OXR1 maintains the retromer to delay brain aging under dietary restriction

Abstract Dietary restriction (DR) delays aging and neurodegeneration, but the mechanisms behind this remain to be elucidated. We identified genetic polymorphisms in mustard (mtd), the fly homolog of Oxidation resistance 1 (OXR1), which influenced lifespan and mtd expression in neurons in response to DR regulated by the transcription factor Traffic jam (TJ). Knockdown of mtd inhibited DR-mediated lifespan extension. We found that mtd expression naturally declines with age and that loss of mtd destabilized the retromer complex, which regulates trafficking and reuse of endocytosed proteins and lipids and maintains proper lysosomal function. Overexpression of retromer genes Vps35 or Vps26 or pharmacological restabilization with the compound R55 rescued lifespan and neurodegeneration in mtd-deficient flies as well as lysosomal defects in cells from patients who suffer from rapid neurological degeneration caused by loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 associates with aging and multiple neurological diseases, including Alzheimer’s disease, and its overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in enhancing retromer function and is critical for neuronal health and longevity across species.