A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila

A familial natural short sleep mutation promotes healthy aging and extends lifespan in Drosophila. Sleep is a conserved physiological process, and sleep loss typically imposes negative effects on animal health. However, natural short sleepers, who sleep less without the usual negative effects of sleep deprivation, exist in the human population. One example are individuals that possess rare genetic mutations in the human dec2 gene; these individuals sleep on average ~6hrs/day rather than the typical 8hrs/day. Like many natural short sleepers, humans harboring the dec2-SS mutation (this allele contains R155M, A298V and P384R mutations) do not exhibit any obvious adverse phenotypes typically associated with sleep loss, suggesting that these individuals may require less total sleep/day to achieve the same physiological outcomes. Potentially, the dec2-SS mutation could activate compensatory mechanisms that allow these individuals to thrive with less sleep. To test this directly, we used a dec2-SS short sleep Drosophila model to understand the effects of the dec2-SS mutation on animal health and dissect the genetic mechanisms that might drive these physiological changes. We found that expression of the mammalian dec2-SS mutation in fly sleep neurons was sufficient to mimic the short sleep phenotype observed in mammals. Remarkably, dec2-SS lived significantly longer with improved health and memory despite having a short sleep phenotype. The improved physiological effects in dec2-SS mutants were enabled, in part, by enhanced mitochondrial fitness and upregulation of multiple stress response pathways. Moreover, we provide evidence that the improved health in dec2-SS mutants may also contribute to the short sleep phenotype, and this may extend to other pro-longevity mutants. The decWT refers to a dec2 transgene that contains the A298V point mutation