• Anne J van der Meer, Brendon P Scicluna, Perry D Moerland, Jiang Lin, Eric W Jacobson, George P Vlasuk, and Tom van der Poll.
• 1Center for Experimental Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, The Netherlands. 2Bioinformatics Laboratory, Department of Clinical Epidemiology, Academic Medical Center, Amsterdam, The Netherlands. 3GlaxoSmithKline, Durham, North Carolina. 4Sirtris, A GSK Company, Cambridge, MA.
• Crit. Care Med.. 2015 Jun 1;43(6):e199-202.

ObjectivesSirtuin 1 influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin 1 activator, SRT2104, on inflammation and coagulation induced by lipopolysaccharide in humans.DesignA randomized, double-blind, placebo-controlled study.SettingAn academic hospital.SubjectsTwenty-four healthy humans.InterventionsAll subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups (n=8 per group): 1) pretreatment with oral SRT2104 for 7 days (2 g/d), 2) pretreatment with a single SRT2104 dose (2 g), or 3) placebo.Measurements And Main ResultsSRT2104 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [p<0.05] and 80.9% [p=0.078] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [p<0.05 vs placebo] and 77.1% [p<0.05 vs placebo] after single and repeated SRT2104 ingestion, respectively, while not affecting tumor necrosis factor-α and interleukin-10 release). SRT2104 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2104 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F1+2 (mean peak levels 57.9% [p<0.05] and 64.2% [p<0.05] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2104.ConclusionsThis is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule.

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