OXR1 maintains the retromer to delay brain aging under dietary restriction-Reference-Cited by-同舟云学术

OXR1 maintains the retromer to delay brain aging under dietary restriction

Published:2024-01-11 Issue:1 Volume:15 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

Wilson Kenneth A.^ORCID,Bar Sudipta^ORCID,Dammer Eric B.^ORCID,Carrera Enrique M.,Hodge Brian A.,Hilsabeck Tyler A. U.^ORCID,Bons Joanna^ORCID,Brownridge George W.,Beck Jennifer N.,Rose Jacob,Granath-Panelo Melia,Nelson Christopher S.,Qi Grace^ORCID,Gerencser Akos A.^ORCID,Lan Jianfeng,Afenjar Alexandra,Chawla Geetanjali^ORCID,Brem Rachel B.,Campeau Philippe M.^ORCID,Bellen Hugo J.^ORCID,Schilling Birgit^ORCID,Seyfried Nicholas T.^ORCID,Ellerby Lisa M.^ORCID,Kapahi Pankaj^ORCID

Abstract

AbstractDietary 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute on Aging

Larry L. Hillblom Foundation

U.S. Department of Health & Human Services | NIH | National Center for Research Resources

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Link

https://www.nature.com/articles/s41467-023-44343-3.pdf

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