Cell-specific RNA isoform remodeling in the aging mouse brain.

Area of Science:

• Neuroscience
• Genomics
• Aging Research

Background:

• Aging increases chronic disease risk and disrupts cellular RNA homeostasis.
• Previous single-cell studies mapped RNA abundance but not complex processing changes like alternative splicing in the aging brain.
• Understanding RNA processing changes is crucial for comprehending brain aging.

Purpose of the Study:

• To investigate temporal changes in RNA transcription, processing, and alternative splicing in the aging mouse brain.
• To characterize full-length RNA isoforms and their usage shifts across different brain cell types throughout the lifespan.
• To identify molecular markers associated with aging and cellular senescence in the brain.

Main Methods:

• Combined single-cell analysis with long-read nanopore sequencing.
• Profiled transcriptomes from mice across a lifespan, from young adult to very old.
• Utilized machine learning models to identify senescence markers.

Main Results:

• Identified non-linear, cell-type-specific changes in isoform expression and usage, primarily driven by transcription start site selection.
• Observed aging-associated isoform alterations affecting gene coding potential and polyadenylation sites.
• Discovered a high prevalence of senescence in immune cells and identified isoform markers to distinguish senescent from normal immune cells.

Conclusions:

• Aging significantly remodels RNA metabolism in a cell-type-specific manner within the mouse brain.
• Full-length RNA isoform analysis provides a deeper understanding of gene expression regulation during aging.
• The identified senescence markers in immune cells could aid in developing diagnostics or therapeutics for age-related conditions.