Knockdown of the fly spliceosome component Rbp1(orthologue of SRSF1) extends lifespan

Abstract

Biological regulation is a highly intricate process and involves many layers of complexity even at the RNA level. Alternative splicing is crucial in the regulation of which components of a protein-coding gene are spliced into a translatable mRNA. During ageing splicing becomes dysregulated and alternative splicing has been shown to be involved in disease and known anti-aging treatments such as dietary restriction (DR) and mTOR suppression. In prior work we have shown that DR and mTOR suppression modulate the expression of the spliceosome in the fly (Drosophila melanogaster). Here, we manipulated the five top genes that change in expression in both these treatments. We found that knockdown (using conditional in vivo RNAi in adults) of some spliceosome components rapidly induce mortality, whereas one, Rbp1, extends lifespan. Treatments that have more instant benefits on longevity are more translatable. We therefore subsequently repeated the Rbp1 experiment, but initiating Rbp1 at later stages in adult life. We find that irrespective of age of induction, knockdown of Rbp1 extends lifespan. Our results posit the spliceosome itself as a hub of regulation that when targeted can extend lifespan, rendering it a promising target for geroscience.