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Ageing is driven by a loss of transcriptional and protein homeostasis1-3 and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses4,5. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.
Expression of specific RNA splicing factors has recently been shown to correlate with longevity in C. elegans, mice and humans6-11, yet links between RNA splicing and the promotion of healthy ageing via interventions such as dietary restriction are unclear. To examine the role of pre-mRNA splicing in dietary restriction using a multicellular system, we used an in vivo fluorescent alternative splicing reporter in the nematode C. elegans. This reporter strain expresses a pair of ret-1 exon 5 reporter minigenes with differential frameshifts, driven by the ubiquitous eft-3 promoter12. GFP expression indicates that exon 5 has been included, whereas expression of mCherry indicates that exon 5 has been skipped (Fig. 1a) and live imaging reveals cell- and tissue-specific ret-1 alternative splicing12 (Fig. 1b, Extended Data Fig. 1a). We examined whether the reporter responded to spliceosome disruption by inhibiting multiple, conserved13 spliceosome components by RNA interference (RNAi) (Extended Data Fig. 1b-o). RNAi of hrp-2, a core spliceosome component in C. elegans...