Age-Dependent Ribosomal DNA Variations in Mice.

Area of Science:

• Genomics
• Aging research
• Molecular biology

Background:

• The ribosomal DNA (rDNA) repeat is a known unstable genomic region, particularly in aging yeast.
• How rDNA instability manifests in aging mammalian cells remains largely unknown.

Purpose of the Study:

• To investigate age-dependent changes in rDNA copy number and methylation in mice.
• To identify specific rDNA sequence variations in aged mice and assess their functional impact.

Main Methods:

• Quantitative single-cell analyses were performed on bone marrow cells from young (4-week-old) and old (2-year-old) mice of two strains (BALB/cA and C57BL/6).
• Analysis included rDNA copy number, methylation levels, pre-rRNA transcript levels, and rDNA sequence variations.
• Yeast strains were engineered with mouse-specific rDNA mutations to evaluate their effect on cellular lifespan.

Main Results:

• Aged mice exhibited increased rDNA copy number and methylation levels compared to young mice.
• Older BALB/cA mice showed reduced pre-rRNA transcript levels.
• Three novel rDNA mutations unique to old mice were identified, with two found in conserved regions also present in yeast.
• Introducing these mutations into yeast shortened cellular lifespan.

Conclusions:

• The ribosomal DNA (rDNA) repeat is fragile in mammalian cells, exhibiting age-dependent alterations.
• These rDNA changes, including copy number variations and mutations, significantly affect cellular function and lifespan.
• Findings suggest conserved mechanisms of rDNA instability across species during aging.