Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
Seungjin Ryu, Irina Shchukina, Yun‐Hee Youm, Hua Qing, Brandon K. Hilliard, Tamara Dlugos, Xinbo Zhang, Yuki Yasumoto, Carmen J. Booth, Carlos Fernández‐Hernando, Yajaira Suárez, Kamal M. Khanna, Tamás L. Horváth, Marcelo O. Dietrich, Maxim N. Artyomov, Andrew Wang, Vishwa Deep Dixit
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.