As well as revealing Rbp1 knockdown as a pro-longevity treatment, more generally our work has unveiled a tantalising prospect; the fine-tuning of individual spliceosome components could be a pathway to increased health and longevity. We’re excited to pull on this thread and find out where it leads!

Perhaps limiting SR protein (such as Rbp1) abundance improves proteostasis by reducing protein synthesis, whereas limiting later components causes complete translational inhibition through spliceosomal stalling, although this needs far more work to tease apart!

We find it fascinating that the components which induce mortality when knocked down are recruited to the spliceosome far later than the point of recruitment of Rbp1, which binds pre-mRNA before even the commitment complex has assembled.

The spliceosome is made up of many different proteins and RNAs, and our work demonstrates that a deficit of some components is highly detrimental to longevity, whereas the shortage of others (eg. Rbp1) may actually be pro-longevity.

Considering that pro-longevity treatments which don’t require lifelong application will be easier to translate to the clinic, we also tested Rbp1 knockdown at later timepoints, and excitingly found that this too produced comparable improvements in life expectancy!

We knocked down the top-changing spliceosome genes using in vivo conditional RNAi and found that several gene knockdowns induced mortality, whereas the knockdown of the gene encoding an SR protein, Rbp1 (orthologue of human SRSF1), extended lifespan.

We’ve previously shown that spliceosome gene expression is modulated under the pro-longevity treatments mTOR suppression and dietary restriction, which are highly consistent and conserved between species.

Massive congratulations Jack, awesome job!

Me please :)

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