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<p>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.</p>

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The mammalian longevity associated acetylome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月22日

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  • S. Feldman-Trabelsi,
  • N. Touitou,
  • R. Nagar,
  • Z. Schwartz,
  • A. Michelson,
  • S. Shaki,
  • M. Y. Avivi,
  • B. Lerrer,
  • S. Snir,
  • H. Y. Cohen

摘要

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.