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
Seungjin Ryu: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
Irina Shchukina: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
Yun-Hee Youm: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
Hua Qing: Department of Internal Medicine, Yale School of Medicine, New Haven, United States.
Brandon Hilliard: Department of Internal Medicine, Yale School of Medicine, New Haven, United States.
Tamara Dlugos: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
Xinbo Zhang: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
Yuki Yasumoto: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
Carmen J Booth: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
Carlos Fern��ndez-Hernando: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
Yajaira Su��rez: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States.
Kamal Khanna: Department of Microbiology, New York University Langone Health, New York, United States.
Tamas L Horvath: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
Marcelo O Dietrich: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
Maxim Artyomov: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
Andrew Wang: Department of Immunobiology, Yale School of Medicine, New Haven, United States. ORCID
Vishwa Deep Dixit: Department of Comparative Medicine, Yale School of Medicine, New Haven, United States. ORCID
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.
