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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 \u03b3\u03b4 T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective \u03b3\u03b4 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.<\/jats:p>","DOI":"10.7554\/elife.66522","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T08:00:33Z","timestamp":1624262433000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.66522","source":"Crossref","is-referenced-by-count":54,"title":["Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6353-8789","authenticated-orcid":true,"given":"Seungjin","family":"Ryu","sequence":"first","affiliation":[{"name":"Department of Comparative Medicine, Yale School of Medicine, New Haven, United States"},{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, United 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