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

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.

Rapid Weight Loss, Central Obesity Improvement and Blood Glucose Reduction Are Associated with a Stronger Adaptive Immune Response Following COVID-19 mRNA Vaccine

“…It seems that a moderate calorie restriction might have been beneficial, confirming studies investigating its impact on the immune system. Moreover, beyond the metabolic improvement, very-low-carbohydrate diets have shown to be immunomodulatory in mouse models, as these were found to be capable of enhancing tumor-reactive CD8+ T cell and NK cell activity in glioblastoma [49] and were protective against influenza virus via an increased number and activity of protective γδ T cells in the lungs [50], a finding that was confirmed on infection with the murine equivalent of SARS-CoV-2 [51]. Moreover, isocaloric ketogenic diets have been proven effective in improving the COVID-19 prognosis in human subjects via immune modulation [52,53].…”

Immune ageing at single-cell resolution

“…For example, γδ T cells are less frequent in the aged liver and lungs but not in the spleen 25 . However, under conditions of acute lung inflammation caused by a murine betacoronavirus, old mice show lower numbers of lung γδ T cells, which could be restored by a ketogenic diet 83 .…”

Metabolic Reprogramming in COVID-19

“…KD, a high fat but low carbohydrate diet, is proposed to switch the metabolism from glycolysis to ketogenesis by lowering the availability of glucose [ 62 ]. Through activation of protective effect of γδ T cell responses, KD restrains infection of coronavirus and influenza virus in mice [ 63 , 64 ]. Retrospective analysis has shown clinical efficacy of KD in COVID-19 cytokine storm [ 65 ].…”