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

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.

Alterations in the hepatocyte epigenetic landscape in steatosis

“…According to the inflamm-aging theory, aging promotes liver inflammation [63]. However, although aging has been reported to increase hepatic lipid accumulation [17,[64][65][66], aging per se has no effect on steatosis in mid-aged mice [67]. Interestingly, there are inconclusive data on the progression of steatosis to NASH in the very elderly [68].…”

“…The lipid composition induced by LDC feeding was analyzed in mice treated in parallel to the animals used for hepatocyte isolation within this project and confirmed massive lipid deposition [ 15 ]. For analysis of DNA methylation related to aging, hepatocytes were isolated from female control C57Bl6/J mice at the age of 10 weeks (young) and 40 weeks (mid-aged); for DNA methylation analyses in liver tissues, livers from female control mice aged 10 (young) and 84–85 (aged) weeks were used [ 17 ].…”