OXR1 maintains the retromer to delay brain aging under dietary restriction

Kenneth A. Wilson, Sudipta Bar, Eric B. Dammer, Enrique M. Carrera, Brian A. Hodge, Tyler A. U. Hilsabeck, Joanna Bons, George W. Brownridge, Jennifer N. Beck, Jacob Rose, Melia Granath-Panelo, Christopher S. Nelson, Grace Qi, Akos A. Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B. Brem, Philippe M. Campeau, Hugo J. Bellen, Birgit Schilling, Nicholas T. Seyfried, Lisa M. Ellerby () and Pankaj Kapahi ()
Additional contact information
Kenneth A. Wilson: Buck Institute for Research on Aging
Sudipta Bar: Buck Institute for Research on Aging
Eric B. Dammer: Emory University School of Medicine
Enrique M. Carrera: Buck Institute for Research on Aging
Brian A. Hodge: Buck Institute for Research on Aging
Tyler A. U. Hilsabeck: Buck Institute for Research on Aging
Joanna Bons: Buck Institute for Research on Aging
George W. Brownridge: Buck Institute for Research on Aging
Jennifer N. Beck: Buck Institute for Research on Aging
Jacob Rose: Buck Institute for Research on Aging
Melia Granath-Panelo: Buck Institute for Research on Aging
Christopher S. Nelson: Buck Institute for Research on Aging
Grace Qi: Buck Institute for Research on Aging
Akos A. Gerencser: Buck Institute for Research on Aging
Jianfeng Lan: Buck Institute for Research on Aging
Alexandra Afenjar: Groupe Hospitalier Universitaire
Geetanjali Chawla: School of Natural Sciences, Shiv Nadar Institute of Eminence
Rachel B. Brem: Buck Institute for Research on Aging
Philippe M. Campeau: Centre Hospitalier Universitaire Saint-Justine Research Center, CHU Sainte-Justine
Hugo J. Bellen: Texas Children’s Hospital, Baylor College of Medicine
Birgit Schilling: Buck Institute for Research on Aging
Nicholas T. Seyfried: Emory University School of Medicine
Lisa M. Ellerby: Buck Institute for Research on Aging
Pankaj Kapahi: Buck Institute for Research on Aging

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44343-3

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