Nature reviews research on whether enhancing DNA repair could slow aging
Nature reviews research on whether enhancing DNA repair could slow aging
On 4 August, the journal explained why cellular repair should be viewed as a network of interconnected systems. The authors discuss DREAM as a shared regulator, a protein complex that limits the activation of repair genes in somatic cells.
DNA is damaged every day by ultraviolet radiation, metabolic byproducts, and environmental substances. According to a Nature review, an ordinary cell can sustain up to 100 000 such lesions each day. Morten Scheibye-Knudsen, a gerontologist at the University of Copenhagen, notes: “The vast majority of damage is repaired. We have very efficient repair.”
Cells repair DNA in several ways. One pathway replaces a damaged component, another removes a section of the strand, and a third joins broken ends. These repair systems are interconnected, so enhancing one can disrupt the others. Researchers are therefore looking for a way to modify several repair programs at once.
Long-lived animals provide one basis for this idea. Bowhead whales live for more than 200 years, and their cells repair double-strand DNA breaks more accurately. When researchers introduced the whale protein CIRBP, which helps cells survive cold stress, into human cells, two types of this repair became more active.
In a 2022 comparative study of 16 mammalian species, the annual rate of somatic mutations, meaning DNA changes that arise in the body’s cells, was inversely associated with lifespan. The same pattern was observed across different types of changes produced by different mechanisms. This finding directs the search toward several repair pathways at once.
One candidate for this role is DREAM, a protein complex that limits the activation of many repair genes in cells that have temporarily stopped dividing. In a 2023 study, researchers reduced DREAM activity in roundworms and blocked DYRK1A, an enzyme that helps assemble the complex, in cultured human cells. Compared with control cells, these cells then activated repair genes more strongly and were less likely to die after ultraviolet exposure or chemical damage.
In a mouse model with a defect in ERCC1, a gene required for one DNA repair pathway, a two-week course of harmine, which blocks DYRK1A, reduced markers of DNA damage and the death of photoreceptors, the light-sensing cells of the retina. “For the first time, we were actually able to increase overall repair capacity,” said Björn Schumacher, an author of the DREAM study.