Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.
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.
Smith
Jesse J
JJ
Sirtris, a GSK company, 200 Technology Square, Cambridge, MA 02139, USA. jessejersmith@gmail.com
Kenney
Renée Deehan
RD
Gagne
David J
DJ
Frushour
Brian P
BP
Ladd
William
W
Galonek
Heidi L
HL
Israelian
Kristine
K
Song
Jeffrey
J
Razvadauskaite
Giedre
G
Lynch
Amy V
AV
Carney
David P
DP
Johnson
Robin J
RJ
Lavu
Siva
S
Iffland
Andre
A
Elliott
Peter J
PJ
Lambert
Philip D
PD
Elliston
Keith O
KO
Jirousek
Michael R
MR
Milne
Jill C
JC
Boss
Olivier
O
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
D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; D013267:Stilbenes; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol