Abstract
BackgroundAltered 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.ResultsTreatment 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.ConclusionsThis 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.
Highlights
Altered expression of Messenger RNA (mRNA) splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism
We set out to rationally design a panel of novel resveratrol-like compounds (Fig. 1a) with the goal of identifying compounds that could restore splicing factor expression to levels comparable with those seen in young cells, but with differing effects on SIRT1 activation and the senescence-associated secretory phenotype (SASP) to allow assessment of molecular mechanism
SIRT1 activation is significantly altered following side chain modification of resveratrol Since RSV has been suggested to exert its pro-longevity effects predominantly through activation of SIRT1, we first tested the ability of our novel compounds to activate SIRT1 in an ex vivo enzyme assay (Fig. 1c), with data normalised against activity detected on treatment with resveratrol (RSV, 1)
Summary
Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells occurs in vivo with advancing age and causes much degenerative age-related pathology. Splicing factor expression is dysregulated in the peripheral blood of aging humans, where they are the major functional gene ontology class whose transcript patterns alter with advancing age [1] and in senescent primary human cells of multiple lineages [2]. Splicing factor expression is known to be dysregulated in senescent cells of multiple lineages [2] and it is well established that the accumulation of senescent cells is a direct cause of multiple aspects of both ageing and age-related disease in mammals [18]
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