The implications of alternative splicing regulation for maximum lifespan

Area of Science:

• Genomics
• Molecular Biology
• Evolutionary Biology

Background:

• Mammalian maximum lifespan (MLS) exhibits vast diversity, but the underlying molecular drivers are not fully understood.
• Alternative splicing (AS) is a key post-transcriptional mechanism that increases proteomic diversity but its role in lifespan regulation is unclear.

Purpose of the Study:

• To investigate the association between alternative splicing events and mammalian maximum lifespan across different tissues.
• To explore the distinct roles of AS in lifespan regulation compared to gene expression and body mass.

Main Methods:

• Cross-species comparative analysis of alternative splicing across six tissues in 26 mammalian species.
• Identification of conserved AS events significantly associated with MLS.
• Analysis of enriched pathways and overlap with gene expression and body mass-associated splicing.

Main Results:

• Hundreds of conserved AS events were found to be significantly associated with MLS, with the brain showing a high number of tissue-specific events.
• MLS-associated AS events are enriched in pathways related to mRNA processing, stress response, neuronal functions, and epigenetics, distinct from gene expression correlates.
• MLS-associated AS events show unique associations in the brain and limited overlap with age-associated splicing, suggesting programmed lifespan adaptation.

Conclusions:

• Alternative splicing represents a distinct, transcription-independent mechanism regulating mammalian lifespan.
• AS provides unique insights into the molecular basis of longevity, complementing gene expression studies.
• The findings highlight AS as a crucial factor in the evolution and determination of maximum lifespan across species.