Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
- Yale University, United States
- Washington University School of Medicine, United States
- Yale University School of Medicine, United States
- New York University Langone Health, United States
- 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.
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Ketogenesis restrains aging-induced exacerbation of COVID in a mouse modelNCBI Gene Expression Omnibus, GSE155346.
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Ketogenesis restrains aging-induced exacerbation of COVID in a mouse modelNCBI Gene Expression Omnibus, GSE155347.
Article and author information
Author details
Marcelo O Dietrich
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.
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.
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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Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
eLife 10:e66522.
https://doi.org/10.7554/eLife.66522
