DNA repair mechanisms help explain why naked mole rats live long

Naked mole rats are one of nature’s most extraordinary creatures. These burrowing rodents can live up to 37 years, about ten times longer than their similarly sized relatives. But what is the secret of their extreme longevity? How can they delay the decomposition and decline that affects other rodents? The answer, at least in part, is due to a change in a common protein that stimulates DNA repair, according to new research published in the journal Science.

One of the main causes of aging in all animals, including humans, is the accumulation of damaged DNA, our genetic instruction manual. When this damage is not repaired, it leads to faulty cells, damaged proteins, and eventually dysfunction of body functions.

To understand why the naked mole rat is so resistant to DNA damage, a study by researchers at Tongji University in China focused on a common protein called cGAS (cyclic GMP-AMP synthase). In most mammals, CGAS interferes with DNA repair, but researchers suspect it may have evolved a different function in long-lived rats.

The team compared the cGAS protein in naked mole rats to that in humans and mice and identified four changes in the amino acids (building blocks of cGAS) that reverse the function of the protein so that it improves a cell’s ability to repair damaged DNA.

Test longevity

To test this, scientists inserted the mole rat’s unique CGAS into human and mouse cells in the laboratory. The result was a significant increase in the cells’ ability to repair their DNA and a reduction in cellular aging. Next, they engineered fruit flies to produce naked mole-rat CGAS and found that they lived about ten days longer than a control group of fruit flies that could not produce CGAS. Finally, they used gene therapy to deliver naked mole rat cGAS to mice. These treated rodents were less fragile, had less gray hair and contained fewer old and worn cells in different organs than the mice that did not receive the gene.

“This alteration endows naked mole rat cGAS with a greater capacity to stabilize the genome, counteract cellular senescence and organ aging, and promote prolonged lifespan and health span,” the researchers commented.

Research of this nature prompts the question of whether it could be used to increase longevity in humans by modifying the amino acids of GASc. It’s possible, but there’s still a long way to go before that happens. In the meantime, scientists have a new target for developing therapies to treat age-related diseases.

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