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Increased fidelity of protein synthesis extends lifespan

Martinez-Miguel, Victoria Eugenia and Lujan, Celia and Espie--Caullet, Tristan and Martinez-Martinez, Daniel and Moore, Saul and Backes, Cassandra and Gonzalez, Suam and Galimov, Evgeniy R and Brown, André EX and Halic, Mario and Tomita, Kazunori and Rallis, Charalampos and von der Haar, Tobias and Cabreiro, Filipe and Bjedov, Ivana (2021) 'Increased fidelity of protein synthesis extends lifespan.' Cell Metabolism, 33 (11). 2288-2300.e12. ISSN 1550-4131

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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.

Item Type: Article
Uncontrolled Keywords: ribosome; translation; protein synthesis; aging; mTOR; translation fidelity; translation accuracy; archaea; proteostasis; RPS23
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 14 Oct 2021 09:04
Last Modified: 06 Jan 2022 14:27
URI: http://repository.essex.ac.uk/id/eprint/31113

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