Abstract
BackgroundSRT2104 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.MethodsOral 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.ResultsSRT2104 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.ConclusionsSRT2104 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.Trial RegistrationClinicalTrials.gov NCT00964340
Highlights
SIRT1 is one of a family of seven nicotinamide adenine dinucleotide (NAD+)-dependent, protein deacetylase enzymes that contribute to the regulation of body energy homeostasis as well as many other responses to cellular stress
Increased SIRT1 expression has been suggested as a target for therapeutic activation in multiple age- related diseases via the modulation of various metabolic pathways, including glucose metabolism [5], fatty acid oxidation [6], regulation of oxidative stress [7], lipid metabolism and fat mobilization in white adipocytes [8,9], as well as improved insulin secretion [1], pancreatic b-cell preservation [9,10] and increased insulin sensitivity [3,9,11]
The statistical analysis was performed using the SASH for Windows software package (Version 9.1.3) (SAS Institute, Cary, North Carolina, USA). This was a pilot Phase I study of non-therapeutic objectives to allow preliminary characterization of safety, tolerability and drug kinetics of SRT2104 in male and female elderly volunteer following single and repeat daily dosing for 28 days
Summary
SIRT1 is one of a family of seven nicotinamide adenine dinucleotide (NAD+)-dependent, protein deacetylase enzymes (called sirtuins) that contribute to the regulation of body energy homeostasis as well as many other responses to cellular stress. Increased SIRT1 expression has been suggested as a target for therapeutic activation in multiple age- related diseases via the modulation of various metabolic pathways, including glucose metabolism [5], fatty acid oxidation [6], regulation of oxidative stress [7], lipid metabolism and fat mobilization in white adipocytes [8,9], as well as improved insulin secretion [1], pancreatic b-cell preservation [9,10] and increased insulin sensitivity [3,9,11]. 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. We report the first clinical trial of SRT2104 in elderly volunteers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
