Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity

Authors

  • Dirk Beher,

    1. Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
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    • Dirk Beher and John Wu have contributed equally.

    • Present address: Department of Global PD/AD Drug Discovery, Merck Serono S. A. - Geneva, 9 Chemin des Mines, 1202 Geneva, Switzerland

  • John Wu,

    1. Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
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    • Present address: Department of Global PD/AD Drug Discovery, Merck Serono S. A. - Geneva, 9 Chemin des Mines, 1202 Geneva, Switzerland

  • Suzanne Cumine,

    1. Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
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  • Ki Won Kim,

    1. Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
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  • Shu-Chen Lu,

    1. Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
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  • Larissa Atangan,

    1. Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
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  • Minghan Wang

    Corresponding author
    1. Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA
      * Corresponding author: Minghan Wang, mwang@amgen.com
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* Corresponding author: Minghan Wang, mwang@amgen.com

Abstract

Resveratrol is a plant polyphenol capable of exerting beneficial metabolic effects which are thought to be mediated in large by the activation of the NAD+-dependent protein deacetylase SIRT1. Although resveratrol has been claimed to be a bona fide SIRT1 activator using a peptide substrate (Fluor de Lys-SIRT1 peptide substrate), recent reports indicate that this finding might be an experimental artifact and need to be clarified. Here, we show that: (i) the Fluor de Lys-SIRT1 peptide is an artificial SIRT1 substrate because in the absence of the covalently linked fluorophore the peptide itself is not a substrate of the enzyme, (ii) resveratrol does not activate SIRT1 in vitro in the presence of either a p53-derived peptide substrate or acetylated PGC-1α isolated from cells, and (iii) although SIRT1 deacetylates PGC-1α in both in vitro and cell-based assays, resveratrol did not activate SIRT1 under these conditions. Based on these observations, we conclude that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.

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