The bare mole rat (Heterocephalus glaber) is a small, hairless rodent native to East Africa, and well-known for residing an astonishingly very long time, as much as round 37 years, almost 10x longer than mammals of comparable dimension. Scientists have lengthy suspected its exceptional longevity comes from diversifications that preserve its DNA intact.
As we age, DNA harm accumulates in our cells. Normally cells restore these breaks utilizing a number of molecular pathways, however errors or inefficiencies in restore make genomes unstable and result in ageing and illness.
One molecule identified to affect this course of is cyclic GMP-AMP synthase (cGAS). In people and mice, cGAS helps detect overseas DNA, similar to that from viruses, and triggers immune responses. However, it additionally suppresses one of many physique’s principal DNA-repair techniques, known as homologous recombination. As a consequence, human cGAS can truly make cells extra susceptible to ageing and most cancers.
Scientists have puzzled whether or not, throughout evolution, the bare mole rat may need modified cGAS in order that it not interferes with DNA restore, or possibly even helps it. A brand new research led by researchers at Tongji University, and not too long ago printed in Science, got down to test this concept.
The researchers in contrast the cGAS genes and proteins of bare mole rats with these of people and mice. They used genetic engineering instruments to modify particular amino acids — the constructing blocks of proteins — between species and observe the consequences on DNA restore. They additionally carried out experiments in cell cultures, fruit flies, and mice to check how these molecular adjustments affected genome stability, mobile ageing, and lifespan.
Thus the crew discovered that in people and mice, cGAS interferes with the homologous recombination pathway — however in bare mole rats cGAS enhances it. The purpose lay in 4 amino acid substitutions in cGAS’s construction, which allowed bare mole rat cGAS to stay certain to DNA for longer after harm occurred as a substitute of being rapidly eliminated. This binding prevented cGAS from being tagged for destruction by a course of known as ubiquitination.
Instead, bare mole rat cGAS introduced collectively two restore proteins, known as FANCI and RAD50, to hurry up homologous recombination and assist repair DNA breaks extra effectively. Cells with this modified cGAS confirmed fewer indicators of stress-induced getting old.
When the scientists put the identical 4 amino acid adjustments into human cGAS, the molecule stopped harming DNA restore.
The discovery is exceptional for exhibiting that longevity can evolve not solely by enhancing useful restore enzymes but in addition by weakening dangerous regulators. In the bare mole rat, evolution basically ‘flipped’ the function of cGAS, supporting the long-standing concept that environment friendly DNA restore is likely one of the principal defenses in opposition to ageing.
“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 researchers wrote of their paper.
Independent consultants have mentioned that if scientists can safely reproduce this impact in different species, together with people, it might open new paths for age-related analysis and therapies. For instance, medicines that regulate how cGAS interacts with DNA would possibly assist cells preserve genome integrity with out compromising the immune system.