Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence. RESULTS: Treatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists. CONCLUSIONS: This is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.This work was supported by The Dunhill Medical Trust [grant number: R386/1114] to Lorna Harries, a studentship to Vishal Birar from the University of Brighton and Glenn Foundation for Medical Research personal Awards to Richard Faragher and Lynne Cox. Work in Lynne Cox’s lab is also supported by BBSRC grant [BB/M006727/1]