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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
Old age is the main risk factor for atherosclerosis, which is the main cause of mortality and morbidity in the World. We found age-related changes in the microcirculation of the liver called pseudocapillarization that provide a mechanism linking old age with atherosclerosis. Pores in the endothelium called fenestrations disappear, impairing the ability of the liver to breakdown fats. New therapies to treat and prevent age-related pseudocapillarization are being developed.
Pelvic Floor Muscle Training For The Management Of Urinary Incontinence In Elderly Women: A Randomized Controlled Trial.
Funder
National Health and Medical Research Council
Funding Amount
$321,240.00
Summary
Urinary incontinence is associated with significant personal shame and social stigma and affects around 10% of Australians. one-third of women over 60 years of age. Incontinence limits physical activity and this in turn can lead to loss of independence and poorer general health. Fewer than one-third of those with regular incontinence seek assistance. Pelvic floor muscle re-education by physiotherapists is the most commonly recommended method of conservative management for urinary incontinence. P ....Urinary incontinence is associated with significant personal shame and social stigma and affects around 10% of Australians. one-third of women over 60 years of age. Incontinence limits physical activity and this in turn can lead to loss of independence and poorer general health. Fewer than one-third of those with regular incontinence seek assistance. Pelvic floor muscle re-education by physiotherapists is the most commonly recommended method of conservative management for urinary incontinence. Pelvic floor muscle training is safe and effective and should thus be offered as the first choice of treatment for stress urinary incontinence. However there is still no strong evidence for the effectiveness of this intervention in the elderly and because of a perception by medical practitioners that pelvic floor muscle re-education is only effective in younger women, relatively few elderly women are referred to physiotherapy for management of incontinence. Although in clinical practice it is customary to complement pelvic floor muscle training with other forms of conservative management of incontinence such as bladder training, a recent influential study suggested that pelvic floor muscle training and bladder training were equally effective in patients with stress urinary incontinence. It is important to distinguish the relative effectiveness of these interventions used in isolation in order to ensure that urinary incontinence is managed in the most effective and efficient way. This project will therefore investigate the effectiveness of two conservative interventions, pelvic floor muscle training and bladder-behavioural training in women with stress urinary incontinence over 70 years of age. Moreover, strong evidence that conservative intervention is effective for urinary incontinence in the elderly will result in appropriate intervention being offered routinely as the first choice of treatment in older women.Read moreRead less
Developing A Skin Test For Early Diagnosis Of Alzheimer's Disease And For Monitoring Effectiveness Of Treatment
Funder
National Health and Medical Research Council
Funding Amount
$285,000.00
Summary
Approximately 140,000 Australians suffer from Alzheimer's disease (AD). As the ageing population continues to grow, this number will double by the middle of the next century unless a cure or prevention is found. Scientists are continuously seeking new, more effective diagnostic tests in an effort to make it easier to diagnose AD in its early stages. Being able to recognize symptoms early and obtain an accurate diagnosis would give affected individuals a greater chance of benefiting from putative ....Approximately 140,000 Australians suffer from Alzheimer's disease (AD). As the ageing population continues to grow, this number will double by the middle of the next century unless a cure or prevention is found. Scientists are continuously seeking new, more effective diagnostic tests in an effort to make it easier to diagnose AD in its early stages. Being able to recognize symptoms early and obtain an accurate diagnosis would give affected individuals a greater chance of benefiting from putative treatments. However, there is no single, comprehensive diagnostic test for AD. Diagnostic tests (including peripheral markers) that can help to reliably diagnose AD at an early stage are needed as are tests that can help in monitoring the progression of AD, including response to therapy. The accuracy and clinical utility of previously proposed peripheral markers (platelets and pupil dilation test) is questionable. The only way to confirm a diagnosis of AD is through autopsy. We have obtained a provisional patent application for the use of a skin test for early diagnosis of AD (Patent No: PQ2881-99). This test is based on our extensive research over the past decade to understand the biochemical mechanisms underlying the txic vascular actions of beta amyloid protein. This protein has been implicated in the pathology of AD and it accumulates in the brain, peripheral tissues and is present in circulating blood of AD patients. The test is based on our discovery that vascular effects of Ab could be detected in the peripheral microcirculation .We now wish to further examine the utility of this novel skin test. If the test is sensitive, it could be used for screening; if it is specific it would be useful for confirmation of suspected AD. If the test is sensitive to change in clinical status it would help select treatments that might cure or improve the symptoms of AD.Read moreRead less