Premature aging in mice with error-prone protein synthesis

Abstract

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 that Rps9 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.

A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein translation

“…There is currently no mouse model for NGPS but a recent study reported the effect of error- prone protein synthesis in mice ( 48 ). Through engineering a specific ribosomal mutation, the authors induced genome-wide translational errors in mice.…”

“…( E ) Translation error rate measured as an increased read-through using a dual luciferase assay. G418 was used as a positive control for the induction of translational errors ( 48 ). Results are derived from the ratio hFluc/hRluc and given as fold induction.…”

Decoupling of mRNA and protein expression in aging brains reveals the age-dependent adaptation of specific gene subsets

“…Therefore, the age-dependent enrichment of ribosome components might affect protein homeostasis and promote a loss of proteostasis, one of the primary hallmarks of aging. Indeed, flawed translation has been described to lead to premature aging (Shcherbakov et al 2022) and even promote early symptoms of Alzheimer’s disease in aging mice (Brilkova et al 2022).…”

“…to lead to premature aging (Shcherbakov et al 2022) and even promote early symptoms of Alzheimer's disease in aging mice (Brilkova et al 2022).…”

Genome-wide screening reveals metabolic regulation of translational fidelity

“…Reduced translational fidelity often leads to detrimental effects such as slow growth, cell death, and neurological disorders (30). Recent studies in yeasts, flies, worms, and mice also demonstrate that increasing translational fidelity by a ribosomal mutation improves the life span, whereas decreasing translational fidelity leads to accelerated aging (31,32). However, maintaining high fidelity also comes with costs, and increasing translational errors have been shown to be beneficial under certain conditions.…”