Differential effects of paraquat-induced oxidative stress on functional aging and lifespan in male and female Drosophila melanogaster

Aging is accompanied by loss of motor function driven by mitochondrial oxidative stress. To examine how genotype and sex modulate this process, we exposed Oregon-R (wild-type) and vestigial (wing-deficient) Drosophila of both sexes to chronic paraquat a mitochondrial stressor generating sustained ROS production at 0, 10, or 20 mM. We tracked climbing performance from day 5–50 alongside survival. Paraquat impaired locomotion dose- dependently, with effects modified by genotype and sex (four-way ANOVA, all p < 0.001). Under control conditions, behavioral half-life (T₅₀) occurred at 21.4 days in Oregon-R males and 25.7 days in females. Vestigial flies declined earlier: 14.8 days (males), 18.3 days (females). At 20 mM, T₅₀ fell 48–53% across groups. Female advantage persisted at 10 mM but narrowed at 20 mM, especially in vestigial flies. Survival mirrored functional decline. The T₅₀-to-lifespan interval compressed under severe stress: 18–28 days (controls) versus 8–12 days (20 mM). Functional-survival coupling was strong (r = 0.87, p < 0.001). Oxidative stress accelerates functional aging through mechanisms shaped by genotype and sex. Climbing performance predicts healthspan and may serve as a translational biomarker for neuromuscular aging.