The Implications of Alternative Splicing Regulation for Maximum Lifespan
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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 new insights into the molecular basis of longevity.
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Of the 39 unique key RBPs (the union of the top 20 motif-enriched RBPs from each tissue), only five (ESRP1, FUS, MBNL1, PCBP2, RBM8A) overlapped with a previously curated list of genes whose expression correlates with MLS9.
It could be useful to also assess proteomic data for these RBPs, as RNA abundance often doesn’t correlate with protein abundance, especially in the context of aging.
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although alternative first exon (AF) was the second most frequent AS event, averaging 22.8% in a single species, comparable to cassette exon (Fig. 1b), none of these were conserved
Since maximum lifespan is not a conserved phenotype, it would be interesting to see if other types of splicing events (e.g. alternative first exons) are enriched for specific biological functions, irrespective of their conservation.
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