Proteins can undergo a large range of post-translational modifications, usually the addition of one or more molecules. This changes the interactions of the protein and its role in cellular biochemistry, and thus post-translational modification is an important aspect of the way in which protein machinery functions in the cell. Acetylation is one such modification, the addition of an acetyl group. Here, researchers assess the acetylome, amounts of all aceltyated proteins in tissues, in search of correlations with species longevity.
Despite extensive studies at the genomic, transcriptomic, and metabolomic levels, the underlying mechanisms regulating longevity are incompletely understood. Post-translational protein acetylation is suggested to regulate aspects of longevity. Analyzing acetylome and proteome data across 107 mammalian species identifies 482 and 695 significant longevity-associated acetylated lysine residues in mice and humans, respectively. These sites include acetylated lysines in short-lived mammals that are replaced by permanent acetylation or deacetylation mimickers, glutamine or arginine, respectively, in long-lived mammals. Conversely, glutamine or arginine residues in short-lived mammals are replaced by reversibly acetylated lysine in long-lived mammals.
Pathway analyses highlight the involvement of mitochondrial translation, cell cycle, fatty acid oxidation, transsulfuration, DNA repair, and others in longevity. A validation assay shows that substituting lysine 386 with arginine in mouse cystathionine beta synthase, to attain the human sequence, increases the pro-longevity activity of this enzyme. Likewise, replacing the human ubiquitin-specific peptidase 10 acetylated lysine 714 with arginine as in short-lived mammals, reduces its anti-neoplastic function. Overall, in this work we propose a link between the conservation of protein acetylation and mammalian longevity.
Link: https://doi.org/10.1038/s41467-025-58762-x
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