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Open Access Highly Accessed Research article

Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo

Jesse J Smith1, Renée Deehan Kenney2, David J Gagne1, Brian P Frushour2, William Ladd2, Heidi L Galonek1, Kristine Israelian1, Jeffrey Song1, Giedre Razvadauskaite1, Amy V Lynch1, David P Carney1, Robin J Johnson2, Siva Lavu1, Andre Iffland1, Peter J Elliott1, Philip D Lambert1, Keith O Elliston2, Michael R Jirousek1, Jill C Milne1 and Olivier Boss1*

Author Affiliations

1 Sirtris, a GSK company 200 Technology Square, Cambridge, MA, 02139, USA

2 Genstruct Inc, One Alewife Center, Cambridge, MA, 02140, USA

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BMC Systems Biology 2009, 3:31  doi:10.1186/1752-0509-3-31

Published: 10 March 2009

Abstract

Background

Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation.

Results

Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet.

Conclusion

CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.