A recent study by researchers at Yale School of Medicine, New York University Langone Health and Washington University School of Medicine, claims that the ketogenic diet (high fat, low carbohydrate diet) is capable of mitigating clinical outcomes of coronavirus disease 2019 (COVID-19) in elderly people by improving immune-metabolic functions and reducing inflammation. The study is currently available on the bioRxiv* preprint server.
Since the emergence of the COVID-19 pandemic, several studies have identified age as the strongest risk factor associated with a high mortality rate in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the United States, about 80% of COVID-19 related deaths occurred in people who were more than 65 years old.
In general, the activity of the immune system is compromised in older adults because of age-related impairment in B cell and T cell activation together with inflammasome-induced low-grade systemic inflammation. However, studies investigating COVID-19 pathophysiology are inadequate because of the limited availability of appropriate aging animal models that mimic the consequences of SARS-CoV-2 infection.
Inflammatory response in young and old mice infected with A59 (mCoV)
Mouse model used in the current study
The current study was conducted on a mouse model of natural murine beta coronavirus infection that summarizes clinical outcomes of COVID-19 in older adults.
Natural infection with mouse hepatitis virus mouse coronavirus-A59 (mCoV-A59) has been extensively used to study a wide range of clinical manifestations of systemic infection. In the current study, the scientists performed intranasal infection of adult and old male mice with mCoV-A59 to mimic COVID-19 clinical characteristics.
They observed that both old and adult mCoV-A59-infected mice had an almost similar viral load in the lungs; however, old mice displayed higher body weight loss, hypoxemia, and anorexia. The old infected mice also displayed significantly decreased CD4+ T cells, CD4+/CD8+ ratio, and γδ T cells in the lungs and spleen and increased levels of neutrophils and monocytes.
Immunohistochemical analysis revealed that old infected mice had severe perivascular inflammation, edema formation, fibrosis, pneumonia, pulmonary thrombosis, and hemorrhage compared to that in young infected mice.
Similar to elderly COVID-19 patients, mCoV-A59-infected old mice showed increased systemic and cardiac inflammation, as evidenced by increased blood levels of interleukins and tumor necrosis factor-alpha and increased infiltration of CD68+ myeloid cells, respectively.
Because both aging and obesity are associated with structural and functional alterations of the adipose tissue, the scientists investigated the impact of mCoV-A59 infection on adipose tissue metabolism. As expected, they detected viral RNA in the visceral adipose tissue, which was accompanied by significantly higher inflammatory mediators and increased activation of the inflammasome, especially in old infected mice. Similar observations were also found in the hypothalamus of old infected mice, and these findings are similar to SARS-CoV-2-mediated changes in the central nervous system. Severe anorexia observed in old infected mice was due to mCoV-A59-mediated reduction of the expression of orexigenic neuropeptide-Y.
How a ketogenic diet protects against mCoV-A59 infection?
Hepatic ketogenesis is a process of converting long-chain fatty acids into short-chain beta-hydroxybutyrate, which is subsequently used as a source of energy during starvation or glucose-deprived conditions. Previous studies have demonstrated that beta-hydroxybutyrate inhibits the activation of the inflammasome and protects mice from influenza-related death.
In the current study, the scientists observed that ketogenic diet-induced elevation in beta-hydroxybutyrate levels prevented the assembly of the inflammasome complex, leading to the prevention of inflammasome activation and reduction of inflammation. Interestingly, they observed that old mCoV-A59-infected mice fed with a ketogenic diet displayed only mild ketosis, indicating the preservation of lipid metabolism. These mice were protected from infection-related weight loss and hypoxemia and showed deactivation of the inflammasome.
Regarding inflammatory responses in the lungs, adipose tissue, and hypothalamus, mCoV-A59 -infected old mice fed with ketogenic diet showed significantly reduced expressions of inflammatory mediators and reduced cardiac infiltration of myeloid cells. Significantly, the ketogenic diet elevated the level of γδ T cells in the lungs of mCoV-A59-infected old mice. Single-cell RNA sequencing using whole lung tissue revealed that ketogenic diet provides protection against mCoV-A59-induced inflammatory changes by significantly increasing goblet cells and γδ T cells and reducing proliferative myeloid cells and monocytes. By conducting bulk RNA sequencing using γδ T cells, the scientists observed that a ketogenic diet increased anti-inflammatory gene expression, induced lipoprotein remodeling, and improved mitochondrial function in γδ T cells. This indicates the importance of ketogenic diet-induced γδ T cell expansion in providing protection against mCoV-A59 infection.
Taken together, the current study findings suggest that a ketogenic diet could be used as a readily available and affordable intervention to improve COVID-19 outcomes in older adults.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.