Codon bias coevolves with longevity

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.