The link between resveratrol (a polyphenol found in grapes) and longevity has been hotly pursued since it was found to activate Sirt1, a member of the sirtuin acetylases believed to be central in mediating the health benefits of caloric restriction. The actual linkages among these molecules and outcomes are still being sorted out, but at least now we have some idea of the mechanism whereby resveratrol exerts its influence, thanks to work by Park and colleagues. The researchers focused on energy metabolism, given its central role in aging, and on the finding that resveratrol activates Sirt1 via AMP-activated protein kinase (AMPK), an energy sensing enzyme. Through direct dissection of the pathways, they were able to pinpoint a set of phosphodiesterases (PDEs) as resveratrol's target and to identify the intermediates from the induction of cyclic AMP production (following PDE inhibition) to Sirt1 activation. Comparing the effects of the PDE inhibitor rolipram to resveratrol in vivo further established the identity of the target; in mice fed a high-fat diet, rolipram raised the transcription level of genes involved with mitochondrial biogenesis in skeletal muscle to levels as to those for resveratrol, suggesting that existing PDE inhibitors may be repurposed to treat age-related diseases. (Cell 148, 421–433, 2012)