Longevity Briefs: A New Path To Slower Ageing Found In Naked Mole Rats

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Naked mole rats continue to be a subject of fascination for scientists studying ageing. What makes these little hairless creatures so special? For the most part, smaller organisms have shorter lifespans. This trend is fairly consistent, but there are outliers like humans – we live quite a bit longer than most similarly sized mammals. Naked mole rats are an extreme outlier, weighing a little more than a large mouse but living around 40 years in captivity – around 10 times as long as captive mice in ideal conditions. There’s clearly something very different about the biology of ageing in naked mole rats, and figuring out what it is might give us clues about how to slow ageing in humans and prevent age-related diseases.

In this study, researchers investigate the role of a protein called cGAS (cyclic GMP-AMP synthase) in the longevity of naked mole rats. cGAS floats around inside the cell and binds to loose pieces of DNA. These loose pieces of DNA could come from pathogens or be a result of damage to the cell’s own DNA. When it detects stray DNA, cGAS activates immune defences to help the cell fight off a potential infection. However, cGAS also binds to intact DNA inside the nucleus, and this can interfere with one of the main processes for repairing double stranded DNA (homologous recombination). Impaired DNA repair capability is an important component of the ageing process that harms tissue function in general and also promotes age-related diseases like cancer.

The discovery:

Since cGAS appears to promote DNA damage by interfering with repair, the researchers wanted to see if naked mole rats had evolved a way to suppress this aspect of cGAS function. What they discovered was actually more interesting – cGAS in naked mole rats had the opposite effect to the human version, enhancing DNA repair by homologous recombination instead of suppressing it. By swapping out parts of the cGAS protein with the human variant, the researchers were able to demonstrate that this difference in function was down to just 4 amino acids (protein building blocks) that were different in the naked mole rat variant. This amino acid sequence allowed cGAS to stick to the DNA for longer after the break occurred, following which it behaved as an anchor for the assembly of the necessary repair proteins around the break region.

The researchers found that when the mole rat sequence was inserted into the human version of cGAS, it stopped inhibiting repair. To see if this would translate to health benefits in living organisms, they genetically engineered fruit flies to produce the mole rat version of cGAS. What they found was that these flies lived longer than controls on average as well as showing some signs of improved health, such as greater climbing ability and gut barrier integrity. These effects did not occur if the four critical amino acids were replaced.

Taking things one step further, the researchers used a harmless virus to introduce a gene encoding either naked mole rat cGAS or a modified form lacking the important amino acids into 17 month old male mice (roughly equivalent to a human in their 50s). Two months later, mice that received the mole rat cGAS had significantly reduced frailty scores, less inflammation, fewer markers of DNA damage and senescent cells (non-dividing cells) and fewer grey hairs than the controls.

The implications:

This study reveals a new potential mechanism for lifespan extension that we probably wouldn’t have discovered had it not evolved in naked mole rats. We don’t know to what extent this unique form of cGAS contributes to the naked mole rat’s exceptional longevity – finding that out would require scientists to engineer naked mole rats with a modified form of cGAS to see how long they lived.Considering their long lifespans, this would be a very long experiment. This study does however provide some preliminary evidence that expressing naked mole rat cGAS in other species can be beneficial.

Given the increasing use of gene therapy to prevent and treat human diseases, there’s no reason why humans couldn’t one day receive a modified form of cGAS to enhance DNA repair and perhaps slow ageing. Whether this would work is impossible to say, as naked mole rat cGAS could behave differently in the context of human biology.