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.Electronic supplementary materialThe online version of this article (10.1186/s12860-017-0147-7) contains supplementary material, which is available to authorized users.

Resveratrol alters the cytokinetics of mammalian cell populations in a dose dependent manner. Concentrations above 25-50µM typically trigger growth arrest, senescence and/or apoptosis in multiple different cell types. In contrast, concentrations below 10µM enhance the growth of log phase cell cultures and can rescue senescence in multiple strains of human fibroblasts.To better understand the structural features that regulate these effects, a panel of 24 structurallyrelated resveralogues were synthesised and evaluated for their capacity to activate SIRT1, as determined by an ex-vivo SIRT1 assay, their toxicity, as measured by lactate dehydrogenase release, and their effects on replicative senescence in MRC5 human fibroblasts as measured by their effects on Ki67 immunoreactivity and senescence-associated β galactosidase activity.Minor modifications to the parent stilbene, resveratrol, significantly alter the biological activities of the molecules. Replacement of the 3,5-dihydroxy substituents with 3,5-dimethoxy groups significantly enhances SIRT1 activity, and reduces toxicity. Minimising other strong conjugative effects also reduces toxicity, but negatively impacts SIRT1 activation.At 100µM many of the compounds, including resveratrol, induce senescence in primary MRC5 cells in culture. Modifications that reduce or remove this effect match those that reduce toxicity leading to a correlation between reduction in labelling index and increase in LDH release.At 10µM, the majority of our compounds significantly enhance the growth fraction of log phase cultures of MRC5 cells, consistent with the rescue of a subpopulation of cells within the culture from senescence. SIRT1 activation is not required for rescue to occur but enhances the size of the effect.

BackgroundCompounds based on trans-1,2-diphenylethene are the subject of intense interest both for their optical properties and as potential leads for drug discovery, as a consequence of their anticancer, anti-inflammatory and antioxidant properties. Perhaps the best known of these is trans-3,5,4′-trihydroxystilbene (resveratrol), that has been identified as a promising lead in the search for anti-ageing therapeutics.ResultsWe report here a new, convenient, one-pot stereo-selective synthesis of resveratrol and other trans-stilbene derivatives. A wide range of known and novel “Resveralogues” were synthesised by using this simple protocol, including examples with electron donating and electron withdrawing substituents, in uniformly high yield. The structures of all compounds were confirmed by standard methods including 1H and 13C NMR, IR and High Resolution Mass spectroscopy.ConclusionsWe have established a simple and convenient protocol for resveralogue synthesis. It is readily scalable, and sufficiently robust and simple for ready use in automated synthesis or for library development of resveralogues. This supersedes previously reported synthetic methods that required inert conditions, extensive purification and/or costly reagents.Graphical abstractOne-pot preparation of diverse Resveralogues - high yields of product with minimal purification.

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