A Pilot Randomized, Placebo Controlled, Double Blind Phase I Trial of the Novel SIRT1 Activator SRT2104 in Elderly Volunteers
Author(s)
Type
Journal Article
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.
Date Issued
2012-12-20
Online Publication Date
2012-12-20
2018-03-09T16:56:42Z
Date Acceptance
2012-10-31
ISSN
1932-6203
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS ONE
Volume
7
Issue
12
Copyright Statement
©
2012 Libri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
2012 Libri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Database
web-of-science
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MAGNETIC-RESONANCE-SPECTROSCOPY
SKELETAL-MUSCLE
MITOCHONDRIAL DISEASE
LIPID-METABOLISM
OXYGEN-UPTAKE
LIFE-SPAN
P-31 MRS
INSULIN
EXERCISE
FAT
Aged
Double-Blind Method
Endpoint Determination
Enzyme Activation
Exercise
Female
Glucose Tolerance Test
Humans
Imidazoles
Lipids
Male
Middle Aged
Pilot Projects
Placebo Effect
Safety
Sirtuin 1
Thiazoles
Time Factors
MD Multidisciplinary
General Science & Technology
Article Number
e51395