Upregulation of splicing regulatory factor expression is associated with senescence rescue

Our results suggest that modification of splicing factor expression has the potential to influence cell senescence phenotypes and could represent a promising target for interventions designed to improve health span in the future

Age is the main risk factor for mostly all common chronic diseases such as cancer, cardiovascular diseases or neurodegeneration. Gradual accumulation over the life-course of senescent cells is likely to contribute to age-related disease and degeneration in humans. Although the precise mechanisms behind as yet unclear, it is known that alternative splicing is deregulated in senescent cells and in aged human population and changes in splicing factor expression have been shown in advancing age.

Consequently, the study of alternative splicing modulation in senescent cells is crucial to a better understanding of ageing processes. Following on from our previous work, where we have observed rescue from senescence with small molecules that influence the expression of splicing factors, we have now carried out a detailed analysis of the molecular basis for this observation.

Treatment with small molecule compounds was able to upregulate splicing factor expression and rescue senescence at the biochemical and molecular level as assessed by a reduction in senescence-associated b-galactosidase staining (SA-b-Gal) and a concordant drop in the expression levels of molecular markers of cellular senescence (CDKN2A, CD248) in all cases. Rescue from senescence was accompanied by an elongation of telomeres and could be mimicked with inhibitors of the ERK and AKT pathways, in a dose dependent manner, indicating the involvement of intracellular signaling in this phenomenon. Furthermore, we have now shown that these changes still occur in the absence of proliferation, indicating that the changes in splicing factor expression are upstream of, rather than an effect of renewed proliferation.