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06 21, 2021;10

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

Seungjin Ryu, Irina Shchukina, Yun-Hee Youm, Hua Qing, Brandon Hilliard, Tamara Dlugos, Xinbo Zhang, Yuki Yasumoto, Carmen J Booth, Carlos Fern��ndez-Hernando, Yajaira Su��rez, Kamal Khanna, Tamas L Horvath, Marcelo O Dietrich, Maxim Artyomov, Andrew Wang, Vishwa Deep Dixit
Author Information
  1. Seungjin Ryu: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
  2. Irina Shchukina: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
  3. Yun-Hee Youm: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
  4. Hua Qing: Department of Internal Medicine, Yale School of Medicine, New Haven, United States.
  5. Brandon Hilliard: Department of Internal Medicine, Yale School of Medicine, New Haven, United States.
  6. Tamara Dlugos: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
  7. Xinbo Zhang: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
  8. Yuki Yasumoto: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
  9. Carmen J Booth: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
  10. Carlos Fern��ndez-Hernando: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
  11. Yajaira Su��rez: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
  12. Kamal Khanna: Department of Microbiology, New York University Langone Health, New York, United States.
  13. Tamas L Horvath: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
  14. Marcelo O Dietrich: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
  15. Maxim Artyomov: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
  16. Andrew Wang: Department of Immunobiology, Yale School of Medicine, New Haven, United States. ORCID
  17. Vishwa Deep Dixit: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
PMID: 34151773 DOI: 10.7554/eLife.66522

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 ���� T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective ���� 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.

Keywords

MHV aging coronavirus gamma delta t cell immunology inflammasome inflammation ketogenic diet mouse

Associated Data

GEO | GSE155346; GSE155347

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Grants

  1. R01 AR070811/NIAMS NIH HHS
  2. AR070811/NIAMS NIH HHS
  3. Glenn Foundation for Medical Research Postdoctoral Fellowships in Aging Research/American Federation for Aging Research
  4. UL1 TR001863/NCATS NIH HHS
  5. MF200400809/G. Harold and Leila Y. Mathers Charitable Foundation
  6. P30 DK056341/NIDDK NIH HHS
  7. P01 AG051459/NIA NIH HHS
  8. P01AG051459/NIA NIH HHS
  9. K08 AI128745/NIAID NIH HHS
  10. 1K08AI128745/National Institute of Allergy and Infectious Diseases

MeSH Term

Age Factors
Aging
Animals
COVID-19
Coronavirus Infections
Diet, Ketogenic
Disease Models, Animal
Glycolysis
Humans
Inflammasomes
Ketone Bodies
Male
Mice
Mice, Inbred C57BL
Murine hepatitis virus
NLR Family, Pyrin Domain-Containing 3 Protein
SARS-CoV-2

Chemicals

Inflammasomes
Ketone Bodies
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000444 (Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model (bulk RNA-seq))

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