SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
Level 5 - mechanism / opinion, no new human data
In vitro biochemical assays and rodent model (preclinical research)
PubMed 20061378 · doi:10.1074/jbc.M109.088682
What was done
Purported SIRT1 activators (SRT1720, SRT2183, SRT1460, and resveratrol) were evaluated in biochemical deacetylation assays comparing native substrates (a non-fluorophore p53-derived peptide and full-length native p53 and acetyl-CoA synthetase 1 proteins) with fluorophore-labeled peptide substrates. Small molecule interactions with fluorophore-tagged peptides were assessed using NMR, surface plasmon resonance, and isothermal titration calorimetry. SRT1720 was also administered to high-fat-diet-fed mice to measure plasma glucose and mitochondrial capacity, and compounds were screened for off-target activities against various receptors, enzymes, transporters, and ion channels.
What was found
SRT1720, SRT2183, SRT1460, and resveratrol produced no apparent activation of SIRT1 when using native peptide or full-length protein substrates, showing activation exclusively with fluorophore-containing substrates. Biophysical analyses demonstrated that these small molecules interacted directly with the fluorophore-bearing peptide substrates. In mice fed a high-fat diet, SRT1720 failed to lower plasma glucose or improve mitochondrial capacity, and all four molecules exhibited off-target interactions across multiple receptors, enzymes, ion channels, and transporters (no quantitative values reported in the abstract).
Why it matters
This study showed that widely studied SIRT1 activators act through assay artifacts caused by fluorescent tags rather than direct catalytic activation of SIRT1 on native substrates.
Limits
The abstract does not disclose sample sizes, doses, statistical test results, or quantitative effect sizes for the biochemical or mouse experiments. Findings derive entirely from non-human preclinical systems.
Cited by
- supports A Pfizer research team published a paper in 2010 claiming that resveratrol activation of SIRT1 was an experimental artifact.