The mammalian longevity associated acetylome

S. Feldman-Trabelsi, N. Touitou, R. Nagar, Z. Schwartz, A. Michelson, S. Shaki, M. Y. Avivi, B. Lerrer, S. Snir and H. Y. Cohen ()
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S. Feldman-Trabelsi: Bar-Ilan University
N. Touitou: Bar-Ilan University
R. Nagar: Bar-Ilan University
Z. Schwartz: Bar-Ilan University
A. Michelson: Bar-Ilan University
S. Shaki: Bar-Ilan University
M. Y. Avivi: Bar-Ilan University
B. Lerrer: Bar-Ilan University
S. Snir: University of Haifa
H. Y. Cohen: Bar-Ilan University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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. To further explore the role of acetylation, we develop 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 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.

Date: 2025
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DOI: 10.1038/s41467-025-58762-x

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