["Archives of Insect Biochemistry and Physiology, Volume 122, Issue 4, August 2026. ", "Spermidine exerts dose‐dependent neuroprotective effects in Drosophila hereditary neurodegenerative model. Low doses (0.5–1 mM) improve survival, sensory behavior, and brain morphology, while high doses (5 mM) induce oxidative stress and physiological decline. Those data highlight the importance of dose optimization in potential therapeutic applications.\n\n\n\n\n\nABSTRACT\nNeurodegenerative disorders are characterized by progressive neuronal loss and functional decline, yet effective interventions remain limited. The polyamine spermidine was suggested to exert neuroprotective effects, but its concentration‐dependent impact on longevity, neuronal integrity, and behavior remains still not well studied. Here, we investigated the effects of spermidine on lifespan, behavioral responses, brain tissue, target gene expression, and antioxidant status in Drosophila melanogaster model of age‐dependent neurodegeneration. Wild‐type flies and swiss cheese (sws1) mutants were exposed to 0.5, 1, and 5 mM spermidine from early adulthood. Lifespan analysis revealed that high‐dose spermidine (5 mM) reduced survival in both wild‐type and sws1 mutants, whereas lower doses (0.5 and 1 mM) significantly improved survival in mutants without affecting wild‐type flies. Behavioral assays revealed that sws1 flies exhibited reduced climbing ability compared to controls, which was further decreased at 5 mM. Lower concentrations did not significantly affect locomotor performance. Taste preference for trehalose, impaired in untreated sws1 mutants, was partially restored by spermidine at all tested concentrations. Histological analysis of 10–13‐day‐old mutants showed a concentration‐dependent reduction in degeneration zones within the lamina and medulla at 0.5 and 1 mM, whereas 5 mM had no effect. Biochemical assays indicated mild pro‐oxidant effects at 5 mM, reflected by increased malondialdehyde (MDA) levels, while 0.5 mM enhanced antioxidant defenses, including catalase activity and Trolox equivalent antioxidant capacity (TEAC). Our results suggest that spermidine at low doses has the potential to be a general‐purpose neuroprotector."]