title: A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers.
abstract: BACKGROUND
  SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD(+)-dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers.
  
  
  METHODS
  Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity.
  
  
  RESULTS
  SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2-4 hours with elimination half-life of 15-20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation.
  
  
  CONCLUSIONS
  SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00964340.
authors.affiliation: The National Institute for Health Research-Wellcome Trust Imperial College Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, United Kingdom. v.libri@imperial.ac.uk
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Libri
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Brown
authors.forename: Giulio
authors.initials: G
authors.lastname: Gambarota
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haddad
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Shields
authors.forename: Helen
authors.initials: H
authors.lastname: Dawes
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinato
authors.forename: Ethan
authors.initials: E
authors.lastname: Hoffman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Elliot
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: Eric
authors.initials: E
authors.lastname: Jacobson
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
mesh_terms: D000368:Aged; D004311:Double-Blind Method; D023381:Endpoint Determination; D004789:Enzyme Activation / Q000187:drug effects; D015444:Exercise / Q000502:physiology; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D015990:Placebo Effect; D012449:Safety; D056564:Sirtuin 1 / Q000378:metabolism*; D013844:Thiazoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
chemical_list: D007093:Imidazoles; D008055:Lipids; D013844:Thiazoles; D056564:Sirtuin 1