A Natural Short Sleep Mutation Promotes Longevity through Mitochondrial Respiration in Drosophila

Author

Pritika Pandey, Louisiana State University and Agricultural and Mechanical CollegeFollow

Degree

Doctor of Philosophy (PhD)

Department

Biological Sciences

Document Type

Dissertation

Abstract

Aging is an irreversible process characterized by progressive physiological decline and an increased risk of metabolic disorders, cognitive impairment, cardiovascular diseases, and neurodegeneration. Disruptions to the circadian clock—whether due to genetic mutations or behavioral factors—accelerate aging and age-related pathologies, highlighting a strong link between circadian regulation and longevity. However, certain individuals harbor a dec2^P384R mutation, which enables natural short sleep without the detrimental effects of chronic sleep deprivation. This suggests that these individuals have evolved adaptations that activate pro-health pathways, allowing them to function optimally with reduced sleep. To investigate the genetic mechanisms underlying these changes, we developed a Drosophila model expressing the dec2^P384R mutation in clock neurons. Our findings demonstrate that dec2^P384R mutants exhibit significantly extended lifespan, enhanced healthspan, and improved cognitive function. Global differential gene expression analysis identified upregulation of multiple mitochondrial and stress-response genes that may collectively contribute to these benefits. Oxidative phosphorylation assays revealed increased complex II-linked mitochondrial respiration and ATP production, directly linking enhanced mitochondrial function to longevity. We further speculate that elevated ROS levels, resulting from enhanced mitochondrial respiration, modulate neuronal activity in clock neurons, thereby influencing sleep regulation. Notably, dec2^P384R expression in wake-promoting neurons reduced sleep, whereas its expression in sleep-promoting neurons increased sleep duration. Together, our findings suggest that dec2^P384R expression in clock neurons promotes healthy aging through improved mitochondrial function, which, in turn, regulates sleep homeostasis.

Date

4-23-2025

Recommended Citation

Pandey, Pritika, "A Natural Short Sleep Mutation Promotes Longevity through Mitochondrial Respiration in Drosophila" (2025). LSU Doctoral Dissertations. 6776.
https://repository.lsu.edu/gradschool_dissertations/6776

Committee Chair

Johnson, Alyssa E.