The Error-Catastrophe Theory of Aging proposes that translation errors can erode translational machinery, resulting in a vicious cycle of ever-increasing translation errors and ultimately death. Despite substantial influence since its first proposal in the 1960s, this theory has failed to stand up to empirical testing of two major predictions, namely an increase in translation errors with age and a correlation between translation fidelity and longevity. Here, we present support for both predictions while explaining previous failures. By assessing the chronological lifespans and translation error rates in a panel of yeast recombinant haploid progeny, we identified the correlation between translational fidelity and longevity, which is obscured by the constrained variation of the highly pleiotropic translation error rate. Genomic analyses with this consideration revealed that the vacuole/lysosome, rather than the translational machinery, as the genetic link underlying the fidelity-longevity correlation. Moreover, genome-wide quantification of two major types of translation errors shows that error loads increase with age in yeasts and mammals, and such increases are biased towards genes involved in tissue-specific functions. Collectively, our results support the role of translation error in aging, and highlight how genomic evolutionary considerations could offer critical insights for functional studies.

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