| dc.identifier.citation | Victoria Eugenia Martinez-Miguel, Celia Lujan, Tristan Espie--Caullet, Daniel Martinez-Martinez, Saul Moore, Cassandra Backes, Suam Gonzalez, Evgeniy R. Galimov, André E.X. Brown, Mario Halic, Kazunori Tomita, Charalampos Rallis, Tobias von der Haar, Filipe Cabreiro, Ivana Bjedov,
Increased fidelity of protein synthesis extends lifespan,
Cell Metabolism,
Volume 33, Issue 11,
2021,
Pages 2288-2300.e12,
ISSN 1550-4131,
https://doi.org/10.1016/j.cmet.2021.08.017.
(https://www.sciencedirect.com/science/article/pii/S1550413121004174)
Abstract: Summary
Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.
Keywords: ribosome; translation; protein synthesis; aging; mTOR; translation fidelity; translation accuracy; archaea; proteostasis; RPS23 | |
| dc.description.abstract | Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging. | en_US |
