Cellular metabolism has a key role in the pathogenesis of Huntington's disease (HD), which is caused by the accumulation of mutant huntingtin protein (HTT). These two studies show that sirtuin 1 (SIRT1), an NAD-dependent protein deacetylase involved in the control of cellular metabolism, has neuroprotective effects in mouse models of HD. Jiang et al. showed that overexpression of SIRT1 in mice with HD (N171-82Q mice) improved motor function, decreased brain atrophy, and attenuated the metabolic abnormalities and decline in brain-derived neurotrophic factor (BDNF) concentration induced by mutant HTT. Furthermore, they showed that mutant HTT interacts with SIRT1 to inhibit its deacetylase activity, which prevents its pro-survival function. In agreement with these findings, Jeong et al. showed that brain-specific SIRT1 overexpression improved the survival, neuropathology and expression of BDNF in another mouse model of HD (R6/2 mice), and that the deacetylase activity of the enzyme is required for its neuroprotective effects. They also showed that mutant HTT disrupts the interaction between cAMP-responsive element binding protein (CREB) and CREB-regulated transcription co-activator 1 (TORC1; indentified as a new SIRT1 substrate), which suppresses the transcription of BDNF; overexpression of SIRT1 restores this interaction by deacetylating and activating TORC1. Together, these findings suggest that modulation of SIRT1 could be beneficial in HD.