Neuronal glycolytic reprogramming drives lethality via accelerated aging in a Drosophila model of tauopathy

Neurometabolic dysfunction is a hallmark of Alzheimer's disease (AD) and tauopathies. Whether these changes drive pathology or represent compensatory, protective responses remains unresolved. Here, we demonstrate that human tau induces Warburg-like metabolism in Drosophila neurons, characterized by coordinated upregulation of glycolytic enzymes and lactate dehydrogenase that mirrors metabolic signatures in human AD. Despite intact mitochondrial oxidative phosphorylation, tau-expressing fly neurons preferentially utilize glycolysis for ATP production and operate with diminished metabolic reserve. Crucially, this metabolic reprogramming drives rather than protects against pathology as genetic suppression of glycolysis or lactate dehydrogenase completely rescued tau-induced lethality. Further, Gompertz mortality analysis revealed that hyperactive glycolysis in tau neurons drives premature lethality by accelerating biological aging rate without affecting baseline mortality. Collectively, these findings establish aberrant neuronal glycolysis as a cause rather than a consequence of tau pathology, and demonstrate that sustained glycolytic metabolism in mature neurons exacts a specific cost in the form of accelerated aging.