Large‐scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals

Lifespan varies significantly among mammals, with more than 100‐fold difference between the shortest and longest living species. This natural difference may uncover the evolutionary forces and molecular features that define longevity. To understand the relationship between gene expression variation and longevity, we conducted a comparative transcriptomics analysis of liver, kidney, and brain tissues of 103 mammalian species. We found that few genes exhibit common expression patterns with longevity in the three organs analyzed. However, pathways related to translation fidelity, such as nonsense‐mediated decay and eukaryotic translation elongation, correlated with longevity across mammals. Analyses of selection pressure found that selection intensity related to the direction of longevity‐correlated genes is inconsistent across organs. Furthermore, expression of methionine restriction‐related genes correlated with longevity and was under strong selection in long‐lived mammals, suggesting that a common strategy is utilized by natural selection and artificial intervention to control lifespan. Our results indicate that lifespan regulation via gene expression is driven through polygenic and indirect natural selection. Synopsis Multi‐tissue transcriptomics of 103 mammalian species provide insight into the genetic differences that correlate with longevity in mammals. PNMA1 expression positively correlates with longevity in liver, kidney, and brain. Translation fidelity pathway gene expression patterns correlate with longevity across mammals. Methionine restriction genes are under strong selection in long‐lived mammals. Essential genes and cancer genes are also important for lifespan control across species. Graphical Abstract Organ‐specific expression patterns of methionine restriction and translation fidelity genes correlate with longevity in 103 mammalian species.