Protective Effect of Melatonin on Age-induced Changes in Circadian Clock and Inflammatory Profile in Rat Liver

Abstract

Background: Aging is associated with a reduction in melatonin secretion and a deteriorating circadian system. In addition, aging is also defined by a chronic low-grade inflammation, also known as inflammaging. Sirtuin 1 (SIRT1) can affect clock function by binding with CLOCK/BMAL1 complexes and can be involved in the regulation of inflammation via deacetylation of high-mobility group box-1 (HMGB1) and inhibit the transcription of inflammation-related genes, NF-κB. Interestingly, melatonin, a hormone mainly secreted by the pineal gland, showed a variety of regulatory effects on circadian rhythm and inflammatory response in age-related liver disease. Objective: It is of interest to examine the effects of melatonin on age-induced changes in the levels of circadian clock protein and inflammation-related factors in rat liver. Materials and Methods: Rats were divided into 3 groups; young control group, aged control group, and aged rat treated with melatonin in drinking water (20 mg/L). After 2 months of melatonin administration, the liver tissues were collected. The levels of BMAL1, REV-ERBα, SIRT1, HMGB1, NF-κB, IL-6, and type I collagen, a marker of hepatic fibrosis, were analyzed by western blot analysis. Results: The present results showed that aged rats exhibited significantly downregulated BMAL1, REV-ERBα, and SIRT1 but upregulated HMGB1, NF-κB, IL-6, and type I collagen in rat liver compared with the young control group. Melatonin treated in aged rats significantly attenuated the age-induced downregulation of BMAL1, REV-ERBα, and SIRT1 and attenuated the age-induced increase in HMGB1, NF-κB, IL-6, and type I collagen protein expression. Conclusion: The present study suggested that the protective effect of melatonin on age-induced changes in clock-related inflammation in rat liver, including increasing the expression of clock and clock-controlled proteins, reducing the release of inflammatory profiles, and inhibiting fibrogenic response. These effects of melatonin may be involving the clock-related SIRT1/HMGB1/NF-κB axis. Keywords: Aging; Melatonin; Inflammaging; Clock gene; Liver; SIRT1; HMGB1; NF-κB