It's a SIRT: Intense attention has focused on the SIRT1 deacetylase as a possible target for anti-aging drugs. But unexpected complications in assays of SIRT1 activity have made it unclear whether compounds thought to be sirtuin-activating compounds (STACs) are really direct regulators of the enzyme. Further exploration of these effects by Hubbard et al. (p. 1216 ; see the Perspective by Yuan and Marmorstein ) revealed that interaction of SIRT1 with certain substrates allows activation of SIRT1 by STACs and identified critical amino acids in SIRT1 required for these effects. Mouse myoblasts reconstituted with SIRT1 mutated at this amino acid lost their responsiveness to STACs.