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

Elife. 2021 Jun 21;10:e66522. doi: 10.7554/eLife.66522.


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.

Keywords: MHV; aging; coronavirus; gamma delta t cell; immunology; inflammasome; inflammation; ketogenic diet; mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Inflammasomes
  • Ketone Bodies
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse

Associated data

  • GEO/GSE155346
  • GEO/GSE155347