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Altered Translation Elongation Contributes to Key Hallmarks of Aging in the Killifish Brain

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Julien Gagneur

Prof. Dr.

Principal Investigator

Computational Molecular Medicine

Abstract

Introduction: Aging brains are characterized by a series of molecular and cellular changes known as aging hallmarks. Among these, a decline in protein homeostasis (proteostasis) marked by reduced clearance and increased protein damage and aggregation has received particular attention as a plausible link between brain aging and those neurodegenerative diseases also characterized by protein aggregation. A notable phenomenon in brain aging is a loss of concordance between mRNA and protein levels, whereby age-linked changes in mRNA do not necessarily lead to proportional changes in protein levels. In this study, we set out to investigate the causes of this “protein-transcript decoupling” and how impaired protein synthesis might contribute to other hallmarks of brain aging.<br>Rationale: We used the short-lived African turquoise killifish, which exhibits a naturally compressed life span and accelerated brain aging, to undertake a comprehensive investigation of age-related decline in brain proteostasis. We compared young, adult, and old killifish brains at the levels of amino acid concentrations, tRNAs, mRNAs (transcriptome), actively translated mRNAs (translatome), proteins (proteome), protein modifications [phosphorylation (Ph), ubiquitylation (Ub), and acetylation (Ac)], and protein solubility and subcellular localization. We also tested whether reduced protein degradation caused by proteasome impairment contributes to protein-transcript decoupling and other aging hallmarks in the killifish brain. Our comprehensive design allowed us to pinpoint aging-vulnerable steps in protein biogenesis and reveal mechanisms connecting proteostasis decline to other aging hallmarks.<br>Results: We observed alterations in all molecular signatures investigated, ranging from amino acid concentrations to protein solubility and localization. A clear pattern of proteostasis dysfunction emerged: Although the synthesis of some proteins was enhanced, there was a widespread reduction of proteins enriched in positively charged (basic) amino acids. Notably, many DNA and RNA binding proteins exhibited reduced abundance in old brains, decreasing at the protein but not the transcript levels. Ribosome profiling (Ribo-seq) revealed that brain aging increased ribosome stalling. Accordingly, ribosome collisions were more frequent in old brains. Crucially, stalling events occurred disproportionately on stretches enriched in lysine and arginine codons, thus affecting translation of mRNAs encoding proteins enriched in these basic amino acids, leading to a decline in their protein levels in old brains. Aging-affected proteins included ribosomal subunits and proteins involved in DNA repair, transcription, chromatin maintenance, and RNA splicing and export, which all mediate processes influenced by aging. Ribosome stalling was also associated with increased protein insolubility, likely owing to nascent polypeptide misfolding. Partial proteasome inhibition affected aging hallmarks distinct from those linked to translation dysfunction and primarily influenced lysosomes and mitochondria.<br>Conclusion: This work identifies altered translation elongation and impaired protein biogenesis as hallmarks of brain aging in a short-lived vertebrate. Increased ribosome pausing is proposed as a key mechanism contributing to the mismatch between mRNA and protein changes observed in aged brains, leading to proteome aging by altering the production of proteins essential for genome integrity, mRNA transcription, splicing, protein synthesis, and mitochondrial function. This mechanism thereby links translation and proteostasis decline to other hallmarks of aging and may also be implicated in neurodegenerative diseases where similar ribosome dysfunction and protein misfolding occur.

article

Science

389.6759. Jul. 2025.
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Authors

D. Di Fraia • A. Marino • J. H. Lee • E. Kelmer Sacramento • M. Baumgart • S. Bagnoli • T. Balla • F. Schalk • S. Kamrad • R. Guan • C. Caterino • C. Giannuzzi • P. T. da Silva • A. K. Sahu • H. Gut • G. Siano • M.  • E. Terzibasi-Tozzini • E. F. Fornasiero • J. Gagneur • C. Englert • K. R. Patil • C. Correia-Melo • D. D. Nedialkova • J. Frydman • A. Cellerino • A. Ori

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DOI

Research Area

 C2 | Biology

BibTeXKey: DML+25

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