High-saturated-fat diet drives female-biased neurodegeneration in Drosophila via oxidative stress and impaired autophagic flux

OBJECTIVE: Dietary saturated fat intake has been increasingly linked to dementia risk, yet the mechanisms through which high-fat diets (HFDs) compromise neuronal integrity remain poorly defined. The model organism Drosophila melanogaster may serve as an ideal model to understand these mechanisms across aging due to its genetic tractability and short lifespan. METHODS: Flies were fed diets containing 30% (w/v) fat from 2 oils with varying saturated-fat content and were assessed for lifespan and climbing ability. Immunohistochemistry and confocal imaging were used to evaluate brain tissue integrity, quantify vacuoles, and assess oxidative stress and activation of an inflammatory pathway. Genetically encoded and UAS-driven fluorescent reporters, along with confocal imaging, were used to assess autophagy and autophagic flux. RESULTS: Both HFDs shortened lifespan but only the highest saturated-fat source (coconut oil) uniquely produced a female-specific decline in climbing ability and significant neurodegeneration, compared to lard and control diets. Mechanistic evaluation revealed no activation of the NF-κB homolog relish in response to a coconut oil HFD however chronic HFD feeding led to elevated neuronal reactive oxygen species and early impairment of autophagic flux, preceding autophagosome accumulation during aging. CONCLUSION: These findings identify oxidative stress and disrupted autophagy as key mediators of saturated-fat-induced neuronal decline and highlight a sex-specific vulnerability to dietary fat composition. This work establishes Drosophila as a powerful model for dissecting nutritional drivers of neural aging and suggests that metabolic stress pathways represent critical early targets in diet-associated neurodegeneration.