Premature aging in mice with error-prone protein synthesis

Area of Science:

• Molecular Biology
• Genetics
• Aging Research

Background:

• Ribosomal decoding of messenger RNA is a primary source of gene expression errors.
• Previous correlative studies suggested a link between translational accuracy and maximum lifespan in rodents.
• Causal evidence for translation errors accelerating aging in vivo and limiting lifespan was lacking.

Purpose of the Study:

• To experimentally investigate the causal relationship between translational accuracy and aging in mammals.
• To determine if errors in protein synthesis accelerate aging and reduce lifespan.
• To explore the impact of a specific ribosomal mutation on aging phenotypes.

Main Methods:

• Created heterozygous knock-in mice expressing the RPS9 D95N mutation for genome-wide error-prone translation.
• Observed and analyzed aging-related phenotypes in the knock-in mouse model.
• Assessed various biomarkers of aging, including DNA methylation and telomere attrition.

Main Results:

• RPS9 D95N knock-in mice exhibited a significantly reduced lifespan.
• These mice showed premature onset of multiple aging phenotypes (e.g., weight loss, physical deformities, poor fur).
• Increased reactive oxygen species damage, accelerated DNA methylation changes, and telomere attrition were observed.

Conclusions:

• This study provides the first experimental evidence linking translational accuracy to lifespan and aging in mammals.
• Errors in protein synthesis can accelerate the aging process and reduce lifespan.
• The findings highlight the ribosome's role in aging and suggest potential therapeutic targets for age-related diseases.