Ageing-related decline of translation as a consequence of transcription dysregulation.

Abstract

The ageing-related decline of translational fidelity disrupts cellular protein homeostasis, thus contributing to the onset of cancer and neurodegeneration. However, it remains unclear what alters speed and accuracy of translation at advanced age. Here, I show that the shift in translation kinetics upon ageing is systematic and a direct consequence of transcription deregulation. Computational modelling of ageing yeast and worm Riboseq data demonstrates that the loss of translational fidelity is independent of codon identity, tRNA abundances or the specificities of anticodon-codon interactions at the ribosome. Instead, large-scale transcriptional changes during ageing perturb the codon usage of the transcriptome, which at the systems level induces a dramatic remodelling and increase in ribosome collisions and stalling. Ribosome collisions in turn reduce control over translation elongation and effect an assimilation of codon translation rates. The presented results thus explain the ageing-related decline of translational fidelity, and provide important insights towards a systems-level understanding of ageing-related human diseases linked to mistranslation and protein homeostasis failure that are especially prevalent in the brain.