Drosophila melanogaster Nepl15 gene deletion promotes anti-aging and anti-obesity phenotypes in a sex-dependent manner.

Aging and obesity are characterized by comorbidities like declines in fertility, lifespan, gut barrier integrity, cardiac function, and motor activity, and an increase in oxidative stress due to altered nutrient and energy homeostasis. A study on Drosophila Neprilysin-like 15 ( Nepl15 ) demonstrated that loss of Nepl15 gene significantly reduced glycogen and glycerolipid reserves in adult males and increased glycogen storage in adult females despite similar food consumption as controls. Therefore, we investigated the sex- and age-specific consequences of Nepl15 loss on cellular and physiological parameters associated with aging and obesity. We observed that egg production, rate of pupariation, and rate of adult fly eclosion were slightly better in the mutant flies. Interestingly, mutant females, but not males, exhibited significantly extended lifespan. Both sexes demonstrated improved locomotor performance, exercise endurance, gut barrier integrity, and preserved heart rate during progressive aging. At the cellular level, female mutants displayed reduced oxidative stress, elevated Sod2 expression, and increased ATP levels, all indicative of enhanced cellular health. Mutant males exhibited an increased mitochondrial membrane potential, indicating an enhanced capacity for rapid ATP production in response to enforced activity. Consistently, the energy-sensing kinase AMPK expression was reduced in the mutants. The lifespan extension of mutant females was supported by downregulation of mTOR and upregulation of Sirt6 expression. However, in mutant males, both mTOR and Sirt6 were downregulated, potentially contributing to improved physiological health without changing their lifespan. Collectively, our findings establish Nepl15 knockout mutation promotes anti-aging and anti-obesity health benefits, with stronger effects in female flies.