Tian, X et al. Cell 177, 622–638.e22 (2019)

The mechanisms responsible for the differences in maximum lifespan (MLS) between various mammals are unclear. Previous studies have shown that DNA repair mutants have accelerated aging phenotypes, suggesting that DNA repair is a longevity determinant. A new systematic analysis of DNA repair in primary fibroblasts isolated from 18 species of rodents with MLS ranging from 3 to 32 years shows that DNA double-strand break (DSB) coevolves with longevity. By showing that NAD-dependent protein deacetylase sirtuin-6 (SIRT6) promotes DSB repair and that differences in SIRT6 activity contribute to the variation in DSB repair efficacy between short-lived and long-lived species, the study provides new targets for anti-aging strategies. Further analysis showed that differences in five amino acids determine the differences in SIRT6 activity between mouse and beaver, two species with very different lifespans.