Research Paper

Translational changes upon aging and dietary restriction in progeroid DNA-repair-deficient mice

Authors

Ivar van Galen^1,2, Rutger A. Ozinga^1,2, Damon A. Hofman^1,2, Jip van Dinter^1,2, Sem A.G. Engels¹, Kimberly Smit^1,2, Sebastiaan van Heesch^1,2, Jan H.J. Hoeijmakers^1,2,3,4, Wilbert P. Vermeij^1,2,#

¹Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

²Oncode Institute, Utrecht, Netherlands

³Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands

⁴Institute for Genome Stability in Ageing and Disease, Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

^#Correspondence to Wilbert P. Vermeij; W.P.Vermeij@prinsesmaximacentrum.nl

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Abstract

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 wildtype 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. Additionally, increased ribosomal pausing and a relative reduction of upstream open reading frame expression were both further intensified by DR. Together these data infer a finetuning of the translational output, e.g. 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.