title: Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sirtris, a GSK company, 200 Technology Square, Cambridge, MA 02139, USA. jessejersmith@gmail.com
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Smith
authors.forename: Renée Deehan
authors.initials: RD
authors.lastname: Kenney
authors.forename: David J
authors.initials: DJ
authors.lastname: Gagne
authors.forename: Brian P
authors.initials: BP
authors.lastname: Frushour
authors.forename: William
authors.initials: W
authors.lastname: Ladd
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Galonek
authors.forename: Kristine
authors.initials: K
authors.lastname: Israelian
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Song
authors.forename: Giedre
authors.initials: G
authors.lastname: Razvadauskaite
authors.forename: Amy V
authors.initials: AV
authors.lastname: Lynch
authors.forename: David P
authors.initials: DP
authors.lastname: Carney
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: Siva
authors.initials: S
authors.lastname: Lavu
authors.forename: Andre
authors.initials: A
authors.lastname: Iffland
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Elliott
authors.forename: Philip D
authors.initials: PD
authors.lastname: Lambert
authors.forename: Keith O
authors.initials: KO
authors.lastname: Elliston
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jirousek
authors.forename: Jill C
authors.initials: JC
authors.lastname: Milne
authors.forename: Olivier
authors.initials: O
authors.lastname: Boss
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D046228:Microarray Analysis; D008957:Models, Genetic; D015394:Molecular Structure; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; D013267:Stilbenes; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol