The ability to manage anxiety, an emotion expressed in threatening or challenging conditions, is necessary for navigating new environments. Treatments for anxiety disorders increase serotonin and norepinephrine levels by inhibiting monoamine oxidases and selective serotonin reuptake. Now, Leonard Guarente and colleagues report that SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, influences anxiety and exploratory behavior by increasing transcription of the Maoa gene encoding monoamine oxidase A (Cell 147, 1459–1472, 2011 ). Mice with a brain-specific knockout of Sirt1 had higher levels of exploratory behavior than wild-type littermates. In contrast, mice that overexpressed Sirt1 had lower levels of exploratory behavior. Knockout mice were more resistant to depression in a 'social defeat' paradigm in which depression manifests in experimental male mice after multiple exposures to more dominating males. Knockout mice also had higher levels of serotonin and noradrenalin but lower levels of 5-hydroxyindoleacetic acid (5-HLAA) than wild-type littermates. MAO-A converts serotonin into 5-H1AA, and Maoa mRNA levels were lower in Sirt1-null mice and higher in Sirt1-overexpressing mice than in wild-type littermates, respectively. Luciferase reporter assays suggested that SIRT1 is needed to directly activate the Maoa promoter. Further experiments showed that SIRT1 deacetylates the NHLH2 transcription factor, which directly modulates the Maoa promoter.