Translational error in mice increases with ageing in an organ-dependent manner

Erik C. Böttger, Harshitha Santhosh Kumar, Adrian Steiner, Emmanuel Sotirakis, Kader Thiam, Patricia Isnard Petit, Petra Seebeck, David P. Wolfer, Dimitri Shcherbakov and Rashid Akbergenov ()
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Erik C. Böttger: Universität Zürich
Harshitha Santhosh Kumar: Universität Zürich
Adrian Steiner: ETH Zürich
Emmanuel Sotirakis: F-69362
Kader Thiam: F-69362
Patricia Isnard Petit: F-69362
Petra Seebeck: University of Zurich
David P. Wolfer: ETH Zürich
Dimitri Shcherbakov: Universität Zürich
Rashid Akbergenov: Universität Zürich

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract The accuracy of protein synthesis and its relation to ageing has been of long-standing interest. To study whether spontaneous changes in the rate of ribosomal error occur as a function of age, we first determined that stop-codon readthrough is a more sensitive read-out of mistranslation due to codon-anticodon mispairing than missense amino acid incorporation. Subsequently, we developed knock-in mice for in-vivo detection of stop-codon readthrough using a gain-of-function Kat2-TGA-Fluc readthrough reporter which combines fluorescent and sensitive bioluminescent imaging techniques. We followed expression of reporter proteins in-vivo over time, and assessed Kat2 and Fluc expression in tissue extracts and by whole organ ex-vivo imaging. Collectively, our results provide evidence for an organ-dependent, age-related increase in translational error: stop-codon readthrough increases with age in muscle (+ 75%, p 0.5). Together with recent data demonstrating premature ageing in mice with an error-prone ram mutation, our findings highlight age-related decline of translation fidelity as a possible contributor to ageing.

Date: 2025
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DOI: 10.1038/s41467-025-57203-z

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