title: Resveratrol, but not dihydroresveratrol, induces premature senescence in primary human fibroblasts.
abstract: Resveratrol, trans-3,5,4'-trihydroxystilbene, is a polyphenolic compound which has been reported to mimic the gene expression patterns seen in whole animals undergoing dietary restriction. The mechanism of action of resveratrol remains poorly understood, but modulation of both cellular proliferation and apoptosis has been proposed as important routes by which the molecule may exert its effects. This study reports the effects of both resveratrol and dihydroresveratrol (a primary in vivo metabolite) on the proliferative capacity of human primary fibroblasts. No generalised reduction in the growth fraction was observed when fibroblasts derived from three different tissues were treated with resveratrol at concentrations of 10 μm or less. However, concentrations above 25 μm produced a dose-dependent reduction in proliferation. This loss of the growth fraction was paralleled by an increase in the senescent fraction as determined by staining for senescence associated beta galactosidase and dose recovery studies conducted over a 7-day period. Entry into senescence in response to treatment with resveratrol could be blocked by a 30-min preincubation with the p38 MAP kinase inhibitor SB203580. No effects on proliferation were observed when cells were treated with dihydroresveratrol at concentrations of up to 100 μm.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, University of Brighton, Moulsecoomb, Brighton, East Sussex, UK. rgaf@bton.ac.uk
authors.forename: Richard G A
authors.initials: RG
authors.lastname: Faragher
authors.forename: Dominic G A
authors.initials: DG
authors.lastname: Burton
authors.forename: Patricia
authors.initials: P
authors.lastname: Majecha
authors.forename: Noel S Y
authors.initials: NS
authors.lastname: Fong
authors.forename: Terence
authors.initials: T
authors.lastname: Davis
authors.forename: Angela
authors.initials: A
authors.lastname: Sheerin
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Ostler
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019394:Ki-67 Antigen / Q000032:analysis; D011725:Pyridines / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D001616:beta-Galactosidase; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D007093:Imidazoles; D019394:Ki-67 Antigen; D011725:Pyridines; D013267:Stilbenes; C544754:dihydroresveratrol; D048051:p38 Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase; C093642:SB 203580; D000077185:Resveratrol