Summary 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.

Alternative splicing is an RNA processing used by the cell to increase its protein diversity and genome plasticity through generation of several transcripts from the same gene. It affects the vast majority of biological processes, from stem cell differentiation to cell metabolism. However, tools to properly study the role of a specific splice variant are still missing. With the discovery of the bacterial CRISPR system, a new era in nucleic acid editing has emerged. RNA-directed CRISPR/Cas13 RNAses were recently shown to efficiently target the RNA with higher specificity than Cas9 to the DNA. In this work, we are taking advantage of the catalytic dead mutant dCas13 family member dCasRx to edit alternative splicing patterns in a physiological context. Thanks to our new strategy, isoform-switching splicing changes are easily obtained at endogenous genes without impacting overall gene expression levels. Moreover, we propose a new application for this dCasRx splicing editing system to identify the key regulatory elements involved in the alternative splicing of a given gene. This new approach will increase the RNA toolkit to properly understand the biological impact and regulatory mechanisms of alternative splicing in a given biological process or pathological scenario.