Dopamine Homeostasis Links Age-Dependent Metabolic Stress Resistance to Longevity in Drosophila melanogaster

Dopamine (DA) functions beyond neurotransmission, yet its relationship with age-dependent stress adaptation and physiological aging remains incompletely understood. Here, we investigated whether genetic alterations in DA biosynthesis are associated with coordinated changes in dopamine homeostasis, metabolic stress resistance, and lifespan in Drosophila melanogaster . We examined Catsup ²⁶, which exhibits elevated DA, and the DA-deficient Pu ᶻ²² and ple ² mutants, together with isogenized w ¹¹¹⁸ controls. HPLC analysis revealed genotype-, tissue-, and sex-dependent alterations in DA and tetrahydrobiopterin (BH₄), linking disruption of the DA biosynthetic pathway to altered homeostasis. Catsup ²⁶ flies exhibited enhanced starvation resistance and extended lifespan, whereas Pu ᶻ²² and ple ² mutants displayed reduced starvation tolerance and longevity. Starvation resistance declined with advancing age, with significant effects of genotype and age and significant genotype × age interactions in both sexes. Acute starvation also increased head DA and BH₄ and produced tissue- and sex-specific changes in peripheral DA and BH₄ levels. Together, these findings identify DA homeostasis as a physiological link between age-dependent metabolic stress resistance and longevity and support modulation of the DA biosynthetic pathway as a potential mechanism influencing stress adaptation during aging in Drosophila .