Translational fidelity and longevity are genetically linked

Abstract Aging is a series of adverse changes over time that increases mortality risk. Several hypotheses have been proposed to explain aging, including Leslie Orgel’s Error-Catastrophe Theory, which asserts that translation errors erode the translational machinery, become self-amplifying, and eventually lead to death. Evidence for the theory is scarce, especially regarding intra-specific fidelity-longevity correlations. Here, we demonstrate that the correlation can be hidden by the constrained evolution of translational fidelity, but remains detectable in long-lived samples. Measuring the lifespan and translational fidelity of a panel of BY × RM yeast recombinant haploid progenies, we validate the fidelity-longevity correlation. QTL analyses reveal that both fidelity and longevity are most strongly associated with a locus encoding vacuolar protein sorting-associated protein 70(VPS70). Replacing VPS70 in BY by its RM allele reduces translation error by ~8.0% and extends lifespan by ~8.9% through a vacuole-dependent mechanism. Our results support the impact of translational fidelity on intra-specific longevity variation.