title: Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis.
abstract: Copper sulfate-induced premature senescence (CuSO4-SIPS) consistently mimetized molecular mechanisms of replicative senescence, particularly at the endoplasmic reticulum proteostasis level. In fact, disruption of protein homeostasis has been associated to age-related cell/tissue dysfunction and human disorders susceptibility. Resveratrol is a polyphenolic compound with proved antiaging properties under particular conditions. In this setting, we aimed to evaluate resveratrol ability to attenuate cellular senescence induction and to unravel related molecular mechanisms. Using CuSO4-SIPS WI-38 fibroblasts, resveratrol is shown to attenuate typical senescence alterations on cell morphology, senescence-associated beta-galactosidase activity, and cell proliferation. The mechanisms implicated in this antisenescence effect seem to be independent of senescence-associated genes and proteins regulation but are reliant on cellular proteostasis improvement. In fact, resveratrol supplementation restores copper-induced increased protein content, attenuates BiP level, and reduces carbonylated and polyubiquitinated proteins by autophagy induction. Our data provide compelling evidence for the beneficial effects of resveratrol by mitigating CuSO4-SIPS stressful consequences by the modulation of protein quality control systems. These findings highlight the importance of a balanced cellular proteostasis and add further knowledge on molecular mechanisms mediating resveratrol antisenescence effects. Moreover, they contribute to identifying specific molecular targets whose modulation will prevent age-associated cell dysfunction and improve human healthspan.
authors.affiliation: Departamento de Biologia Experimental, Faculdade de Medicina, IBMC, Instituto de Biologia Molecular e Celular and I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal.
authors.forename: Liliana
authors.identifier: 0000-0003-4188-532X
authors.initials: L
authors.lastname: Matos
authors.affiliation: Departamento de Biologia Experimental, Faculdade de Medicina, IBMC, Instituto de Biologia Molecular e Celular and I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal; Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal.
authors.forename: Alexandra Monteiro
authors.identifier: 0000-0001-8784-4246
authors.initials: AM
authors.lastname: Gouveia
authors.affiliation: Departamento de Biologia Experimental, Faculdade de Medicina, IBMC, Instituto de Biologia Molecular e Celular and I3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Henrique
authors.identifier: 0000-0002-3036-3211
authors.initials: H
authors.lastname: Almeida
mesh_terms: D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects*; D003300:Copper / Q000633:toxicity*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D011506:Proteins; D013267:Stilbenes; D003300:Copper; D056564:Sirtuin 1; D000077185:Resveratrol