Somatic mutations drive carcinogenesis and aging, shortening animal lifespan. Since gene vulnerability strongly depends on the abundance of mutation hotspots, we tested whether negative selection of hypermutable (e.g., CpG-bearing) codons could contribute to the evolution of mammalian longevity. Our studies showed that the CGA codon was significantly more depleted in long-lived than short-lived mammals, suggesting negative selection of this hypermutable stopogenic codon. Interestingly, our analyses revealed lifespan-dependent codon-usage changes in most amino acids. For a few amino acids, altered codon usage favored translationally optimal codons in long-lived animals, reducing mistranslation and abnormal protein formation. Surprisingly, for a larger group of amino acids, codon usage in long-lived animals favored translationally nonoptimal codons lacking matching isodecoder tRNAs. The most likely explanation for this observation is that slower translation at these codons facilitates co-translational folding, thereby reducing the chances of misfolding and aggregation of misfolded proteins in long-lived animals. Our results suggest that changes in codon usage may produce more balanced proteostasis and a lower rate of cellular aging in long-lived animals. Our finding is consistent with the notion that a hallmark of aging is loss of proteostasis, manifested in the accumulation of abnormal, misfolded proteins.