OXR1 and Retromer Function in Aging
Researchers here employ a combination of genetic manipulation and calorie restriction in order to find mechanisms that might be important in aging. This leads them to retromer function, where the retromer is a complex system involved in recycling receptor proteins found in the cell membrane. Reduced retromer function leads to changes in cell behavior and survival that contribute to aging and disease. The gene OXR1 is necessary for retromer function, but its expression declines with age, suggesting it as a target for therapies to slow this aspect of age-related cellular dysfunction.
Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects.
Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.