Here's the latest paper by Sinclair using SIRT1 knockout mice to show that SIRT1 is, according to them, required for AMPK activation and the beneficial effects of resveratrol.
They also indicate that dosage is a critical factor. The approx. doses are listed in the Method's section: "S1Δex4ERT2 and control mice were placed on one of four different diets: a standard diet (SD), a high-fat diet (HF; 60% FDC), a high-fat diet supplemented with 400 mg resveratrol/kg of food (HFLR), or a high-fat diet supplemented with a high dose of 4 g resveratrol/kg of food (HFHR). The former is a relatively low dose used in our laboratories' previous studies, while the latter dose is similar to the concentrations used by other groups (Lagouge et al., 2006) (Figure 2A). Feeding of these diets resulted in an approximate daily dose of 25–30 mg/kg per day and 215–230 mg/kg of body weight per day, respectively."
Cell Metab. 2012 May 2;15(5):675-90.
SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function.
Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA. Glenn Labs for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD(+) levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1 mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrol no improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo.
Copyright © 2012 Elsevier Inc. All rights reserved. PMID: 22560220