Autophagic decline accompanies with age and deteriorates proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for autophagic degradation and exocytosis. Loss of Drosophila rab27 in abp brain neurons enhances longevity, underscoring its neuronal role and systemic effect. To understand the underlying mechanisms, we characterized the cell autonomous and non-autonomous functions of rab27. Rab27 expression increased in midlife, providing a temporal manipulation window. Depleting rab27 at that timepoint activated autophagy and sustained neuronal maintenance. At the organismic level, EGFR ligand was reduced and Akt under-phosphorylated in the rab27KO fly body, indicating a widespread signaling cascade. Finally, rab27KO ameliorates the neurotoxicity in a fly a-synucleinopathy model. Altogether, our results highlight a neuronal autophagy regulator exerting systemic effects crucial in Parkinson’s disease progression.