Increased fidelity of protein synthesis extends lifespan

Article


Martinez-Miguel, V. E., Lujan, C., Espie-Caullet, T., Martinez-Martinez, D., Moore, S., Backes, C., Gonzalez, S., Galimov, E. R., Brown, A. E. X., Halic, M., Tomita, K., Rallis, C., von der Haar, T., Cabreiro, F. and Bjedov, I. 2021. Increased fidelity of protein synthesis extends lifespan. Cell Metabolism. 33 (11), pp. 2288-2300.e12. https://doi.org/10.1016/j.cmet.2021.08.017
AuthorsMartinez-Miguel, V. E., Lujan, C., Espie-Caullet, T., Martinez-Martinez, D., Moore, S., Backes, C., Gonzalez, S., Galimov, E. R., Brown, A. E. X., Halic, M., Tomita, K., Rallis, C., von der Haar, T., Cabreiro, F. and Bjedov, I.
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.

JournalCell Metabolism
Journal citation33 (11), pp. 2288-2300.e12
ISSN1550-4131
Year2021
PublisherElsevier (Cell Press)
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Digital Object Identifier (DOI)https://doi.org/10.1016/j.cmet.2021.08.017
Publication dates
Online14 Sep 2021
Print02 Nov 2021
Publication process dates
Accepted30 Aug 2021
Deposited20 Sep 2021
FunderEuropean Research Council
Cancer Research UK
The Royal Society
Wellcome Trust
Medical Research Council
Biotechnology and Biological Sciences Research Council
National Institutes of Health
Copyright holder© 2021 The Author(s)
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