A study evaluated whether SRT1720, SRT2183, SRT1460, and resveratrol directly activate SIRT1. Using biochemical assays with native substrates, including p53-derived peptides and full-length proteins, the researchers found that these compounds do not activate SIRT1. Instead, they only activate SIRT1 when a fluorophore is attached to the peptide substrate. Further studies using NMR, surface plasmon resonance, and isothermal calorimetry showed that these compounds interact with fluorophore-containing substrates. Additionally, the compounds did not lower plasma glucose or improve mitochondrial capacity in mice fed a high-fat diet. The study also found that these compounds have multiple off-target activities against various receptors, enzymes, transporters, and ion channels. The results indicate that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.A study evaluated whether SRT1720, SRT2183, SRT1460, and resveratrol directly activate SIRT1. Using biochemical assays with native substrates, including p53-derived peptides and full-length proteins, the researchers found that these compounds do not activate SIRT1. Instead, they only activate SIRT1 when a fluorophore is attached to the peptide substrate. Further studies using NMR, surface plasmon resonance, and isothermal calorimetry showed that these compounds interact with fluorophore-containing substrates. Additionally, the compounds did not lower plasma glucose or improve mitochondrial capacity in mice fed a high-fat diet. The study also found that these compounds have multiple off-target activities against various receptors, enzymes, transporters, and ion channels. The results indicate that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.