Translational Changes upon Aging and Dietary Restriction in Progeroid DNA-Repair-Deficient Mice

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Aging is a complex multifactorial phenomenon largely driven by damaged macromolecules.We showed recently that with aging, time-and exposure-dependent accumulation of DNA damage derails the basal process of transcription, physically stalling RNA polymerase, lowering and skewing the transcriptional landscape in a gene-length-dependent fashion.However, how this influences the translational output and whether translation is similarly affected is largely unknown.Here, we present a parallel analysis of transcriptional and translational liver profiles from the well-characterized Ercc1 Δ/-progeroid, DNA repair-deficient mouse model compared to wild-type under ad libitum conditions and upon dietary restriction (DR), which strongly delays aging in this mutant.Using ribosome profiling, we found that transcriptional changes during accelerated, normal, and delayed aging are largely preserved at the translational level, ruling out a major translational impact on gene expression in aging.Moreover, in both Ercc1 Δ/-and aged wild-type mice there was a prioritization of inflammation, metabolic redesign, and expression of translation initiation factors, along with a shift in codon occupancy.While translation initiation factors were further increased by DR, absolute codon occupancy was partially normalized, showing a discordant response.In addition, increased ribosomal pausing and a relative reduction of upstream open reading frame expression were both further intensified by DR.Together these data infer a fine-tuning of the translational output, for example, by regulating upstream open reading frames under various cellular stress situations.This study uncovers a complex interplay between DR, DNA damage, aging, and translational regulation, highlighting the potential of DR to modify DNA damage-driven translational dynamics during aging.

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