Increased fidelity of protein synthesis extends lifespan

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 hyper accuracy 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.

Automated summary

The loss of proteostasis is a fundamental process driving aging, and the accuracy of translation significantly affects proteostasis. A rare amino acid substitution found in certain hyperthermophilic archaea, when introduced into other organisms, improves translation accuracy, heat shock resistance, and longevity. Anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors and extend organismal longevity, particularly in mutants with high translation accuracy due to this unique substitution in the RPS23 protein.