This is several orders of magnitude higher compared to DNA mutations, which are estimated at 1.4 × 10 −8 per nucleotide site per generation for base substitutions in humans ( Lynch et al., 2016). The frequency of protein errors is estimated at 10 −3 to 10 −6, depending on the organism and codon ( Ke et al., 2017 Kramer et al., 2010 Salas-Marco and Bedwell, 2005 Stansfield et al., 1998). This is despite mistranslation being the most erroneous step in gene expression.

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. These findings pave the way for identifying novel translation accuracy interventions to improve aging. This implies a unified mode of action for diverse pharmacological anti-aging therapies. 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. 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.

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. 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.

Loss of proteostasis is a fundamental process driving aging.

Life in middle east v0.8