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OXR1 maintains the retromer to delay brain aging under dietary restriction

Author

Listed:
  • Kenneth A. Wilson

    (Buck Institute for Research on Aging
    University of Southern California)

  • 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
    University of Southern California)

  • 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
    The Afilliated Hospital of Guilin Medican University)

  • Alexandra Afenjar

    (Groupe Hospitalier Universitaire
    Sorbonne Universités, Hôpital Trousseau)

  • Geetanjali Chawla

    (School of Natural Sciences, Shiv Nadar Institute of Eminence)

  • Rachel B. Brem

    (Buck Institute for Research on Aging
    University of Southern California
    University of California, Berkeley)

  • 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
    University of Southern California)

  • Pankaj Kapahi

    (Buck Institute for Research on Aging
    University of Southern California)

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.

Suggested Citation

  • 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-Pane, 2024. "OXR1 maintains the retromer to delay brain aging under dietary restriction," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44343-3
    DOI: 10.1038/s41467-023-44343-3
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    References listed on IDEAS

    as
    1. Alexander Lachmann & Denis Torre & Alexandra B. Keenan & Kathleen M. Jagodnik & Hoyjin J. Lee & Lily Wang & Moshe C. Silverstein & Avi Ma’ayan, 2018. "Massive mining of publicly available RNA-seq data from human and mouse," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    2. Lawrence A. David & Corinne F. Maurice & Rachel N. Carmody & David B. Gootenberg & Julie E. Button & Benjamin E. Wolfe & Alisha V. Ling & A. Sloan Devlin & Yug Varma & Michael A. Fischbach & Sudha B. , 2014. "Diet rapidly and reproducibly alters the human gut microbiome," Nature, Nature, vol. 505(7484), pages 559-563, January.
    3. Gemma Cadby & Corey Giles & Phillip E. Melton & Kevin Huynh & Natalie A. Mellett & Thy Duong & Anh Nguyen & Michelle Cinel & Alex Smith & Gavriel Olshansky & Tingting Wang & Marta Brozynska & Mike Ino, 2022. "Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Joseph H.A. Vissers & Samuel A. Manning & Aishwarya Kulkarni & Kieran F. Harvey, 2016. "A Drosophila RNAi library modulates Hippo pathway-dependent tissue growth," Nature Communications, Nature, vol. 7(1), pages 1-6, April.
    5. Nicolas Nègre & Christopher D. Brown & Lijia Ma & Christopher Aaron Bristow & Steven W. Miller & Ulrich Wagner & Pouya Kheradpour & Matthew L. Eaton & Paul Loriaux & Rachel Sealfon & Zirong Li & Haruh, 2011. "A cis-regulatory map of the Drosophila genome," Nature, Nature, vol. 471(7339), pages 527-531, March.
    6. Ben C. Collins & Christie L. Hunter & Yansheng Liu & Birgit Schilling & George Rosenberger & Samuel L. Bader & Daniel W. Chan & Bradford W. Gibson & Anne-Claude Gingras & Jason M. Held & Mio Hirayama-, 2017. "Multi-laboratory assessment of reproducibility, qualitative and quantitative performance of SWATH-mass spectrometry," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
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