Rewiring of the ubiquitinated proteome determines ageing in C. elegans

Ageing is driven by a loss of cellular integrity(1). Given the major role of ubiquitin modifications in cell function(2), here we assess the link between ubiquitination and ageing by quantifying whole-proteome ubiquitin signatures in Caenorhabditis elegans. We find a remodelling of the ubiquitinated proteome during ageing, which is ameliorated by longevity paradigms such as dietary restriction and reduced insulin signalling. Notably, ageing causes a global loss of ubiquitination that is triggered by increased deubiquitinase activity. Because ubiquitination can tag proteins for recognition by the proteasome(3), a fundamental question is whether deficits in targeted degradation influence longevity. By integrating data from worms with a defective proteasome, we identify proteasomal targets that accumulate with age owing to decreased ubiquitination and subsequent degradation. Lowering the levels of age-dysregulated proteasome targets prolongs longevity, whereas preventing their degradation shortens lifespan. Among the proteasomal targets, we find the IFB-2 intermediate filament(4) and the EPS-8 modulator of RAC signalling(5). While increased levels of IFB-2 promote the loss of intestinal integrity and bacterial colonization, upregulation of EPS-8 hyperactivates RAC in muscle and neurons, and leads to alterations in the actin cytoskeleton and protein kinase JNK. In summary, age-related changes in targeted degradation of structural and regulatory proteins across tissues determine longevity.

Automated summary

Ageing is driven by a loss of cellular integrity, with ubiquitin modifications playing a major role in cell function. Age-related remodelling of the ubiquitinated proteome is influenced by longevity paradigms like dietary restriction and reduced insulin signalling. The global loss of ubiquitination during ageing is linked to increased deubiquitinase activity, impacting the targeted degradation of structural and regulatory proteins which ultimately determine longevity.