Neuronal Syndecan reduction modulates age- and sex-specific changes in sleep architecture and metabolic remodeling in Drosophila melanogaster.

Age-related deterioration of sleep is a conserved feature of aging and is closely associated with metabolic dysregulation and neurodegeneration. However, the molecular mechanisms that sustain sleep stability across the lifespan remain incompletely defined. We investigated the role of neuronal Syndecan (Sdc), a transmembrane heparan sulfate proteoglycan, in sleep regulation, energy balance, and memory across age and sex in Drosophila melanogaster. Pan-neuronal Sdc knockdown increased total sleep duration during both day and night in young and aged flies of both sexes, without altering the temporal organization of sleep-wake behavior under light-dark conditions. Increases in sleep duration were accompanied by context-dependent changes in sleep architecture. Aged neuronal Sdc knockdown males exhibited increased nighttime fragmentation alongside enhanced daytime consolidation, whereas females showed modest and largely age-independent changes. Feeding behavior and organismal metabolic rate exhibited sex-, age-, and time-of-day-dependent effects. Memory performance was not altered. Transcriptomic profiling of aged male heads identified differential expression of genes involved in glutamatergic signaling, amino acid metabolism, and glutathione-associated redox pathways. Targeted analysis of tryptophan-kynurenine pathway metabolites, which influence glutamatergic activity, revealed sex-specific differences in kynurenic acid/tryptophan and 3-hydroxykynurenine/tryptophan. Together, these findings suggest that neuronal Sdc contributes to context-dependent modulation of sleep architecture and metabolic state.