immune protein in question, called cGAS, is found in many animals. Its main function would be to sound the alarm when it detects DNA outside a cell’s nucleus, which could be a sign of cancer or a viral attack.
But CGAS is also found in the nucleus of cells. In humans and mice, it has been shown to suppress DNA repair, thereby increasing mutation rate and cancer risk. The exact reason is unclear – it may be an unwanted side effect rather than an evolved function.
Mao’s team has now shown that the version of cGAS found in naked mole rats has the opposite effect in the nucleus, actually stimulating DNA repair. This is due to differences between four of the amino acids that make up the cGAS protein. If these four amino acids are altered in mole-rat cells, the animal’s cGAS no longer stimulates DNA repair. Conversely, if these are modified in the human version of cGAS, the protein no longer inhibits DNA repair.
Additionally, when the team genetically engineered fruit flies to produce the naked mole-rat version of cGAS, they lived nearly 70 days, compared to about 60 days for the unmodified flies.
So, could the fact that human cells produce naked mole-rat CGAS prolong our lives? “Yes, gene editing and mRNA delivery could be potential ways to improve DNA repair and promote longevity in humans,” says Mao. But it wouldn’t be easy to get enough of our body’s key cells to produce the modified GASc, he says.
Another approach could be to find small-molecule drugs that interact with the human cGAS protein and make it behave like that of the mole rat, Mao says.
The study does indeed suggest that GASc influences lifespan, says Vera Gorbunova of the University of Rochester, New York, whose team showed that a molecule called hyaluronic acid also contributes to the long life of naked mole rats. “[So] Modulating GASc activity by pharmacological or genetic means may have beneficial effects on health and lifespan,” she says.
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