Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibrob
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RESEARCH ARTICLE
Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts Vishal C. Birar . Angela N. Sheerin . Elizabeth L. Ostler
. Richard G. A. Faragher
Received: 18 July 2020 / Accepted: 7 August 2020 Ó Springer Nature B.V. 2020
Abstract Resveratrol alters the cytokinetics of mammalian cell populations in a dose dependent manner. Concentrations above 25–50 lM typically trigger growth arrest, senescence and/or apoptosis in multiple different cell types. In contrast, concentrations below 10 lM 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 structurally-related 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 b 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 100 lM 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 10 lM, 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. Keywords SIRT1
Resveratrol Senescence Toxicity
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10522-020-09896-6) contains supplementary material, which is available to authorized users. V. C. Birar A. N. Sheerin E. L. Ostler (&) R. G. A. Faragher School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Moulsecoomb, Brighton BN2 4GJ, UK e-mail: [email protected]
During the latter decades of the twentieth century organismal ageing was regularly conceptualised as the potential result of the interplay of dozens, if not hundreds, of biological mechanisms, each of which exerted small effects on lifespan (Kirkwood and Franceschi 1992; Medvedev 1990). However, more recently the adoption of a criterion-based approach for
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Biogerontology
potential mechanisms (that they manifest during normal agein
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