Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans
Authors: Gitte Hoffmann Bruun
Anne Lanjuin
Ianessa Morantte
Carlos Giovanni Silva-García
Heather J Weir
Brage S Andresen
Caroline Heintz
Yue Zhang
Sneha Dutta
Caroline Escoubas
Brendan D Manning
Gerta Hoxhaj
William B Mair
Thomas Koed Doktor
Journal: Nature (2017)
Discipline: Multidisciplinary
Keywords: Ageing; transcriptional; protein homeostasis; chronic diseases; interventions
Affiliations: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA., Department of Biochemistry and Molecular Biology, and Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark., Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS, UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Faculty of Medicine, Nice, France.

Abstract:  Ageing is driven by a loss of transcriptional and protein homeostasis 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 illnesses. 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. 

Retracted: No

PubPeer comments:
null, 
 Congratulations for this beautiful work. I see no concern with Figure 4. The panels represent the same condition, so a repeat of the picture is not problematic. The same is true in Extended Data Fig.1o. ![file] It did, however, draw my attention to the fact that the size of the wild-type worm varies too much between experiments (compare  i with  m ). Could the authors provide an explanation, please? A little more worrying is when you compare Figure 1C with Extended Data Fig. 1o. Not only do I notice a potential duplicate, but the picture was flipped and changed slightly in color. Do they truly represent the same condition? It looks like that the Extended Data Fig. 1o is an RNAi experiment. Could the authors check if a mistake occurred when this particular figure was assembled? ![file] ,