Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans
Author: ["Caroline Heintz","Thomas K. Doktor","Anne Lanjuin","Caroline C. Escoubas","Yue Zhang","Heather J. Weir","Sneha Dutta","Carlos Giovanni Silva-García","Gitte H. Bruun","Ianessa Morantte","Gerta Hoxhaj","Brendan D. Manning","Brage S. Andresen","William B. Mair"]
CITE.CC academic search helps you expand the influence of your papers.
Abstract
Precursor mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans and defects in global pre-mRNA splicing associated with age are reduced by dietary restriction via splicing factor 1. The collapse of protein homeostasis and increasing error rates in transcription are key risk factors for various chronic diseases, and are associated with ageing. William Mair and colleagues demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans, and that defects in global pre-mRNA splicing associated with age are reduced by dietary restriction via splicing factor 1 (SFA-1). SFA-1 is specifically required for lifespan extension both by dietary restriction, and modulation of TORC1 pathway components. Overexpression of SFA-1 is sufficient to extend lifespan. This work suggests that modulation of specific spliceosome components can promote healthy ageing. Ageing is driven by a loss of transcriptional and protein homeostasis1,2,3 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.
Cite this article
Heintz, C., Doktor, T., Lanjuin, A. et al. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102–106 (2017). https://doi.org/10.1038/nature20789
