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Effects Of Ageing On Hepatic Drug Clearance And Mechanisms Of Drug Induced Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
With increasing age, there is increase in disease, for which medications may provide benefit, and an increase in the risk of adverse drug reactions, even after considering the increase in medication use by older people. We will investigate how the liver clears drugs from the blood in old age. This will guide dosing of medications for older people. We will also study how drugs injure the liver in old age and test interventions to prevent this toxicity.
The Effect Of Hepatic Pseudocapillarisation Of Old Age On The Disposition Of Chylomicron Remnants And Chylomicrons
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
Old age is the major risk factor for atherosclerosis, and vascular disease secondary to atherosclerosis (eg heart attacks and strokes) is the major cause of death and disability in the Western World. As yet there has not been any clear explanation for why old age itself is a risk factor for atherosclerosis. In this study, we are investigating how changes in the liver in old age predispose to hyperlipidaemia and hence vascular disease. We recently discovered changes in the blood vessels of the li ....Old age is the major risk factor for atherosclerosis, and vascular disease secondary to atherosclerosis (eg heart attacks and strokes) is the major cause of death and disability in the Western World. As yet there has not been any clear explanation for why old age itself is a risk factor for atherosclerosis. In this study, we are investigating how changes in the liver in old age predispose to hyperlipidaemia and hence vascular disease. We recently discovered changes in the blood vessels of the liver that occur with old age that we have called pseudocapillarisation. These changes have profound effects on the transport 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. In this study we are interested in the transfer of fats called chylomicron remnants from blood into the liver. Chylomicron remnants are lipoproteins rich in triglycerides that are produced after meals and broken down by the liver. In order to be metabolised, chylomicron remnants must pass through pores in the liver blood vessels called fenestrations. In old age, we have found that these fenestrations are reduced substantially, which will impair the uptake of chylomicron remnants by the liver, leading to marked increases in fat in the blood stream after meals. In this study, we will examine the effects of old age on the ability of the liver to metabolise chylomicron remnants, in particular focussing on the effects of the age-related loss of fenestrations on chylomicron remnant uptake. As well as providing an understanding of the crucial link between ageing and atherosclerosis, the studies will provide a potential new therapeutic target for the prevention of atherosclerosis in older people.Read moreRead less
Caloric Restriction, Ageing And The Liver Sinusoidal Endothelium: Mechanisms And Implications
Funder
National Health and Medical Research Council
Funding Amount
$366,216.00
Summary
Old age is the major risk factor for many diseases yet the mechanism is unknown. We discovered age-related changes in the liver sinusoidal endothelial cell that provide a mechanism for the link between old age, lipid metabolism and vascular disease. The liver sinusoidal endothelial cell influences the transfer of substrates between the blood and liver cells, therefore changes in the liver sinusoidal endothelial cell affect liver function. We discovered major structural changes in the liver sinus ....Old age is the major risk factor for many diseases yet the mechanism is unknown. We discovered age-related changes in the liver sinusoidal endothelial cell that provide a mechanism for the link between old age, lipid metabolism and vascular disease. The liver sinusoidal endothelial cell influences the transfer of substrates between the blood and liver cells, therefore changes in the liver sinusoidal endothelial cell affect liver function. We discovered major structural changes in the liver sinusoidal endothelial cell in old age called pseudocapillarization, consisting of loss of pores, increased thickness and deposition of collagen and basal lamina. We showed that the loss of pores prevented the uptake by the liver of some lipoproteins, with implications for age-related changes in lipid metabolism and vascular disease. We have now found that caloric restriction delays pseudocapillarization. Caloric restriction is the only intervention known to increase maximal life span. This effect of caloric restriction is mediated by a protein called SIRT1 through actions on mitochondria and cell death. A naturally occurring agonist of SIRT1 called resveratrol has been found to increase longevity in yeast, worms and flies. We hypothesize that caloric restriction prevents age-related cardiovascular disease by delaying pseudocapillarization and hence maintaining hepatic metabolism of lipoproteins, particularly chylomicron remnants. We propose that caloric restriction will prevent age-related pseudocapillarization via its effects on the SIRT1 pathways and therefore pseudocapillarization will be delayed by resveratrol. Confirmation of these hypotheses will generate a unique target - pores in the liver sinusoidal endothelial cell - for the prevention of vascular disease in older people and provide a platform for the development of novel pharmacological agents such as resveratrol that act by maintaining the porosity of the liver sinusoidal endothelial cell.Read moreRead less