Mechanisms for ageing changes in the hepatic sinusoid

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We recently discovered changes in the blood vessels of the liver that occur with old age that we have called pseudocapillarisation. These changes include thickening of the liver sinusoidal endothelium, deposition of basal lamina and collagen, and marked loss of specialized pores within the endothelium called fenestrations. These changes have profound effects on the transfer of many substrates including toxins, drugs, oxygen, hormones and lipids from the blood into the liver and thus may explain in part the fact that old age is the major risk factor for many diseases and adverse drug reactions. To further understand the mechanisms for these important ageing liver changes, we are proposing several studies. First, the effects of caloric restriction on the liver blood vessels will be studied because caloric restriction delays the primary ageing process. Second we will study the effects of ageing on F-actin, ATP, caveolin-1 and VEGF because these mechanisms have established roles in regulating the structure and function of the liver blood vessels and in particular their fenestrations. Finally we will determine whether VEGF can reverse the ageing changes in the liver blood vessels and stimulate the formation of new fenestrations within these blood vessels. Our research provides one mechanism for the inexorable association between old age and susceptibility to disease - based on primary ageing changes in the liver. As well as increasing our understanding of the cellular changes for ageing and the basic mechanisms involved in the regulation of the liver endothelial cells and their fenestrations, this proposed research will provide a foundation for the development of therapeutic interventions for the prevention and treatment of some age-related disorders.