Despite extensive studies at the genomic, transcriptomic, and metabolomic levels, the underlying mechanisms regulating longevity remain incompletely understood. Post-translational protein acetylation has been suggested to regulate aspects of longevity. To further explore the role of acetylation, we developed the PHARAOH computational tool, based on the 100-fold differences in longevity within the mammalian class. Analyzing acetylome and proteome data across 107 mammalian species identified multiple significant longevity-associated acetylated lysine residues in mice and humans, controlling many longevity-related pathways. Specifically, we found that longevity-associated acetylation sites help resolve the Peto Paradox: the enigma of why animals with increased body size live longer yet do not exhibit much higher cancer incidence. Our findings show a significant positive correlation between these new acetylation sites and protection against multiple types of cancer in humans. Moreover, mutating these sites reduced the anti-neoplastic functions of the acetylated proteins. These findings provide new insights into the pivotal role of protein acetylation in mammalian longevity, suggesting potential interventions to extend human healthspan.
