Substrate-specific Activation of Sirtuins by Resveratrol

Abstract

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.

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…Several effects of resveratrol have been shown to be dependent on SirT1 (Howitz et al, 2003;Picard et al, 2004;Wood et al, 2004;Yeung et al, 2004), although the mechanism of resveratrol activity is controversial (Borra et al, 2005;Kaeberlein et al, 2005). In the present study, resveratrol-mediated reduction of tumor incidence was largely dependent on SirT1, yet the presence of SirT1 itself was not protective against tumorigenesis.…”

Aging by epigenetics—A consequence of chromatin damage?

“…Remarkably, addition of a SirT1 activator, resveratrol, to the diet of mice fed a high fat diet prolongs the healthy lifespan of those mice [114,115], apparently mimicking the well-established contribution of dietary caloric restriction to longevity [116]. Although there are questions as to whether resveratrol extends lifespan through SirT1 and whether SirT1 acts through chromatin [117,118], these studies demonstrate the potential of chemopreventative strategies to combat aging. Considerable evidence, discussed in the text, supports the idea that heterochromatin redistributes in cells during cellular and organismal aging.…”

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

“…1 and 3). However, RSV has many additional targets within the cell, including general modulators of transcription Sirtuins (class III histon deacetylases) [48,49], transcription factors NF-κB and STAT3 [16,17] and many enzymes of general cell metabolism [46]. RSV treatment of several melanoma lines induced a relatively modest decrease in the high basal NF-κB activity and NF-κB-dependent transcription in these cells, while downregulation of STAT3 levels and STAT3-dependent transcription was more pronounced (Fig.…”