Open AccessPremature aging in mice with error-prone protein synthesis
Author(s) -
Dimitri Shcherbakov,
Martiigri,
Rashid Akbergenov,
Margarita Brilkova,
Matilde Mantovani,
Patricia Isnard Petit,
Amandine Grimm,
Agnieszka Karol,
Youjin Teo,
Adrián Cortés Sanchón,
Yadhu Kumar,
Anne Eckert,
Kader Thiam,
Petra Seebeck,
David P Wolfer,
Erik C. Böttger
Publication year - 2022
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abl9051
Subject(s) - biology , translation (biology) , phenotype , telomere , mutation , senescence , longevity , messenger rna , genetics , life span , dna damage , gene , microbiology and biotechnology , dna , evolutionary biology
The main source of error in gene expression is messenger RNA decoding by the ribosome. Translational accuracy has been suggested on a purely correlative basis to positively coincide with maximum possible life span among different rodent species, but causal evidence that translation errors accelerate aging in vivo and limit life span is lacking. We have now addressed this question experimentally by creating heterozygous knock-in mice that express the ribosomal ambiguity mutation RPS9 D95N, resulting in genome-wide error-prone translation. Here, we show thatRps9 D95N knock-in mice exhibit reduced life span and a premature onset of numerous aging-related phenotypes, such as reduced weight, chest deformation, hunchback posture, poor fur condition, and urinary syndrome, together with lymphopenia, increased levels of reactive oxygen species–inflicted damage, accelerated age-related changes in DNA methylation, and telomere attrition. Our results provide an experimental link between translational accuracy, life span, and aging-related phenotypes in mammals.