Substrate-specific Activation of Sirtuins by Resveratrol*

By Matt Kaeberlein, Thomas McDonagh, Birgit Heltweg, J. Hixon, Eric A. Westman, Seth D Caldwell, A. Napper, R. Curtis, P. Distefano, Stanley Fields and 2 more. Journal of Biological Chemistry, 2005

760 citations recorded by the source corpus.

Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined.

Subfields: Aging, Geriatrics and Gerontology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/f65ed2b4594f86bdc8f9c96b036cda4289c1a524

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

In Geriatrics and Gerontology

Citations in the corpus

Therapeutic potential of resveratrol: the in vivo evidence (2006, background): “The in vitro activity of SIRT1 against short, unconjugated peptide substrates is not enhanced by resveratrol, leading some to argue that the original observation was an artefact of the fluorescent substrate used to monitor the reactio”
SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “However, other studies failed to show activation of SIRT1 by resveratrol (163, 239) and suggested that previous reports on the activation of SIRT1 by resveratrol could be due to an interaction between resveratrol and the fluorophore used in the assay (163, 239).”
AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol (2009, background): “However, whether the putative Sirt1 activators such as resveratrol actually target Sirt1 in vivo is controversial because resveratrol increases Sirt1 activity in vitro only if the substrate is modified with a fluorescent tag (9,10).”
Target identification using drug affinity responsive target stability (DARTS) (2009, background): “The molecular mechanisms underlying resveratrol’s lifespan effect have been controversial (16, 17), and whether Sir2 serves as a direct target for resveratrol is an interesting problem that is being pursued.”
Sirtuins in aging and age-related disease. (2006, background): “However, other groups have shown that the stimulatory effects of resveratrol on Sirtuin enzyme activation are specific to this nonnative substrate (Borra et al., 2005; Kaeberlein et al., 2005c).”
Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. (2006, background): “The effect of resveratrol is mimicked by overexpression of sirtuins [6, 7, 28], but does not seem to be mediated by direct action on sirtuins [32, 33].”
Epigenetics and the environment: emerging patterns and implications (2012, background): “, the action of sirtuins is enhanced by resveratro”
A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice (2008, result): “However, recent studies have failed to reproduce these life extension results [5,6], and other studies have demonstrated that the ability of resveratrol to activate yeast Sir2 or human SIRT1 is substrate-specific in vitro [7] and resveratrol has no effect on Sir2 activity in vivo [5].”
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “One school of thought is that the direct activation of SIRT1 by resveratrol is an in vitro artifact (Beher et al., 2009; Borra et al., 2005; Kaeberlein et al., 2005; Pacholec et al., 2010) and that resveratrol works primarily by activating AMPK (Canto et al.”