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Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation
Open accessAbstract
The natural polyphenolic compound resveratrol (3,4,5-trihydroxy-trans-stilbene) has broad spectrum health beneficial activities including antioxidant, anti-inflammatory, anti-aging, anti-cancer, cardioprotective, and neuroprotective effects. Remarkably, resveratrol also induces apoptosis and cellular senescence in primary and cancer cells. Resveratrol's anti-aging effects both in vitro and in vivo attributed to activation of a (NAD)-dependent histone deacetylase family member sirtuin-1 (SIRT1) protein. In mammals seven members (SIRT1-7) of sirtuin family have been identified. Among those, SIRT1 is the most extensively studied with perceptive effects on mammalian physiology and suppression of the diseases of aging. Yet no data has specified the role of sirtuins, under conditions where resveratrol treatment induces senescence. Current study was undertaken to investigate the effects of resveratrol in human primary dermal fibroblasts (BJ) and to clarify the role of sirtuin family members in particular SIRT1 and SIRT2 that are known to be involved in cellular stress responses and cell cycle, respectively. Here, we show that resveratrol decreases proliferation of BJ cells in a time and dose dependent manner. In addition the increase in senescence associated β-galactosidase (SA-β-gal) activity and methylated H3K9-me indicate the induction of premature senescence. A significant increase in phosphorylation of γ-H2AX, a surrogate of DNA double strand breaks, as well as in levels of p53, p21CIP1 and p16INK4A is also detected. Interestingly, at concentrations where resveratrol induced premature senescence we show a significant decrease in SIRT1 and SIRT2 levels by Western Blot and quantitative RT-PCR analysis. Conversely inhibition of SIRT1 and SIRT2 via siRNA or sirtinol treatment also induced senescence in BJ fibroblasts associated with increased SA-β-gal activity, γ-H2AX phosphorylation and p53, p21CIP1 and p16INK4A levels. Interestingly DNA damaging agent doxorubicin also induced senescence in BJ fibroblasts associated with decreased SIRT1/2 levels. In conclusion our data reveal that resveratrol induced premature senescence is associated with SIRT1 and SIRT2 down regulation in human dermal fibroblasts. Here we suggest that the concomitant decline in SIRT1/2 expression in response to resveratrol treatment may be a cause for induction of senescence, which is most likely mediated by a regulatory mechanism activated by DNA damage response.
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Some studies have highlighted RSV's ability to also act as a pro-oxidant molecule, and this dual role depends upon cell type, used dosage, and exposure time.
“Although RSV’s antioxidant properties have been widely demonstrated, some studies [349,350] have highlighted its ability to also act as a pro-oxidant molecule. This dual role depends upon cell type, used dosage, and exposure time [336].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [349]
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Metadata
- Authors
- Kilic Eren, M., Kilincli, A., & Eren, Ö.
- Affiliations
- Adnan Menderes University (TR)
- ORCID
- Eren, Özkan
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-04-29
- Volume
- 10
- Issue
- 4
- Pages
- e0124837
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4414559
- OpenAlex
- W1989666486
- Cited by
- 68
- References
- 44
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 7 · 2018: 6 · 2017: 8 · 2016: 10
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- resveratrol, premature senescence, cellular senescence, SIRT1, SIRT2, sirtuins, DNA damage, dermal fibroblasts, γH2AX, p53, p21, p16INK4a, sirtinol, doxorubicin, NAD+-dependent histone deacetylase
- MeSH terms
- Resveratrol, DNA Damage, Fibroblasts, Gene Expression Regulation, Humans, Stilbenes, Cellular Senescence, Cell Proliferation, Sirtuin 1, Sirtuin 2, Primary Cell Culture
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