Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model (bulk RNA-seq)

Impaired immunometabolic response in the elderly regulates inflammation-driven COVID-19 severity which confers the greatest risk of mortality. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain A59 (mCoV-A59) that recapitulated majority of hallmarks of COVID-19. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of ?d T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective ?d T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs during aging. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of ketogenic immunometabolic checkpoint as potential treatment against COVID-19 in the elderly. Overall design: Aged mice (20-21 months old) were fed a KD or chow diet for 5 days and then intranasally infected with mCoV-A59. gdT cells were sorted from lungs.