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

Biological regulation is an intricate process involving many layers of complexity, including 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 is implicated in disease and known anti-ageing 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 induces 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 initiated Rbp1 knockdown at later stages in adult life. We find that irrespective of the 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.