Age-related neuroprotection by dietary restriction requires OXR1-mediated retromer function
Authors: Kenneth Wilson 1; Sudipta Bar 1; Enrique Carrera 1,2; George Brownridge III 1; Jennifer Beck 1; Tyler Hilsabeck 1,3; Christopher Nelson 1; Geetanjali Chawla 4; Rachel Brem 1,3,5; Hugo Bellen 6; Lisa Ellerby 1; Pankaj Kapahi 1,3
Affiliations: 1) Buck Institute for Research on Aging, Novato, CA; 2) Dominican University of California, San Rafael, CA; 3) Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA; 4) Regional Centre for Biotechnology, Faridabad, Haryana, India; 5) Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA; 6) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
Keywords: f. dietary restriction/fasting; m. lysosomes
Dietary restriction (DR) is the most robust method to delay aging and the onset of neurodegeneration, though the mechanisms behind this phenomenon remain unclear. Further, it remains unknown which factors influence why different individuals will respond to dietary interventions to different degrees. We reared over 150 fully sequenced fly strains from the Drosophila Genetic Reference Panel under ad libitum feeding or diet-restricted conditions and measured lifespan as well as healthspan. Through genome-wide association study, we identified genetic variants associated with influencing these traits under each dietary condition. A variant in one gene, mustard (mtd, called Oxidation resistance 1, OXR1, in humans), significantly associated with DR-specific lifespan. We demonstrate that mtd/OXR1 in neurons is necessary for DR-mediated lifespan extension and that neuronal overexpression of human OXR1 is sufficient to extend lifespan upon DR in flies. Neuronal knockdown of mtd also inhibits dietary restriction-associated slowing of age-related visual decline, arguing for a specific role of mtd/OXR1 in DR-mediated neuroprotection. We additionally identified that natural variants of mtd in the promoter region are associated with enhanced longevity upon DR and are regulated by the transcription factor Traffic jam (TJ). We further show that mtd is essential for stabilizing the retromer complex, which is necessary for trafficking transmembrane proteins for reuse. As a result of OXR1 deficiency, the retromer destabilizes and lysosomes become overused. Overexpression of retromer proteins or supplementation with chaperone compound R55 rescues the lifespan defects and neurodegeneration seen in mtd-deficient flies, and R55 is capable of rescuing lysosomal aggregation and OXR1-retromer co-localization in cells from humans with OXR1 deficiency. Thus, mtd/OXR1 enhances protein recycling in response to DR through the retromer, improving neuronal health and lifespan.