SummarySleep loss typically imposes negative effects on animal health. However, humans with a rare genetic mutation in thedec2gene (dec2P384R) present an exception; these individuals sleep less without the usual effects associated with sleep deprivation. Thus, it has been suggested that thedec2P384Rmutation activates compensatory mechanisms that allows these individuals to thrive with less sleep. To test this directly, we used aDrosophilamodel to study the effects of thedec2P384Rmutation on animal health. Expression of humandec2P384Rin fly sleep neurons was sufficient to mimic the short sleep phenotype and, remarkably,dec2P384Rmutants lived significantly longer with improved health despite sleeping less. The improved physiological effects were enabled, in part, by enhanced mitochondrial fitness and upregulation of multiple stress response pathways. Moreover, we provide evidence that upregulation of pro-health pathways also contributes to the short sleep phenotype, and this phenomenon may extend to other pro-longevity models.