SIRT6 in Longer Lived Mammals Produces More Efficient DNA Repair
The sirtuin gene SIRT6 is involved in DNA repair, among many other processes. Researchers here report that differences in SIRT6 between shorter and longer lived mammals give rise to more efficient DNA repair in the longer-lived species. This might be taken as evidence for nuclear DNA damage to be significant in aging, but the challenge is always in isolating just the one effect. So while altering fly SIRT6 to look more like that of mammals results in extended life spans, proving that this is all due to DNA repair is a challenging project yet to be accomplished.
SIRT6 is often called the "longevity gene" because of its important role in organizing proteins and recruiting enzymes that repair broken DNA; additionally, mice without the gene age prematurely, while mice with extra copies live longer. The researchers hypothesized that if more efficient DNA repair is required for a longer lifespan, organisms with longer lifespans may have evolved more efficient DNA repair regulators. Is SIRT6 activity therefore enhanced in longer-lived species?
To test this theory, the researchers analyzed DNA repair in 18 rodent species with lifespans ranging from 3 years (mice) to 32 years (naked mole rats and beavers). They found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes - the SIRT6 proteins - are more potent. That is, SIRT6 is not the same in every species. Instead, the gene has co-evolved with longevity, becoming more efficient so that species with a stronger SIRT6 live longer.
The researchers then analyzed the molecular differences between the weaker SIRT6 protein found in mice versus the stronger SIRT6 found in beavers. They identified five amino acids responsible for making the stronger SIRT6 protein more active in repairing DNA and better at enzyme functions. When the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. The beaver SIRT6 also better increased the lifespan of fruit flies versus fruit flies with mouse SIRT6. Next steps in the research involve analyzing whether species that have longer lifespans than humans - like the bowhead whale, which can live more than 200 years - have evolved even more robust SIRT6 genes.