Chemical inhibitors and activators of SIRT1. Over the past 10 years, a variety of small-molecule SIRT1-activating compounds (STACs) or inhibitors have been published. The known IC50s and EC1.5s for SIRT1 are shown in parentheses. Of all the inhibitors, only nicotinamide (NAM) is a physiological inhibitor, although analogs of NAM can activate sirtuins, apparently by occluding the C-pocket (see Figure 1). Polyphenolic activators such as resveratrol appear to bind the same site and activate via the same mechanism (i.e., primarily a lowering of the Michaelis constant effect) as that used by more potent activators such as SRT1720. The potency of inhibition is expressed as IC50 (the concentration to inhibit 50% activity), and activation is expressed as EC1.5 (the concentration to activate 1.5-fold).