Increased fidelity of protein synthesis extends lifespan

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

doi:10.1016/j.cmet.2021.08.017

Abstract

SummaryLoss 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.

Highlights

In stark contrast to the well-established effect of DNA mutations on multi-cellular organismal aging and disease (Garinis et al, 2008), the role of translation errors is far less studied and understood
A single substitution in the ribosomal decoding center, RPS23 K60R, reduces stop-codon readthrough translation errors and is evolutionarily conserved in certain archaea Structural studies of the ribosomal decoding center in evolutionarily distant organisms point to the importance of the RPS23 protein for translation accuracy due to its role in domain closure and insertion of the aminoacyl-tRNA into the peptidyl transferase center (Figures 1A, 1B, and S1A–S1C) (Loveland et al, 2017; Rodnina et al, 2017; Schmeing and Ramakrishnan, 2009)
We performed an extensive unbiased phylogenetic analysis of RPS23 in organisms ranging from archaea to eukaryotes, using different databases, and we have consistently found a lysine residue to be remarkably conserved in the KQPNSA region of ribosomal RPS23, nearly invariant throughout evolution

Summary

SUMMARY

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. 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. We show that anti-aging drugs such as rapamycin, Torin, 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

INTRODUCTION

RESULTS AND DISCUSSION

Conclusions

METHOD DETAILS