Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates aging in mice

Highlights•(PR)n peptides trigger a generalized accumulation of polysome-unbound r-proteins•(PR)n-resistant cells present low rates of ribosome biogenesis•mTOR inhibition or MYC depletion increases resistance to (PR)n peptides•(PR)97 expression accelerates aging in mice, which is alleviated by rapamycinSummaryNucleolar stress (NS) has been associated with age-related diseases such as cancer or neurodegeneration. To investigate how NS triggers toxicity, we used (PR)n arginine-rich peptides present in some neurodegenerative diseases as inducers of this perturbation. We here reveal that whereas (PR)n expression leads to a decrease in translation, this occurs concomitant with an accumulation of free ribosomal (r) proteins. Conversely, (PR)n-resistant cells have lower rates of r-protein synthesis, and targeting ribosome biogenesis by mTOR inhibition or MYC depletion alleviates (PR)n toxicity in vitro. In mice, systemic expression of (PR)97 drives widespread NS and accelerated aging, which is alleviated by rapamycin. Notably, the generalized accumulation of orphan r-proteins is a common outcome of chemical or genetic perturbations that induce NS. Together, our study presents a general model to explain how NS induces cellular toxicity and provides in vivo evidence supporting a role for NS as a driver of aging in mammals.Graphical abstract