Genome-wide RNA polymerase stalling shapes the transcriptome during aging.

Area of Science:

• Molecular Biology
• Genetics
• Aging Research

Background:

• Gene expression profiling reveals numerous age-related changes, but underlying mechanisms remain unclear.
• Understanding these mechanisms is crucial for addressing age-related decline.

Purpose of the Study:

• To investigate the mechanisms driving gene expression alterations in aged mice.
• To identify the causes of transcriptional changes associated with aging.

Main Methods:

• Combined nascent RNA sequencing and RNA polymerase II ChIP-seq in aged mice.
• Analyzed gene expression and transcriptional activity in liver tissue.

Main Results:

• Found 40% of elongating RNA polymerases stalled in aged mouse liver, reducing productive transcription.
• Demonstrated that endogenous DNA damage causes this transcriptional stress.
• Showed this stress explains most age-related gene expression changes in postmitotic organs, affecting hallmark aging pathways.

Conclusions:

• Accumulated DNA damage during aging leads to transcriptional stress, altering the transcriptome.
• This process underlies age-related dysfunction in key pathways like nutrient sensing, autophagy, and proteostasis.
• DNA damage is a fundamental driver of normal aging processes.