Dietary restriction (DR) is the most robust means to extend lifespan and healthspan, especially as it pertains to the onset of neurodegeneration, but the mechanisms behind this remain unclear. Through genome-wide association screens to identify genetic markers for diet-responsive factors which influence longevity and health, we identified genetic regulators of triglyceride levels, body mass, starvation resistance, longevity, and health. In our screen for longevity we found that polymorphisms in the fly gene mustard (mtd), the homolog of Oxidation Resistance 1 (OXR1), influenced lifespan in response to DR. Knockdown of mtd in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and interacts with the retromer complex, which regulates endocytic trafficking of proteins and lipids. Loss of mtd/OXR1 causes severed neurological defects, whereas its overexpression increases lifespan through regulation of the endolysosomal network. Overexpression of retromer genes or pharmacological restabilization with the compound R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. We further found that loss of OXR1 induces cellular senescence, but retromer stabilizatin can improve neuronal function in normal aging and in neurons with Alzheimer's-related genetic alterations. In all, this work shows that OXR1 plays a conserved role in preserving retromer function in response to dietary interventions and is critical for neuronal health and longevity.