When we age, we have numerous reduced, or even loss of, bodily functions. The liver is no exception - despite being one of the most robust organs in the body, the liver also ages. One such age-affected function is the communication between the blood and the liver's major cells, the hepatocytes. In this project we will optimize our approach towards reversing age-related changes in liver sinusoidal endothelial cells (LSEC) which form the physical border between the blood and the hepatocytes, and line the 1 billion blood vessels permeating the liver. So, with ageing, the most dramatic age-related liver changes are within the LSEC, where LSEC become thicker and lose their porosity. The purpose of this project is therefore to test newly invented drugs and new drug formulations on LSEC, to determine if they can reverse ageing effects in LSEC. Initial pilot studies are very encouraging - using these new drugs we can restore lost porosity in LSEC from old mice. In this qualification project we therefore intend to optimise the drugs and drug formulations to further improve their ability to reverse such age-related changes in the liver.
There is an exponential increase in most diseases with old age, and consequently ageing is established as the most significant risk factor for disease. Novel therapeutic approaches targeting biological changes of ageing have been increasingly advocated, e.g. by the National Institutes of Health USA and journals such as Cell, Nature, Nature Medicine and Science. About 75% of people over 75 years have diabetes or pre-diabetes and/or hyperlipidaemia. These are established risk factors for cardiovascular outcomes, and risk factors for geriatric conditions such as dementia, sarcopenia, frailty and osteoporosis. Our research has focused on age-related changes in the liver microcirculation, in particular within liver sinusoidal endothelial cells (LSEC), as a cause for this susceptibility to dyslipidaemia and insulin resistance in old age, and loss of liver mediated waste clearance functions essential for homeostasis. Finding ways to reverse these age-related changes in LSEC will fill a significant gap in therapeutic options available for the treatment of ageing disorders. These therapies may also benefit patients with fibrotic livers, since LSEC in this disease mimic ageing LSEC in many aspects.