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

Ryu, Seungjin; Shchukina, Irina; Youm, Yun-Hee; Qing, Hua; Hilliard, Brandon; Dlugos, Tamara; Zhang, Xinbo; Yasumoto, Yuki; Booth, Carmen J; Fernández-Hernando, Carlos; Suárez, Yajaira; Khanna, Kamal; Horvath, Tamas L; Dietrich, Marcelo O; Artyomov, Maxim; Wang, Andrew; Dixit, Vishwa Deep

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.