Projects
Our current projects are:
- Ageing Biology and the Ageing Liver - details here
- Ageing Biology, Diet and Sirtuins - details here
Specific and ongoing projects are:
- Calorie restriction delays age-related defenestration of the liver sinusoidal endothelium - details here
- Diabetes accelerates age-related defenestration of the liver sinusoid - details here
- Immunology of the Liver - details here
- Mechanisms of Age-Related Defenestration - details here
Ageing Biology and the Ageing Liver
Old age is the main risk factor for disease and disability. Our research studies the effects of ageing and disease on the hepatic microcirculation. We discovered that with advancing age there are major changes in the liver microcirculation that we called pseudocapillarization. These changes influence the liver metabolism of lipoproteins, thereby providing an explanation for why old age is the major risk factor for cardiovascular diseases such as heart attacks and strokes. Currently we are working towards therapies that prevent or reverse these age-related changes in the liver microcirculation and we believe will have a dramatic impact on the prevalence of vascular disease in older people. This work involves an NHMRC-supported drug discovery programme in collaboration with the Eskitis Institute.
In addition, we are studying other factors that link the ageing liver with age-related diseases, such as diabetes mellitus, apolipoprotein E, caloric restriction and the sirtuin pathways. We are also studying the effect of a severe premature ageing disease, called Werners syndrome in transgenic Werners mice
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Ageing Biology, Diet and Sirtuins
Diet has a profound effect on ageing. The ageing process can be markedly delayed by caloric restriction and by altering the ratio of protein to other dietary constituents. These effects are in part mediated by a cellular switch called sirtuins. We are studying the blood samples from CHAMP (Concord Health and Ageing in Men Project) to determine whether changes in sirtuins are associated with frailty, ageing and death. In collaboration with David Sinclair and Rafael de Cabo in the USA, we are studying the role of sirtuins in the ageing liver. In collaboration with Steve Simpson we are studying the effects of different protein dietary regimens on the ageing process in mice. We have just gained a new NHMRC grant to escalate the study of dietary protein and ageing in humans. These studies will provide new targets for delaying ageing and age-related disease
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Calorie restriction delays age-related defenestration of the liver sinusoidal endothelium
HA Jamieson, VC Cogger, SN Hilmer, R Cheluvappa, A Everitt, R Fraser, D Abernethy, R de Cabo, DG Le Couteur
Previous work by our group has demonstrated that aging causes changes in the liver sinusoidal endothelium including a loss of sinusoidal fenestrae and an increase in thickness of the endothelium. This delays the clearance of chylomicron-remnants and may partly explain why ageing is a risk factor for the cardiovascular diseases such as strokes and heart attacks.
Limiting the caloric intake of animals by approximately 30% has been consistently shown to extend lifespan and reduce the incidence of age-related diseases. In this collaborative project with the United States National Institute on Aging, we showed that calorie restriction prevented the development of age-related defenestration. This is the first time that a treatment has been shown to prevent defenestration in old animals. This provides a potential mechanism for how calorie restriction extends lifespan in mammals. Future work will assess if calorie restriction affects the clearance of lipid rich blood particles.
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Diabetes accelerates age-related defenestration of the liver sinusoid
HA Jamieson, VC Cogger, R Cheluvappa, R Fraser, SM Twigg, SV McClennan, R de Cabo, DG Le Couteur
In this work we demonstrated that diabetes caused an increase in age-related defenestration. This confirms that the age-related loss of fenestrae can be accelerated. We hypothesised that this may contribute to the delayed chylomicron remnant clearance and the increased rate of atherosclerosis that occurs in diabetes.
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Immunology of the Liver
A.Warren, D. Le Couteur, P. Bertolino (Centenary Institute)
Alessandra Warren completed her PhD entitled, “Hepatic sinusoidal cells in liver immunology and ageing” in 2006. Part of her work focused on understanding a key issue in immune-mediated liver disease: how T lymphocytes interact with hepatocytes in the presence of a sinusoidal endothelial cell barrier. Electron microscopy studies of a murine model, in collaboration with Dr Patrick Bertolino from the Centenary Institute of Cancer Medicine and Cell Biology (Sydney) , demonstrated that intrahepatic and naive T lymphocytes present cytoplasmic extensions which protrude through sinusoidal cell fenestrations and contact hepatocyte’s microvilli. Moreover, fenestrations appear to be important for infiltration of inflammatory cells from the circulation into the parenchyma during autoimmune-hepatitis. These findings suggest that hepatic sinusoidal endothelial cell fenestrations have an important role in liver immunology leading to future studies on their therapeutical implications. Further work was undertaken at University of Tromso (Norway) studying endocytosis of bacterial antigens by hepatic sinusoidal endothelial cells.
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Mechanisms of Age-Related Defenestration
J O’Reilly, M Muller, D Le Couteur
This ongoing project is examining the potential for isolating LSECs from young and old livers in order to provide purified cells for experiments to investigate mechanisms related to defenestration. Previously, we found that depleting isolated LSECs of ATP caused rapid defenestration. Consequently, we compared the ATP status of young and old isolated LSECs. Although we found no significant difference between the ATP levels of these two groups of cells, we did find that within 24 hours of isolation LSECs lose the ability to retain their fenestrae and their viability declines markedly. The poor survival of these cells outside of the liver currently limits their usefulness for defenestration studies.
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