DNA repair mechanisms help explain why naked mole-rats live a long life

Naked mole-rats are one of nature’s most extraordinary creatures. These burrowing rodents can live for up to 37 years, around ten times longer than relatives of a similar size. But what is the secret to their extreme longevity? How are they able to delay the decay and decline that befalls other rodents? The answer, at least in part, is due to a switch in a common protein that boosts 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 fixed, it leads to defective cells, damaged proteins and eventually a breakdown in the body’s functions.

To understand how the naked mole-rat is so resistant to DNA damage, a study led 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 the researchers suspected it may have evolved a different function in the long-living rats.

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

Testing longevity

To test this, the scientists inserted the mole-rat’s unique cGAS into human and mouse cells in the lab. The result was a significant boost in the cells’ ability to repair their DNA and a reduction in cellular aging. Then, they engineered fruit flies to produce naked mole-rat cGAS and found that they lived around ten days longer than a control group of fruit flies that couldn’t produce cGAS. Finally, they used gene therapy to give the naked mole-rat cGAS to mice. These treated rodents were less frail, had less gray hair and there were fewer old, worn out cells in different organs than mice that didn’t receive the gene.

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

Research of this nature makes it tempting to wonder if it could be used to increase longevity in humans by modifying amino acids in cGAS. Well, possibly, but there is a long way to go before that could happen. In the meantime, scientists have a new target for developing therapies to treat age-related diseases.

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