The ageing process shows marked variability between individuals but also between different organs within an individual. This proposal focusses on the ageing liver, key in maintenance of whole body homeostasis. Therefore, age-related deterioration of liver functioning contributes to susceptibility to develop age-related diseases. Several hallmarks of ageing are known to impact on the different cell types of the liver. Yet, the factors that actually modulate ageing of the liver are unclear. Recent data indicates that metabolism of bile acids (BAs) is changed under conditions associated with increased life- and healthspan and, vice versa, that altered BA metabolism impacts human health. Primary BAs are formed in the liver and facilitate intestinal absorption of dietary fats. During their enterohepatic cycling, BAs interact with the gut microbiome leading to formation of secondary BAs. As a result, the human liver is exposed to a high (grams/day) load of differently structured BAs. It has been established in recent years that BAs also have hormone-like functions through activation nuclear and membrane-bound receptors involved in control of metabolic and inflammatory pathways as well as of detoxification reactions. Particularly secondary BAs have strong signalling capabilities. Our recent work has revealed great interindividual variability in BA pool composition in humans, related to genetic makeup of their microbiomes. Importantly, BAs have been associated with human longevity. Several new secondary BAs have been identified recently of which biological functions remain to be established. Using innovative mouse models with humanized BA metabolism, mechanisms of liver ageing will be identified and validated in a unique series of human liver biopsies, human donor livers on normothermic machine perfusion and liver-on-a-chip. Since the gut microbiome is amendable to manipulation, outcome of this work can contribute to new strategies to promote healthy (liver) ageing.
THIS PAGE IS UNDER CONSTRUCTION!
Update your browser to view this website correctly. Update my browser now
