I would like to call attention to this paper. The abstract gives just a hint of what the authors have actually accomplished. Biomol's Fluor de Lys peptide was shown to be necessary for resveratrol to activate SIRT1(1), casting doubt on the SIRT1 activity of this and of many other substances that had shown a positive response. The authors developed an alternate assay for SIRT1 activity, using an acetylated peptide of p53 as a substrate. They then evaluated 36 substances, including many that Sirtris had evaluated, and came up with somewhat different conclusions.
It turned out that resveratrol was not the most potent activator of SIRT1; piceatannol was almost three times more potent. Several other substances were about as effective as resveratrol. Some substances that had been reported as activators or SIRT1 turned out to inhibit its activity; among these was quercetin, as I've long suspected. I am going to post the tables showing relative potencies in a follow-up.
J Pharmacol Sci. 2008 Nov;108(3):364-71. Epub 2008 Nov 13.
A novel chalcone polyphenol inhibits the deacetylase activity of SIRT1 and cell growth in HEK293T cells.
Kahyo T, Ichikawa S, Hatanaka T, Yamada MK, Setou M.
Mitsubishi Kagaku Institute of Life Sciences (MITILS), Machida, Tokyo, Japan.
Abstract
SIRT1 is one of seven mammalian orthologs of yeast silent information regulator 2 (Sir2), and it functions as a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase. Recently, resveratrol and its analogues, which are polyphenols, have been reported to activate the deacetylase activity of SIRT1 in an in vitro assay and to expand the life-span of several species through Sir2 and the orthologs. To find activators or inhibitors to SIRT1, we examined thirty-six polyphenols, including stilbenes, chalcones, flavanones, and flavonols, with the SIRT1 deacetylase activity assay using the acetylated peptide of p53 as a substrate. The results showed that 3,2',3',4'-tetrahydroxychalcone, a newly synthesized compound, inhibited the SIRT1-mediated deacetylation of a p53 acetylated peptide and recombinant protein in vitro. In addition, this agent induced the hyperacetylation of endogenous p53, increased the endogenous p21CIP1/WAF1 in intact cells, and suppressed the cell growth. These results indicated that 3,2',3',4'-tetrahydroxychalcone had a stronger inhibitory effect on the SIRT1-pathway than sirtinol, a known SIRT1-inhibitor. Our results mean that 3,2',3',4'-tetrahydroxychalcone is a novel inhibitor of SIRT1 and produces physiological effects on organisms probably through inhibiting the deacetylation by SIRT1.
PMID: 19008647
(1) Chem Biol Drug Des. 2009 Dec;74(6):619-24. Epub 2009 Oct 20. Resveratrol is not a direct activator of SIRT1 enzyme activity. Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M.
Edited by maxwatt, 01 January 2011 - 04:46 PM.
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