Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice

  1. Seungjin Ryu
  2. Irina Shchukina
  3. Yun-Hee Youm
  4. Hua Qing
  5. Brandon Hilliard
  6. Tamara Dlugos
  7. Xinbo Zhang
  8. Yuki Yasumoto
  9. Carmen J Booth
  10. Carlos Fernández-Hernando
  11. Yajaira Suárez
  12. Kamal Khanna
  13. Tamas L Horvath
  14. Marcelo O Dietrich
  15. Maxim N Artyomov
  16. Andrew Wang  Is a corresponding author
  17. Vishwa Deep Dixit  Is a corresponding author
  1. Yale University, United States
  2. Washington University School of Medicine, United States
  3. Yale University School of Medicine, United States
  4. New York University Langone Health, United States
  5. Yale School of Medicine, United States

Abstract

Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic-diet (KD) impacts immune-surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.

Data availability

The single cell RNA-sequencing and bulk RNA-sequencing data has been uploaded to Gene Expression Omnibus (GSE155346 and GSE155347) respectively.

The following data sets were generated

Article and author information

Author details

  1. Seungjin Ryu

    Comparative Medicine and Immunobiology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Irina Shchukina

    Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yun-Hee Youm

    Comparative Medicine and Immunobiology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hua Qing

    Internal Medicine, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Brandon Hilliard

    Internal Medicine, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tamara Dlugos

    Comparative Medicine and Immunobiology, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Xinbo Zhang

    Comparative Medicine, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yuki Yasumoto

    Comparative Medicine, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Carmen J Booth

    Department of Comparative Medicine, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Carlos Fernández-Hernando

    Comparative Medicine and Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Yajaira Suárez

    Comparative Medicine and Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Kamal Khanna

    New York University Langone Health, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Tamas L Horvath

    Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7522-4602
  14. Marcelo O Dietrich

    Comparative Medicine, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9781-2221
  15. Maxim N Artyomov

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Andrew Wang

    Yale School of Medicine, New Haven, United States
    For correspondence
    andrew.wang@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6951-8081
  17. Vishwa Deep Dixit

    Comparative Medicine and Immunobiology, Yale University School of Medicine, New Haven, United States
    For correspondence
    vishwa.dixit@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5341-6494

Funding

National Institute on Aging (P01AG051459)

  • Vishwa Deep Dixit

National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR070811)

  • Vishwa Deep Dixit

American Federation for Aging Research (Glenn Foundation for Medical Research Postdoctoral Fellowships in Aging Research)

  • Seungjin Ryu

National Institute of Allergy and Infectious Diseases (1K08AI128745)

  • Andrew Wang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Chyung-Ru Wang, Northwestern University, United States

Ethics

Animal experimentation: All experiments and animal use were conducted in compliance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee (IACUC) protocol (#2019-11572 and 2020-20149) of Yale University.

Version history

  1. Received: January 13, 2021
  2. Accepted: June 15, 2021
  3. Accepted Manuscript published: June 21, 2021 (version 1)
  4. Version of Record published: June 30, 2021 (version 2)

Copyright

© 2021, Ryu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Seungjin Ryu
  2. Irina Shchukina
  3. Yun-Hee Youm
  4. Hua Qing
  5. Brandon Hilliard
  6. Tamara Dlugos
  7. Xinbo Zhang
  8. Yuki Yasumoto
  9. Carmen J Booth
  10. Carlos Fernández-Hernando
  11. Yajaira Suárez
  12. Kamal Khanna
  13. Tamas L Horvath
  14. Marcelo O Dietrich
  15. Maxim N Artyomov
  16. Andrew Wang
  17. Vishwa Deep Dixit
(2021)
Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
eLife 10:e66522.
https://doi.org/10.7554/eLife.66522

Share this article

https://doi.org/10.7554/eLife.66522

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