Endotoxin Tolerance Acquisition and Altered Hepatic Fatty Acid Profile in Aged Mice

SIMPLE SUMMARY: Diseases that are characterized by inflammation such as sepsis, fatty liver or severe COVID-19 are more critical in the elderly population. Endotoxin tolerance is a tolerance towards pathogen components like lipopolysaccharides from bacterial cell walls. Tolerance is developed by the host to avoid strong inflammatory responses when repeatedly being in contact with these endotoxins. We hypothesized that aging is linked to a loss of this tolerance and to elevated fat content in the liver, potentially contributing to an increased risk of inflammatory diseases in the elderly. In this study, mice underwent a treatment protocol that allowed us to study the markers of tolerance in the blood and in the tissues. Based on the markers found in the blood serum and the lung tissue, the old mice showed a clear potential for endotoxin tolerance. They also showed a different fat composition in their liver compared to the young mice. Thus, we conclude that endotoxin tolerance is not necessarily affected by advanced age, but that changes in metabolic tissue homeostasis may lead to an altered immune response in old individuals. An understanding of how the immune response changes with advanced age and changed fat metabolism is important in order to understand age-related inflammatory diseases, which will help in the development of therapies for these diseases. ABSTRACT: (1) Background: Aging is linked to an altered immune response and metabolism. Inflammatory conditions, such as sepsis, COVID-19, and steatohepatitis are more prevalent in the elderly and steatosis is linked both to severe COVID-19 and sepsis. We hypothesized that aging is linked to a loss of endotoxin tolerance, which normally protects the host from excessive inflammation, and that this is accompanied by elevated levels of hepatic lipids. (2) Methods: An in vivo lipopolysaccharide (LPS) tolerance model in young and old mice was used and the cytokine serum levels were measured by ELISA. Cytokine and toll-like receptor gene expression was determined by qPCR in the lungs and the liver; hepatic fatty acid composition was assessed by GC–MS. (3) Results: The old mice showed a distinct potential for endotoxin tolerance as suggested by the serum cytokine levels and gene expression in the lung tissue. Endotoxin tolerance was less pronounced in the livers of the aged mice. However, the fatty acid composition strongly differed in the liver tissues of the young and old mice with a distinct change in the ratio of C18 to C16 fatty acids. (4) Conclusions: Endotoxin tolerance is maintained in advanced age, but changes in the metabolic tissue homeostasis may lead to an altered immune response in old individuals.