Method for identifying a modulator of Sirt6, PfSir2a, or Sirt7 deacylase activity, wherein a fatty-acylated substrate containing an acyl-lysine moiety and an indicator moiety is contacted with Sirt6, PfSir2a, or Sirt7 in the presence of a candidate compound under conditions for Sirt6, PfSir2a, or Sirt7 to deacylate the substrate, wherein the acyl is a hydrophobic fatty acyl group containing a hydrocarbon group having at least three carbon atoms connected by carbon-carbon bonds; contacting the deacylated substrate with a cleavage agent that cleaves the linkage between the lysine and indicator moiety to generate a detectable signal; and correlating a quantified Sirt6, PfSir2a, or Sirt7 deacylase activity therefrom. Modulating compounds of Sirt6, PfSir2a, or Sirt7 deacylase activity are also described, as are pharmaceutical compositions thereof, methods of treatment by administration of the modulating compounds, and kits for practicing the method.