Centre for Healthy Ageing
The number of Australians aged 65 and over is projected to more than double from 3.7 million in 2016 to 8.7 million in 2057. Furthermore, the cost to the country’s budget will be A$36 billion by 2028-29.
Ageing is a complex biological process driven by molecular and cellular mechanisms, many of which are yet to be fully understood.
Critically, ageing not only leads to a progressive degeneration and fragility of the body over time but is also the most important risk factor for many of the major chronic diseases facing society today. The biological process of ageing contributes to the incidence and severity of major diseases like frailty, dementia, heart disease, diabetes, stroke, COPD, cirrhosis and cancer.
With increasing longevity and an ageing population, it is imperative that new strategies are developed to limit the growing burden of disease and to improve health span.
Beyond the individual and societal health benefits of combatting disease in an ageing population, economic impacts are another consideration. The clinical problem presents a huge medical and economic burden on governments.
The fundamental recognition that ageing as a process can be subject to medical intervention, like cancer or hypertension, has led to a global interest to develop therapeutics and diagnostics for its prevention and amelioration.
Centenary has made the strategic decision to establish a Centre for Healthy Ageing to assemble the skills and competencies to systematically attack this health challenge.
Mission
Attack society’s major health and economic problem, namely the fragility, disability and cost of an ageing population.
Discover and bring to use tests, therapies and interventions that will diagnose, treat and prevent undesirable consequences of the ageing process.
Vision
The centre is the first comprehensive organisation in Australia to address the biology of ageing.
We research the mechanisms that underlie disease to develop new diagnostics, treatments and cures for some of the most deadly and debilitating diseases affecting society today.
Our research will focus on six fundamental processes thought to drive cellular ageing: cell senescence, DNA damage, inflammation, epigenetics, proteostasis and mitochondrial dysfunction.
Using this knowledge, we will determine how ageing accelerates the rate and severity of diseases affecting key organs such as the brain, lung, heart, liver, skin and skeletal muscle. Collectively, the overriding goal of the centre is to develop therapeutic strategies to prevent the onset of chronic disease to allow individuals to maintain heath, physiological function and independence during the ageing process.
It is only when the biology of disease is fully understood, that safe and effective medical therapeutics can then be successfully developed to delay or prevent chronic diseases of ageing.
Dementia is a general term for disorders affecting brain function impacting a person’s memory, thinking, behaviour and ability to carry out everyday activities. There are approximately 500,000 Australians currently living with dementia, and Alzheimer’s disease accounts for up to 70% of these cases.
Alzheimer’s disease
Alzheimer’s is an age-related neurodegenerative disease consisting of plaque build-up within the cellular networks of the brain, which disrupts cell function and neuronal communication. A cure has yet to be found.
Centenary’s Vascular Biology team, led by Professor Jennifer Gamble, is focused on the blood vessels of the brain and their potential role in Alzheimer’s development and progression. More specifically, her team is investigating endothelial cells–the cells that line blood vessels and which are responsible for preserving the blood-brain barrier.
They have identified significant age-related changes in these cells which, over time, can become impaired and ‘leaky’ and unable to inhibit inflammation. Professor Gamble is determining if the breakdown and dysfunction of these cells with age actually leads to Alzheimer’s or makes the disease more likely. If this is the case, the work will open the door to an entirely new approach to combatting the disease–through targeting our aged blood vessels.
In addition to her work on blood vessels and dementia, Professor Gamble’s team is investigating the link between injured blood vessels that induce chronic inflammation may also determine the outcome of atherosclerosis.
Heart valve disease is a progressive disorder
Calcific aortic valve disease (CAVD) is a disease of the aged affecting 2-4% of people over 65 years old and is the most common type of heart valve disease in Western countries. It’s a progressive disorder where calcium deposits form on the aortic valve in the heart, narrowing and stiffening the valve’s opening. It has the potential to impact blood flow through the valve and can lead to heart failure.
Centenary’s Vascular Biology team, led by Professor Jennifer Gamble, is investigating why CAVD develops with age as well as the specific cells and signalling pathways associated with the disease. She hopes to uncover potential drug targets once the mechanisms of disease initiation and progression
are known.
Ageing arteries and atherosclerosis
Atherosclerosis is a chronic condition in which arteries harden and narrow over time due to a build-up of fatty plaque on the arterial wall. Although the use of blood cholesterol-lowering medications can be successful in halting or reducing this plaque build-up, atherosclerosis remains the leading cause of cardiovascular disease-related death worldwide.
In his research, Dr Yanfei (Jacob) Qi, Head of Centenary’s Lipid Cell Biology Laboratory, is studying how fat products within blood vessel cells affect their fitness as well as influence atherosclerosis.
He’s identified a critical regulator of both fat movement and storage within cells. The novel factor is implicated in blood vessel health. This protein serves as a ‘catapult’, hurling unhealthy fat products within blood vessel cells–this leading to a higher risk of cellular injury.
Dr Qi is now exploring how this fat regulator functions in the endothelial cell lining of blood vessels, to generate new understanding of the initiation and progression of atherosclerosis. The research could lead to the development of an entirely new class of drugs to treat this age-associated arterial disease.
Heart failure
“Stiff” heart failure, or Heart Failure with preserved Ejection Fraction (HFpEF), is now the commonest form of heart failure in the world, causing considerable morbidity and mortality, but with no effective therapies. One in 10 persons in the world aged 40 or more will develop HFpEF, the most common form of chronic cardiovascular disease for which almost no effective therapies exist.
All standard heart failure therapies have failed to improve outcomes in HFpEF2. Recently, an anti-diabetic sodium glucose cotransporter 2 inhibitor (SGLT2i) therapy was the first to improve outcomes in HFpEF, suggesting that HFpEF is a metabolic disorder which is exacerbated by ageing.
Associate Professor John O’Sullivan and his team at the Heart Research Institute (HRI), are exploring whether deficiency of oxidized nicotinamide adenine dinucleotide (NAD+), a critical energy intermediate within the cell, is a critical factor driving HFpEF development.
To achieve this, Associate Professor O’Sullivan and his team are leading two clinical trials CardioNAD and pEFNAD, in partnership with the NHMRC Clinical Trials Centre to test whether increasing NAD+, with the dietary precursor Nicotinamide Riboside, can improve clinical outcomes and longevity in patients with HFpEF.
This work is part of an ongoing program of work by Associate Professor O’Sullivan through the ‘Stiff Heart Failure Alliance’ that he will lead with colleagues at Hospitals throughout Sydney and Sydney Health Partners.
The goal of this alliance is to harmonise and formalise HFpEF diagnosis and management across SLHD and Sydney Health Partners, responsible for >2.7 million patients.
Chronic obstructive pulmonary disease (COPD), also known as emphysema, is an often fatal condition where the lungs are damaged and airflow is impeded making it difficult to breathe. The disease is characterised by severe lung inflammation and emphysema that intensify as the disease progresses.
Major risk factors are long-term exposure to lung and airway irritants such as cigarette/tobacco smoke and bushfire smoke, air pollution, chemicals and dusts. Critically, there is increasing evidence that, in COPD, the ageing of the lung is accelerated. That is, that age associated changes in the structure and function of the lung are important in the disease’s development and progression.
There is currently no cure for COPD, the fifth leading cause of death in Australia, third globally.
At Centenary, research into COPD is led by Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation. He is looking at the impact of inflammation and potential treatments for COPD across multiple areas. These include fibrotic tissue remodelling, molecular impacts of infections and oxidative stress on the lungs.
Professor Hansbro’s recent findings also suggest a link between COPD and the gut microbiome and its metabolites. The ‘microbiome’ describes all of the microbes, particularly bacteria that exist in an individual.
His work suggests that an unhealthy or altered microbiome could be responsible for promoting inflammatory diseases such as COPD. The team is now aiming to determine the role and potential for modulating the gut microbiome and their products as potential new therapies for COPD.
Other respiratory disease areas being studied by Professor Hansbro include idiopathic pulmonary fibrosis (IPF) and severe asthma. They are both associated with the ageing process.
IPF, a scarring of the lungs making it hard to breathe, is a progressive and often fatal disease, mainly affecting people aged 50 years and older. It is believed that
age-related changes in cellular function may play a role in IPF.
Likewise, the underlying mechanics of severe asthma are being investigated in the hope of identifying new therapeutic targets and treatments. Older adults have some of the highest rates of asthma morbidity and mortality. It appears possible that the mechanisms underlying airway inflammation in this older population may differ to those found in younger people.
Severe chronic liver diseases, including cancer, fatty liver disease, cirrhosis and liver failure, all increase with age, independently of all other disease drivers. The ageing process adversely affects the ability of the liver to recover after injury and inflammation – healthy tissue tends to not regenerate as well or as quickly, more scar tissue accumulates and vascular operations are less efficient. Further, immune responses are less effective. The combination of these factors significantly impacts liver disease development in the elderly.
Professor Geoff McCaughan, Head of Centenary’s Liver Injury and Cancer Program, is investigating the underlying mechanisms that drive primary liver cancer and disease across a background of liver inflammation, fibrosis and the liver stem cell response.
Cellular senescence in the liver is a major area of interest. Senescent cells (cells that no longer grow) accumulate during ageing and have been implicated in promoting a variety of age-related diseases. Premature senescence of liver cells is a key feature of liver response during chronic liver injury. Professor McCaughan speculates that use of agents that selectively eliminate senescent cells may offer up new therapeutic approaches for treatment.
Professor Mark Gorrell who leads the Liver Enzymes in Metabolism and Inflammation Program is focused on the four enzymes of the dipeptidyl peptidase IV (DPP4) gene family – DPP4, DPP8, DPP9 and FAP. He investigates the enzymes’ roles in disease, including diabetes, a disease that is affected and impacted by ageing.
Many patients with age-related diabetes develop severe liver disease at ages 65 and over. This is despite patient control of their cardiovascular risk factors. Professor Gorrell has shown that the amount of DPP4 in the blood of patients with diabetes is associated with fat accumulation in the liver. There is supportive data from both preclinical and clinical studies, showing that an existing diabetes drug that targets DPP4 lowers liver damage. Professor Gorrell continues to explore this area to help determine new and improved therapeutic outcomes.
Joint leaders of Centenary’s Liver Immunology Program, Associate Professor Patrick Bertolino and Associate Professor David Bowen investigate the unique relationship between the liver and the immune system ageing has a major influence on the immune properties of the liver leading to these opposing immune responses. These properties involve two cell types that the Liver Immunology group has extensive expertise in – T cells and myeloid cells.
T cells interact with hepatocytes (liver cells) through sinusoidal endothelial cell fenestrations (pores). The loss of these ‘pores’ due to ageing is likely to significantly influence interactions between hepatocytes and immune cells. As one of the main immune roles of hepatocytes is to interact with auto reactive T cells and induce their elimination, the loss of these interactions would likely predispose ageing individuals to autoimmunity issues in later life. This is an area of study that the Program is looking to advance.
Age-associated musculoskeletal decline is a global health problem. Musculoskeletal conditions have been estimated to affect 1.71 billion people globally. The two most common age-associated musculoskeletal conditions are osteoporosis (loss of bone) and sarcopenia (loss of muscle), which lead to pain and weakness of the musculoskeletal system.
Sarcopenia leads to frailty, loss of mobility, an increased risk of falls and fractures, a diminished quality of life, and in some cases premature mortality. 3.7 million people in Australia are currently over 65 years old, with projections suggesting this number will more than double to 8.7 million by 2050.
It has been estimated that about 30% of those aged 75-84 suffer from sarcopenia, indicating that approximately 330,000 people in Australia would currently be considered sarcopenic, with this number predicted to exceed 780,000 by 2050. It is currently unknown why the musculoskeletal system gets weaker with age, and what biological cues dictate the rate and severity of this transition.
Research by Dr Andy Philp, Head, Biology of Ageing Program, aims to understand the factors that cause age-associated muscle weakness to develop therapeutics to prevent sarcopenia. A fundamental cellular process thought to be involved in this problem is the development of mitochondrial dysfunction, which leads to a reduction in energy production in our cells. Recent research suggests that skeletal muscle mitochondrial dysfunction may be causal in the development of sarcopenia.
Dr Philp’s current research, is investigating whether pharmacological approaches to increase mitochondrial activity in skeletal muscle can be used for the treatment and prevention of sarcopenia. To achieve this, Dr Philp’s group are examining how mitochondrial dysfunction develops during ageing. Using this information, they will then determine whether mitochondrial-targeted therapies can protect old skeletal muscle from ageing, short-term inactivity, or muscle damage.
Finally, using a novel model of sarcopenia ‘in a dish’, Dr Philp aims to discover novel therapeutic targets to improve skeletal muscle function. Collectively, the goals of Dr Philp’s work are to develop new therapeutic strategies for the treatment of sarcopenia with clear translational potential.
Sarcopenia is prominent in patients with advanced liver disease, from any cause, and is associated with worse patient outcomes. Data from sarcopenia patients is being analysed to determine sarcopenia frequency and its correlation with energy expenditure, malnutrition and frailty. Professor McCaughan will study the molecular and cellular aspects of sarcopenia from blood and tissue samples taken from patients, to advance knowledge of this disorder.
Cancer is a major cause of illness and is one of the leading causes of death accounting for approximately 50,000 Australian lives every year. Cancer is a group of many related diseases where abnormal cells grow in an uncontrolled manner, damaging tissue and organs.
The risk of cancer increases with age–more than four times as many cancers are diagnosed in people over
60 years of age, as compared to those aged under 60. Over 41,000 Australians aged 60 and older died of cancer in 2020.
Nicotinamide, the immune system and ageing
The body’s immune response can be compromised by the development of a state called T-cell exhaustion that leads to the ineffective clearance of cancers or infections. T-cells are an essential part of the immune system but decline in effectiveness in older people or when overly stimulated by disease.
Professor Peter Hersey, Head of Centenary’s Melanoma Oncology and Immunology Program, has shown in T-cell culture studies that T-cell exhaustion can be prevented by the addition of nicotinamide, a form of vitamin B3.
Professor Hersey and his team are aiming to investigate the possible metabolic effects of nicotinamide on mitochondrial function which are the essential power houses in the T-cell that provide energy. They hope to test T-cell subpopulations and functions, and include tests on nicotinamide at pharmacologic doses in normal human subjects.
Nicotinamide’s ability to reduce skin cancers in older people is also of interest to Professor Hersey, as is a possible role for nicotinamide in improving COVID-19 vaccine response in individuals aged 80 plus.
Fighting cancer
The Centenary Institute is dedicated to developing new cancer diagnostics, treatments and cures through its dedicated ACRF Centenary Cancer Research Centre.
Headed up by Professor Philip Hogg, the ACRF Centenary Cancer Research Centre is focused on two areas of research–an understanding of the inflammatory and metabolic causes of cancer; as well as the drivers behind cancer-driven thrombosis (blood clotting) which is a leading cause of death in cancer patients. Thrombosis accounts for about 9% of cancer-related deaths.
An innovative break-through from Professor Hogg and his team was the recent discovery of an entirely novel aspect of how thrombosis proteins form and operate. With this understanding, work is now taking place to determine why some individuals have an increased tendency to form thrombi and why they are often resistant to anti-thrombotic drugs that are commonly used for treatments.
COVID-19 a new disease of the aged
Risk of severe illness and death from COVID-19 increases markedly with age and for those individuals with pre-existing health conditions. Approximately 85% of all COVID-19 deaths occur in people aged 65 or older. The likely reasons for this are a weakened immune system due to ageing, decreasing the body’s ability to fight the viral infection effectively; and higher levels of existing health conditions in the elderly, which is known to complicate COVID-19 infection.
At Centenary, a number of COVID-19 research programs are taking place under the leadership of Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation. This includes the study of both the pathogenesis of COVID-19 as well as the mechanisms of viral infection. Novel drug therapies are also being developed and tested, that aim to suppress the inflammatory damage in the lungs to help improve patient recovery. Additionally, and in collaboration with the University of Sydney, research is taking place on the development of a unique, single-shot vaccine against COVID-19 with a focus on new variants of concern.
Long Covid
SARS-CoV-2 infection-induced COVID-19 manifestations range from mild disease with fever, cough and fatigue, to severe and often fatal disease from acute respiratory distress syndrome (ARDS) and multi-systemic organ failure.
Most patients recover in a few weeks; however, it is now established that in some, especially older individuals, disease symptoms persist for months despite the resolution of infection. This is termed acute-post COVID syndrome or long COVID. The long-term damage following COVID-19 is poorly defined and little is known as to what causes long covid and how long covid alters the progression and severity of other diseases of ageing.
Professor Philip Hansbro and his team have developed a unique K18-hACE2 long COVID-19 mouse model to experimentally examine long covid and determine the impact on established diseases of ageing in peripheral tissues. Utilising this experimental model, the goal is to develop new therapeutics to treat the debilitating effects of long-covid and associated disease.
We research the mechanisms that underlie disease to develop new diagnostics, treatments and cures for some of the most deadly and debilitating diseases affecting society today.
Our research will focus on six fundamental processes thought to drive cellular ageing: cell senescence, DNA damage, inflammation, epigenetics, proteostasis and mitochondrial dysfunction.
Using this knowledge, we will determine how ageing accelerates the rate and severity of diseases affecting key organs such as the brain, lung, heart, liver, skin and skeletal muscle. Collectively, the overriding goal of the centre is to develop therapeutic strategies to prevent the onset of chronic disease to allow individuals to maintain heath, physiological function and independence during the ageing process.
It is only when the biology of disease is fully understood, that safe and effective medical therapeutics can then be successfully developed to delay or prevent chronic diseases of ageing.
Dementia is a general term for disorders affecting brain function impacting a person’s memory, thinking, behaviour and ability to carry out everyday activities. There are approximately 500,000 Australians currently living with dementia, and Alzheimer’s disease accounts for up to 70% of these cases.
Alzheimer’s disease
Alzheimer’s is an age-related neurodegenerative disease consisting of plaque build-up within the cellular networks of the brain, which disrupts cell function and neuronal communication. A cure has yet to be found.
Centenary’s Vascular Biology team, led by Professor Jennifer Gamble, is focused on the blood vessels of the brain and their potential role in Alzheimer’s development and progression. More specifically, her team is investigating endothelial cells–the cells that line blood vessels and which are responsible for preserving the blood-brain barrier.
They have identified significant age-related changes in these cells which, over time, can become impaired and ‘leaky’ and unable to inhibit inflammation. Professor Gamble is determining if the breakdown and dysfunction of these cells with age actually leads to Alzheimer’s or makes the disease more likely. If this is the case, the work will open the door to an entirely new approach to combatting the disease–through targeting our aged blood vessels.
In addition to her work on blood vessels and dementia, Professor Gamble’s team is investigating the link between injured blood vessels that induce chronic inflammation may also determine the outcome of atherosclerosis.
Heart valve disease is a progressive disorder
Calcific aortic valve disease (CAVD) is a disease of the aged affecting 2-4% of people over 65 years old and is the most common type of heart valve disease in Western countries. It’s a progressive disorder where calcium deposits form on the aortic valve in the heart, narrowing and stiffening the valve’s opening. It has the potential to impact blood flow through the valve and can lead to heart failure.
Centenary’s Vascular Biology team, led by Professor Jennifer Gamble, is investigating why CAVD develops with age as well as the specific cells and signalling pathways associated with the disease. She hopes to uncover potential drug targets once the mechanisms of disease initiation and progression
are known.
Ageing arteries and atherosclerosis
Atherosclerosis is a chronic condition in which arteries harden and narrow over time due to a build-up of fatty plaque on the arterial wall. Although the use of blood cholesterol-lowering medications can be successful in halting or reducing this plaque build-up, atherosclerosis remains the leading cause of cardiovascular disease-related death worldwide.
In his research, Dr Yanfei (Jacob) Qi, Head of Centenary’s Lipid Cell Biology Laboratory, is studying how fat products within blood vessel cells affect their fitness as well as influence atherosclerosis.
He’s identified a critical regulator of both fat movement and storage within cells. The novel factor is implicated in blood vessel health. This protein serves as a ‘catapult’, hurling unhealthy fat products within blood vessel cells–this leading to a higher risk of cellular injury.
Dr Qi is now exploring how this fat regulator functions in the endothelial cell lining of blood vessels, to generate new understanding of the initiation and progression of atherosclerosis. The research could lead to the development of an entirely new class of drugs to treat this age-associated arterial disease.
Heart failure
“Stiff” heart failure, or Heart Failure with preserved Ejection Fraction (HFpEF), is now the commonest form of heart failure in the world, causing considerable morbidity and mortality, but with no effective therapies. One in 10 persons in the world aged 40 or more will develop HFpEF, the most common form of chronic cardiovascular disease for which almost no effective therapies exist.
All standard heart failure therapies have failed to improve outcomes in HFpEF2. Recently, an anti-diabetic sodium glucose cotransporter 2 inhibitor (SGLT2i) therapy was the first to improve outcomes in HFpEF, suggesting that HFpEF is a metabolic disorder which is exacerbated by ageing.
Associate Professor John O’Sullivan and his team at the Heart Research Institute (HRI), are exploring whether deficiency of oxidized nicotinamide adenine dinucleotide (NAD+), a critical energy intermediate within the cell, is a critical factor driving HFpEF development.
To achieve this, Associate Professor O’Sullivan and his team are leading two clinical trials CardioNAD and pEFNAD, in partnership with the NHMRC Clinical Trials Centre to test whether increasing NAD+, with the dietary precursor Nicotinamide Riboside, can improve clinical outcomes and longevity in patients with HFpEF.
This work is part of an ongoing program of work by Associate Professor O’Sullivan through the ‘Stiff Heart Failure Alliance’ that he will lead with colleagues at Hospitals throughout Sydney and Sydney Health Partners.
The goal of this alliance is to harmonise and formalise HFpEF diagnosis and management across SLHD and Sydney Health Partners, responsible for >2.7 million patients.
Chronic obstructive pulmonary disease (COPD), also known as emphysema, is an often fatal condition where the lungs are damaged and airflow is impeded making it difficult to breathe. The disease is characterised by severe lung inflammation and emphysema that intensify as the disease progresses.
Major risk factors are long-term exposure to lung and airway irritants such as cigarette/tobacco smoke and bushfire smoke, air pollution, chemicals and dusts. Critically, there is increasing evidence that, in COPD, the ageing of the lung is accelerated. That is, that age associated changes in the structure and function of the lung are important in the disease’s development and progression.
There is currently no cure for COPD, the fifth leading cause of death in Australia, third globally.
At Centenary, research into COPD is led by Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation. He is looking at the impact of inflammation and potential treatments for COPD across multiple areas. These include fibrotic tissue remodelling, molecular impacts of infections and oxidative stress on the lungs.
Professor Hansbro’s recent findings also suggest a link between COPD and the gut microbiome and its metabolites. The ‘microbiome’ describes all of the microbes, particularly bacteria that exist in an individual.
His work suggests that an unhealthy or altered microbiome could be responsible for promoting inflammatory diseases such as COPD. The team is now aiming to determine the role and potential for modulating the gut microbiome and their products as potential new therapies for COPD.
Other respiratory disease areas being studied by Professor Hansbro include idiopathic pulmonary fibrosis (IPF) and severe asthma. They are both associated with the ageing process.
IPF, a scarring of the lungs making it hard to breathe, is a progressive and often fatal disease, mainly affecting people aged 50 years and older. It is believed that
age-related changes in cellular function may play a role in IPF.
Likewise, the underlying mechanics of severe asthma are being investigated in the hope of identifying new therapeutic targets and treatments. Older adults have some of the highest rates of asthma morbidity and mortality. It appears possible that the mechanisms underlying airway inflammation in this older population may differ to those found in younger people.
Severe chronic liver diseases, including cancer, fatty liver disease, cirrhosis and liver failure, all increase with age, independently of all other disease drivers. The ageing process adversely affects the ability of the liver to recover after injury and inflammation – healthy tissue tends to not regenerate as well or as quickly, more scar tissue accumulates and vascular operations are less efficient. Further, immune responses are less effective. The combination of these factors significantly impacts liver disease development in the elderly.
Professor Geoff McCaughan, Head of Centenary’s Liver Injury and Cancer Program, is investigating the underlying mechanisms that drive primary liver cancer and disease across a background of liver inflammation, fibrosis and the liver stem cell response.
Cellular senescence in the liver is a major area of interest. Senescent cells (cells that no longer grow) accumulate during ageing and have been implicated in promoting a variety of age-related diseases. Premature senescence of liver cells is a key feature of liver response during chronic liver injury. Professor McCaughan speculates that use of agents that selectively eliminate senescent cells may offer up new therapeutic approaches for treatment.
Professor Mark Gorrell who leads the Liver Enzymes in Metabolism and Inflammation Program is focused on the four enzymes of the dipeptidyl peptidase IV (DPP4) gene family – DPP4, DPP8, DPP9 and FAP. He investigates the enzymes’ roles in disease, including diabetes, a disease that is affected and impacted by ageing.
Many patients with age-related diabetes develop severe liver disease at ages 65 and over. This is despite patient control of their cardiovascular risk factors. Professor Gorrell has shown that the amount of DPP4 in the blood of patients with diabetes is associated with fat accumulation in the liver. There is supportive data from both preclinical and clinical studies, showing that an existing diabetes drug that targets DPP4 lowers liver damage. Professor Gorrell continues to explore this area to help determine new and improved therapeutic outcomes.
Joint leaders of Centenary’s Liver Immunology Program, Associate Professor Patrick Bertolino and Associate Professor David Bowen investigate the unique relationship between the liver and the immune system ageing has a major influence on the immune properties of the liver leading to these opposing immune responses. These properties involve two cell types that the Liver Immunology group has extensive expertise in – T cells and myeloid cells.
T cells interact with hepatocytes (liver cells) through sinusoidal endothelial cell fenestrations (pores). The loss of these ‘pores’ due to ageing is likely to significantly influence interactions between hepatocytes and immune cells. As one of the main immune roles of hepatocytes is to interact with auto reactive T cells and induce their elimination, the loss of these interactions would likely predispose ageing individuals to autoimmunity issues in later life. This is an area of study that the Program is looking to advance.
Age-associated musculoskeletal decline is a global health problem. Musculoskeletal conditions have been estimated to affect 1.71 billion people globally. The two most common age-associated musculoskeletal conditions are osteoporosis (loss of bone) and sarcopenia (loss of muscle), which lead to pain and weakness of the musculoskeletal system.
Sarcopenia leads to frailty, loss of mobility, an increased risk of falls and fractures, a diminished quality of life, and in some cases premature mortality. 3.7 million people in Australia are currently over 65 years old, with projections suggesting this number will more than double to 8.7 million by 2050.
It has been estimated that about 30% of those aged 75-84 suffer from sarcopenia, indicating that approximately 330,000 people in Australia would currently be considered sarcopenic, with this number predicted to exceed 780,000 by 2050. It is currently unknown why the musculoskeletal system gets weaker with age, and what biological cues dictate the rate and severity of this transition.
Research by Dr Andy Philp, Head, Biology of Ageing Program, aims to understand the factors that cause age-associated muscle weakness to develop therapeutics to prevent sarcopenia. A fundamental cellular process thought to be involved in this problem is the development of mitochondrial dysfunction, which leads to a reduction in energy production in our cells. Recent research suggests that skeletal muscle mitochondrial dysfunction may be causal in the development of sarcopenia.
Dr Philp’s current research, is investigating whether pharmacological approaches to increase mitochondrial activity in skeletal muscle can be used for the treatment and prevention of sarcopenia. To achieve this, Dr Philp’s group are examining how mitochondrial dysfunction develops during ageing. Using this information, they will then determine whether mitochondrial-targeted therapies can protect old skeletal muscle from ageing, short-term inactivity, or muscle damage.
Finally, using a novel model of sarcopenia ‘in a dish’, Dr Philp aims to discover novel therapeutic targets to improve skeletal muscle function. Collectively, the goals of Dr Philp’s work are to develop new therapeutic strategies for the treatment of sarcopenia with clear translational potential.
Sarcopenia is prominent in patients with advanced liver disease, from any cause, and is associated with worse patient outcomes. Data from sarcopenia patients is being analysed to determine sarcopenia frequency and its correlation with energy expenditure, malnutrition and frailty. Professor McCaughan will study the molecular and cellular aspects of sarcopenia from blood and tissue samples taken from patients, to advance knowledge of this disorder.
Cancer is a major cause of illness and is one of the leading causes of death accounting for approximately 50,000 Australian lives every year. Cancer is a group of many related diseases where abnormal cells grow in an uncontrolled manner, damaging tissue and organs.
The risk of cancer increases with age–more than four times as many cancers are diagnosed in people over
60 years of age, as compared to those aged under 60. Over 41,000 Australians aged 60 and older died of cancer in 2020.
Nicotinamide, the immune system and ageing
The body’s immune response can be compromised by the development of a state called T-cell exhaustion that leads to the ineffective clearance of cancers or infections. T-cells are an essential part of the immune system but decline in effectiveness in older people or when overly stimulated by disease.
Professor Peter Hersey, Head of Centenary’s Melanoma Oncology and Immunology Program, has shown in T-cell culture studies that T-cell exhaustion can be prevented by the addition of nicotinamide, a form of vitamin B3.
Professor Hersey and his team are aiming to investigate the possible metabolic effects of nicotinamide on mitochondrial function which are the essential power houses in the T-cell that provide energy. They hope to test T-cell subpopulations and functions, and include tests on nicotinamide at pharmacologic doses in normal human subjects.
Nicotinamide’s ability to reduce skin cancers in older people is also of interest to Professor Hersey, as is a possible role for nicotinamide in improving COVID-19 vaccine response in individuals aged 80 plus.
Fighting cancer
The Centenary Institute is dedicated to developing new cancer diagnostics, treatments and cures through its dedicated ACRF Centenary Cancer Research Centre.
Headed up by Professor Philip Hogg, the ACRF Centenary Cancer Research Centre is focused on two areas of research–an understanding of the inflammatory and metabolic causes of cancer; as well as the drivers behind cancer-driven thrombosis (blood clotting) which is a leading cause of death in cancer patients. Thrombosis accounts for about 9% of cancer-related deaths.
An innovative break-through from Professor Hogg and his team was the recent discovery of an entirely novel aspect of how thrombosis proteins form and operate. With this understanding, work is now taking place to determine why some individuals have an increased tendency to form thrombi and why they are often resistant to anti-thrombotic drugs that are commonly used for treatments.
COVID-19 a new disease of the aged
Risk of severe illness and death from COVID-19 increases markedly with age and for those individuals with pre-existing health conditions. Approximately 85% of all COVID-19 deaths occur in people aged 65 or older. The likely reasons for this are a weakened immune system due to ageing, decreasing the body’s ability to fight the viral infection effectively; and higher levels of existing health conditions in the elderly, which is known to complicate COVID-19 infection.
At Centenary, a number of COVID-19 research programs are taking place under the leadership of Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation. This includes the study of both the pathogenesis of COVID-19 as well as the mechanisms of viral infection. Novel drug therapies are also being developed and tested, that aim to suppress the inflammatory damage in the lungs to help improve patient recovery. Additionally, and in collaboration with the University of Sydney, research is taking place on the development of a unique, single-shot vaccine against COVID-19 with a focus on new variants of concern.
Long Covid
SARS-CoV-2 infection-induced COVID-19 manifestations range from mild disease with fever, cough and fatigue, to severe and often fatal disease from acute respiratory distress syndrome (ARDS) and multi-systemic organ failure.
Most patients recover in a few weeks; however, it is now established that in some, especially older individuals, disease symptoms persist for months despite the resolution of infection. This is termed acute-post COVID syndrome or long COVID. The long-term damage following COVID-19 is poorly defined and little is known as to what causes long covid and how long covid alters the progression and severity of other diseases of ageing.
Professor Philip Hansbro and his team have developed a unique K18-hACE2 long COVID-19 mouse model to experimentally examine long covid and determine the impact on established diseases of ageing in peripheral tissues. Utilising this experimental model, the goal is to develop new therapeutics to treat the debilitating effects of long-covid and associated disease.