Heat shock factor 1 ( HSF1) is essential for protecting cells from protein- damaging stress associated with misfolded proteins and regulates the insulin- signaling pathway and aging. Here, we show that human HSF1 is inducibly acetylated at a critical residue that negatively regulates DNA binding activity. Activation of the deacetylase and longevity factor SIRT1 prolonged HSF1 binding to the heat shock promoter Hsp70 by maintaining HSF1 in a deacetylated, DNA- binding competent state. Conversely, down- regulation of SIRT1 accelerated the attenuation of the heat shock response ( HSR) and release of HSF1 from its cognate promoter elements. These results provide a mechanistic basis for the requirement of HSF1 in the regulation of life span and establish a role for SIRT1 in protein homeostasis and the HSR.