# The implications of alternative splicing regulation for maximum lifespan

## TL;DR

Alternative splicing in the brain is linked to longer lifespans in mammals, offering new insights into longevity.

## Contribution

Identifies conserved alternative splicing events associated with maximum lifespan, distinct from gene expression patterns.

## Key findings

- Hundreds of AS events in the brain are strongly associated with maximum lifespan across 26 mammalian species.
- MLS-associated AS events are enriched in stress response and epigenetic regulation pathways.
- MLS-AS events show stronger RNA-binding protein motif coordination compared to age-associated splicing.

## Abstract

Mammalian maximum lifespan (MLS) varies over a hundred-fold, yet the molecular mechanisms underlying this diversity remain unclear. We present a cross-species analysis of alternative splicing (AS) across six tissues in 26 mammals, identifying hundreds of conserved AS events significantly associated with MLS, with the brain containing twice as many tissue-specific events as peripheral tissues. MLS-AS events are enriched in pathways related to mRNA processing, stress response, neuronal functions, and epigenetic regulation, and are largely distinct from genes whose expression correlates with MLS, indicating that AS captures unique lifespan-related signals. The brain exhibits certain associations divergent from peripheral tissues and reduced overlap with body mass (BM)-associated splicing; neither is observed at the gene expression level. While MLS- and age-associated AS events show limited overlap, the shared events are enriched in intrinsically disordered protein regions, suggesting a role in protein flexibility and stress adaptability. Furthermore, MLS-associated AS events display stronger RNA-binding protein (RBP) motif coordination than age-associated ones, highlighting a more genetically programmed adaptation for lifespan determination, in contrast to the more variable splicing changes seen with chronological aging. These findings suggest alternative splicing as a distinct, transcription-independent axis of lifespan regulation, offering insights into the molecular basis of longevity.

The molecular basis for differing life spans in mammals is unclear. Here, the authors show that alternative splicing, a form of gene regulation, is strongly linked to longevity across 26 species, with the brain exhibiting unique patterns.