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.
Latest exciting work from me and @mirresimons.bsky.social (and the first bit of data from my @vivensa.bsky.social ECR Fellowship) now out as a preprint, looking at effects of knocking down individual spliceosome components on lifespan in vivo: www.biorxiv.org/content/10.1...
New preprint. ATF4 activation is thought to lead to longer lifespans. However, our study shows that suppression rather than activation extends lifespan in the fly. New Qs: how we can target ATF4 or its downstream targets to gain targeted longevity benefits.
www.biorxiv.org/content/10.1...
Latest. Dan tested the importance of Drosophila immune cells by ablating or expanding them using conditional genetics. Turns out no lifespan phenotype, perhaps because there is compensation within the immune cell lineage. More exciting biology to discover.
journals.biologists.com/jeb/article/...
Massive congratulations Jack, awesome job!
Me please :)
Really excited to say that from January I'll be starting as an ECR Fellow with the Dunhill Medical Trust based at the University of Sheffield, using Drosophila to look at RNA splicing in ageing!
Seems as good a first post on here as I can come up with!
Please add me if you're happy to!
