Live long and prosper: Chinese scientists find age-well protein in naked mole-rats
Longevity of the rodent family could inspire new therapeutic anti-ageing strategy to improve the health and lifespan of humans, study suggests
The remarkable longevity and disease resistance of naked mole rats are linked to a version of a protein involved in DNA repair that is also found in humans, Chinese scientists have discovered.
The team led by researchers from Shanghai’s Tongji University found that introducing this modified protein in flies and mice reduced the genetic damage associated with ageing and helped to extend lifespan, according to results of their study published earlier this month.
Their findings suggest that the longevity of naked mole rats could inspire a new therapeutic anti-ageing strategy to improve the health and lifespan of humans.
“Our work provides a molecular basis for how DNA repair is activated to contribute to the exceptional longevity during evolution in naked mole-rats,” the team said in a paper published in the peer-reviewed journal Science on October 9
Naked mole-rats are burrowing rodents with a maximum lifespan of around 37 years, which is extraordinary for a mammal of their size.
These hairless rodents not only have a long lifespan, but are also extremely resistant to cancer and age-related symptoms and conditions.
Naked mole-rats also have protein coding sequences and messenger molecules that are more similar to humans than mice, making them a good model to study the molecular mechanisms behind successful ageing, according to the team.
These unique traits have spurred research into the genetic adaptations that protect them from genomic instability – a primary cause of ageing – such as an increase in DNA damage and a decline in DNA repair capacity.
Earlier studies have found that an enzyme called cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is involved in initiating immune defence responses and plays a role in DNA repair.
In humans and mice, cGAS suppresses a type of DNA repair known as homologous recombination within the cell’s nucleus. Defects in this repair pathway have been associated with premature ageing.
The team, which also included researchers from Fudan University, Central South University and the Chinese Academy of Sciences, found that the opposite was true in naked mole-rats.
After studying the naked mole-rat cGAS, the researchers found that it had changes in four specific amino acids, or protein building blocks. These changes allowed their cGAS to enhance rather than inhibit this kind of DNA repair.
“This alteration confers naked mole-rat cGAS with a greater capacity to stabilise the genome, counteract cellular senescence and organ ageing, and promote extended lifespan and health span,” the team said.
Cellular senescence is a state in which cells stop dividing but do not die, and the accumulation of such cells is linked to age-related diseases.
“Manipulating cGAS might therefore constitute a mechanism for lifespan extension,” the researchers said.
The team found that fruit flies expressing the naked mole-rat cGAS had reduced cellular senescence, less organ degeneration, and an extended lifespan.
In mice, expressing naked mole-rat cGAS reduced frailty and hair greying, and decreased cellular senescence markers in multiple tissues.
The team also examined the role of human versus naked mole-rat cGAS in tumour formation, and found that the human cGAS promoted cell transformation to a cancerous state, which could be prevented by making those four amino acid substitutions.
“These findings support the notion that efficient DNA repair decelerates the ageing process and raise the possibility that targeting cGAS to enhance DNA repair could provide an intervention strategy for promoting longevity,” the researchers wrote.