The primary objective of this research is to advance our understanding of the molecular mechanisms that regulate mammalian longevity. While previous studies have extensively investigated genomic, transcriptomic, and metabolomic factors associated with lifespan, the specific role of post-translational modifications, particularly protein acetylation, in longevity regulation remains incompletely understood. This project aims to explore the connection between protein acetylation and mammalian longevity using a tool we developed named PHARAOH (Feldman-Trabelsi et al., Nat Commun 2025; https://doi.org/10.1038/s41467-025-58762-x). By leveraging the natural diversity of longevity across 107 mammalian species, spanning up to a 100-fold difference in lifespan, this research identified over 1,000 novel longevity assisted acetylation sites. Following this identification, we have successfully validated the functional importance of two key sites through experimental assays. Building upon these findings, the next phase of the research aims to identify mutations in human populations that impact those longevity associated acetylation sites, and to establish a connection between these mutations and specific phenotypic traits related to healthspan and lifespan. This integrative approach combining computational, experimental, and population-level analyses is expected to provide deeper insights into the biological role of protein acetylation in aging and longevity.
