Aspirin or cellular acetyl-CoA could directly acetylate proteins to affect diversity functions. We identify HDACs could be the directly acetylated substrates of aspirin. The inside functional lysine of SIRT1 could be acetylated by aspirin or acetyl-CoA but not be deacetylated by active SIRT1. This irreversible acetylation of SIRT1 inhibits its activity and regulates healthy aging in C. elegans.