The Implications of Alternative Splicing Regulation for Maximum Lifespan

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Mammalian maximum lifespan (MLS) exhibits over a hundred-fold variation.
• The molecular underpinnings of this lifespan diversity are not fully understood.
• Alternative splicing (AS) is a key regulator of gene function.

Purpose of the Study:

• To investigate the role of conserved alternative splicing events in mammalian maximum lifespan.
• To compare AS patterns across different tissues and their association with MLS.
• To explore the relationship between AS, gene expression, body mass, and aging.

Main Methods:

• Cross-species analysis of alternative splicing across six tissues in 26 mammalian species.
• Identification of conserved AS events significantly associated with MLS.
• Comparison of MLS-associated AS events with gene expression and body mass correlations.
• Analysis of RNA-binding protein motif coordination in MLS- and age-associated AS events.

Main Results:

• Hundreds of conserved AS events were identified and significantly associated with MLS.
• The brain showed a higher prevalence of tissue-specific MLS-associated AS events compared to peripheral tissues.
• MLS-AS events are enriched in pathways related to mRNA processing, stress response, neuronal functions, and epigenetics, distinct from expression-level correlations.
• MLS-associated AS events exhibit stronger RNA-binding protein motif coordination, suggesting programmed lifespan adaptation.

Conclusions:

• Alternative splicing represents a distinct, transcription-independent mechanism regulating mammalian lifespan.
• MLS-associated AS events provide unique insights into longevity, particularly in neural tissues.
• These findings highlight AS as a crucial factor in the evolution and determination of lifespan across mammals.