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

ABSTRACT: 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 dec2P384R mutation 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 dec2P384R mutation could activate compensatory mechanisms that allow these individuals to thrive with less sleep. To test this directly, we used a dec2P384R short sleep Drosophila model to understand the effects of the dec2P384R mutation on animal health and dissect the genetic mechanisms that might drive these physiological changes. We found that expression of the mammalian dec2P384R mutation in fly sleep neurons was sufficient to mimic the short sleep phenotype observed in mammals. Remarkably, dec2P384R lived significantly longer with improved health and memory despite having a short sleep phenotype. The improved physiological effects in dec2P384R 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 dec2P384R mutants may also contribute to the short sleep phenotype, and this may extend to other pro-longevity mutants.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE230462 | GEO | 2023/04/26

REPOSITORIES: GEO

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Project description:Short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (e.g., genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of short habitual sleep duration on gene expression. Therefore, we sought to investigate gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD=18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with two-weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Next, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. The mean 24 hour sleep duration of the total sample was 439.2 minutes (SD=46.8 minutes; range 325.4 to 521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD=21.2; range 45.9 to 114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular and inflammatory outcomes.

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

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