Reconstructing mammalian lifespan evolution reveals strong phylogenetic effects and lifespan-associated genes

BACKGROUND: Despite the extraordinary diversity in mammalian lifespans, the evolutionary trajectories and underlying molecular mechanisms governing this variation remain largely uncharacterized. RESULTS: By reconstructing maximum lifespan evolution across 968 mammalian species, we found that ~ 23 lineages evolved relatively longer lifespans, while ~ 25 evolved relatively shorter lifespans. To understand the phylogenetic influence on lifespan evolution, we tested 9 evolutionary models and found that Pagel's lambda was the most suitable, indicating a strong effect of shared evolutionary histories on the evolution of mammalian lifespans. Through comparative genomic analysis of 15,231 one-to-one ortholog genes across 122 mammalian species, we identified 628 genes associated with variation in relative lifespan (i.e., longevity quotient). Genes whose evolutionary rates negatively correlated with relative lifespans were enriched for functions related to cell division and DNA repair, whereas those with positive correlations were primarily involved in ion transport and muscle contraction. In vivo experiments further validated the functional relevance of 11 candidate genes in C. elegans. In particular, inhibition of the phi-53 gene extended lifespan, which was associated with upregulation of genes enriched in immune-related functions and downregulation of genes enriched in reproduction-related functions. CONCLUSIONS: Our findings highlight the crucial role of phylogenetic history in shaping mammalian lifespan evolution and provide important molecular insights into the mechanisms governing lifespan variations in mammals.