Experimental Gerontology 37 (2002) 1301–1308 www.elsevier.com/locate/expgero
Aging Research Worldwide
Experimental gerontological research in Australia Gary R. Andrewsa,*, Zeinab Khalilb, David G. Le Couteurc a
Centre for Ageing Studies, Flinders University, Adelaide, Australia National Ageing Research Institute, University of Melbourne, Parkville, Australia c Centre for Education and Research on Ageing ANZAC Research Institute, University of Sydney, Concord, Australia b
Received 1 July 2002; accepted 18 July 2002
Abstract Recently there has been recognition in Australia of the importance of experimental gerontological research. To date, the major areas of research into the biology of ageing have been oxidative stress and mitochondrial dysfunction. Future directions for gerontological research in Australia are likely to place more emphasis on comprehensive studies that integrate basic biological research, with clinical studies and the behavioural and social domains of ageing. Priority will be given to studies incorporating biological markers that are population based and longitudinal. The growing interest in experimental gerontological research complements Australian research strengths in other domains such as disease-based research, social gerontology, population studies and health policy research. q 2002 Elsevier Science Inc. All rights reserved. Keywords: Experimental gerontology; Research; Australia
1. Introduction The influence of the ageing population on Australia has been similar to that seen in other industrialised countries. In Australia 9% of the population was greater than the age of 65 years in 1976. By 1998, this was 12% and the projection for 2051 is 26%. The number of very elderly people is increasing at an even faster rate. In 1997, 1.2% of the population was older than 85 years and this will increase four-fold within fifty years (Office for Older Australians, 2002). There are over 700,000 older Australians with profound, severe or moderate disability (Flicker, 2000) and health care expenditure for people over the age of 65 * Corresponding author. Tel.: þ 61-88201-7552; fax: þ 6188201-7551. E-mail address:
[email protected] (G.R. Andrews).
years is approximately four-fold greater than for younger people (Lim and Woodward, 1999). There are about 72,000 nursing home beds and 63,000 hostel beds and funding for residential aged care has increased from $2.5 billion in 1995 – 1996 to an estimated $3.9 billion in 2000– 2001 (Flicker, 2000). As a result of ageing, it is predicted that the health care expenditure as a fraction of gross domestic product will double over the next forty years (Office for Older Australians, 2002). As a direct consequence, there has been increasing priority afforded to ageing research, and a trend towards increased research activity in ageing. This has been most apparent in the domains of health service research and social gerontology, less so in geriatric medicine and has been more limited in the area of experimental gerontology. Ageing is the result of complex interactions between biological, social,
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psychological and pathological processes. The linkages between these processes are crucial for understanding healthy ageing and for generating appropriate health care planning for older people. Recently there have been clear signals that experimental gerontology has become an increased priority area for Australian researchers and funding bodies (Le Couteur et al., 2002b; Kendig et al., 2000).
2. Policy and infrastructure for experimental gerontology and ageing research The National Strategy for an Ageing Australia is a multifaceted policy document that deals with all aspects of ageing in Australia. This identified the following major issues for Australia: (1) an ageing workforce and the need for action as the supply of younger entrants drops dramatically but the demand for economic growth persists; (2) the need for adequate levels and sustainable sources of retirement incomes to support retirement living; (3) the need for positive attitudes towards ageing; (4) the need for agefriendly infrastructure and community support, including housing, transport and communications; and (5) a growing demand for accessible, high-quality health and aged care services (Office for Older Australians, 2002). In its Executive Summary, the National Strategy for an Ageing Australia also states that “research will underpin the National Strategy for an Ageing Australia and fine tune its implementation. We need to understand and reassess what is happening as the population ages. A good evidence base will support the policy and administrative decisions that will need to be made by a broad range of individuals and organisations”. This policy document clearly places ageing research as a priority and highlights the following specific areas for research: active ageing, enhanced quality of life, improved life expectancy, maintain functioning over the lifespan, chronic disease prevention and management, promoting health habits, falls prevention, medication use, incontinence prevention and management and health promotion (Office for Older Australians, 2002). The major government funding body for biomedical research in Australia is the National Health and Medical Research Council (NHMRC). The NHMRC
Strategic Plan for 2000– 2003 states that the ageing population is one of the major health system issues that should be addressed by biomedical research in Australia (NHMRC, 2000 – 2003). Previously, the NHMRC and Australian Science and Technology Council published a forward looking and strategic plan for health in Australia that identified ageing as the key issue for Australia and recommended specific funding for ageing research in Australia (ASTEC, 1997). Since 1997, the NHMRC has set aside funding to develop strategic capability in areas where the research effort is ‘not commensurate with the magnitude of its importance to health care in Australia’. In the first triennium, the Strategic Research and Development Committee (SRDC) of the NHMRC determined research priorities for this triennium, and these are ageing, indigenous health, mental health, oral health and systems of care for chronic diseases. The NHMRC has responded with several initiatives in response to this strategic direction. First, it established a Working Committee on Research on Ageing. Second, this committee commissioned a report on biological ageing research in Australia. The NHMRC have also dedicated $2 million for ageing research projects and created three new postgraduate scholarships specifically for ageing research. In 1999, the International Year of Older Persons, the National Ageing Research Institute (NARI) convened the first national conference on The Science of Ageing “Ageing in the Third Millennium” to raise the profile of ageing research in Australia. The conference highlighted the continuous need for a platform for researchers in biological ageing to facilitate the dissemination of exciting developments in the field. One of the major achievements of this inaugural meeting is the formation of the Australian Society for Cellular and Molecular Gerontology in March 2001 creating an important new forum for ageing biology research. Two other organisations, the Australian Association for Gerontology and the Australian Society for Geriatric Medicine both support ageing research although their focus has primarily been on social gerontology, health services and geriatric medicine. Research institutions specifically investigating ageing biology include NARI—www.mednwh.unimelb.edu.au, Centre for Education and Research on
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Ageing (CERA, University of Sydney)—www.cera. usyd.edu.au and the ANZAC Research Institute (University of Sydney)—www.anzac.usyd.edu.au/ researchinstitute/. NARI and CERA are multidisciplinary organisations with a range of research domains from biogerontology to health services. Biological research at NARI led by McLean and Khalil focuses on the understanding increased vulnerability to disease with advancing age, specifically delayed wound repair, neurodegenerative diseases, chronic pain and susceptibility to falls. The ANZAC Institute was opened this year and includes laboratories investigating oxidative stress and liver ageing, endocrine and bone changes with ageing, and neurodegenerative disorders. Biological research at CERA focuses on oxidative stress in hepatic and endothelial tissues and neuropathological changes in the ageing brain.
3. Experimental gerontology research The Office for Older Australians of the Federal Department of Health and Aged Care sponsors the Australian Ageing Research Directory, now in its sixth edition (Office for Older Australians, 2000). The Australian Ageing Research Directory lists many organisations involved with ageing research in Australia. The directory includes 731 projects from 202 research organisations. Seven multidisciplinary agencies account for more than one quarter of all entries (Centre for Ageing Studies, Centre for Applied Gerontology, Centre for Education and Research on Ageing, Community Disability and Ageing Program, Healthy Ageing Unit, Lincoln Gerontological Centre and National Ageing Research Institute). There has been a recent expansion in the number of entries, primarily due to the substantial increase in research in health and behavioural sciences and social sciences. Dementia is the single field of research that generates most research activity. Biogerontology represents only 4.2% of the entries. Overall, biogerontological research in Australia can be divided into several broad domains: (1) oxidative stress and the Free Radical Theories of Ageing; (2) mitochondrial impairment and agerelated changes in mitochondrial DNA; (3) telomeres
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and cellular senescence; (4) changes in gene expression and longevity genes; (4) apoptosis; and (5) mechanisms for the effects of caloric restriction. (Le Couteur et al., 2002b) In terms of health care and policy, there are three important issues: (1) ageing is a risk factor for disease; (2) ageing is a cause of disability in the absence of disease; and (3) ageing is associated with impaired response to therapeutic interventions. Some Australian contributions in each of these areas are described below. A collaborative research project between the NARI and CERA is investigating the role of oxidative stress in hepatic ageing, neural tissues and wound healing in older people. With respect to the liver, the research program has studied the role of oxidative stress in the pathogenesis of microvascular changes within the aged liver termed pseudocapillarisation (Le Couteur and McLean, 1998; Cogger et al., 2001). Pseudocapillarisation of the ageing sinusoidal endothelium involves loss of fenestrations within the endothelium, which becomes thickened and associated with early basal lamina formation and perisinusoidal fibrosis (Le Couteur et al., 2002a,b). Pseudocapillarisation of the hepatic endothelium has physiological significance because it generates a barrier to the diffusion of oxygen (Le Couteur and McLean, 1998) with alteration of hepatic high-energy metabolites. In addition, pseudocapillarisation impairs the passage of neurotoxins and lipids (Le Couteur et al., 2002a,b; Yang et al., 2002) thus providing a mechanistic link between oxidative stress and susceptibility to neurotoxic diseases and atherosclerosis. With respect to the effects of oxidative stress on neural function, the research has shown that oxidative stress plays a major role in delayed recovery of injured neurones and prolonged hyperalgesia in older people. Antioxidants that act on peroxynitrite radicals were found to reduce oxidative stress and improve neural function in old age (Khalil and Khodr, 2001). In addition, wound healing was found to be delayed in old age and this could be modified by antioxidants such as tirilazad (Khodr and Khalil, 2001). The decline in wound repair efficacy in old age was associated with age-related changes in the modulation of skin vascular reactivity by sensory nerves, and importantly, was improved by transcutaneous electrical stimulation that selectively activate these nerves
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to increase endogenous release of growth factors at the injury site to accelerate tissue repair (Khalil and Merhi, 2000). Khalil’s group also provided the first evidence in Australia to implicate vascular mechanisms, involving oxidative stress, in the toxic effects of beta-amyloid protein involved in Alzheimer’s disease. Oxidative stress has also been investigated in Alzheimer’s disease by the Mental Health Research Institute of Victoria (Lynch et al., 2000) and in cardiac disease by the Heart Research Institute in Sydney (Dean et al., 1992). The Centre for Molecular Biology and Medicine led by Linnane has an established record in mitochondrial research and ageing. They originally postulated the role of oxidative stress on generating age-related changes in mitochondrial DNA (Linnane et al., 1989) and subsequently found an age-related 5 kb deletion in the mitochondrial genomes of these subjects. The deletion occurs between nucleotide positions 8470 and 13,459 of the mitochondrial genome, and is flanked by a 13 bp direct repeat (Linnane et al., 1990). Mitochondrial DNA mutations were found to be most prevalent in muscle and least common in liver (Kovalenko et al., 1998). More recently, by analysing individual muscle cells, the group have been able to demonstrate a direct association between the amount of amplifiable mitochondrial DNA and the activity of cytochrome c oxidase (Kopsidas et al., 2002). Strategies to reduce mitochondrial dysfunction through the use of targeted antioxidants such as Coenzyme Q10 and tocopherol have been investigated particularly in relationship to cardiac muscle in older people (Rosenfeldt et al., 1999; Rosenfeldt et al., 2002). Another research team at Monash University Department of Biochemistry and Molecular Biology, led by Nagley, has been studying mitochondrial DNA mutations for several years. This group has made major contributions to the understanding of mitochondrial DNA in ageing (Nagley and Wei, 1998). For example, this group was the first to show the prevalence of multiple mitochondrial DNA deletions in human ageing (Zhang et al., 1992). The age-associated accumulation of point mutations in human skeletal muscle was analysed (Zhang et al. 1998) and the differential accumulation of deletions and point mutations in various human tissues was described
(Liu et al., 1998). Khalil and Nagley have extended this mitochondrial research into age-related changes in neural function. For example, they have found a 300-fold increase in a mitochondrial DNA deletion (mt3834) in the dorsal root ganglia of old rats, moreover the increased levels of mitochondrial DNA mutations correlated strongly with reduced physiological indices of tissue function (Nagley et al., 2001). The original discovery of the apoptotic process was made by an Australian, Kerr in the early 1970s (Kerr et al., 1972). Other Australian scientists have also contributed significantly to this area, notably, Suzanne Cory whose work with colleagues on Bcl-2 has been ground breaking and who is now the Director of the Walter and Eliza Hall Institute. (Adams and Cory, 1998) Since that time, there has been substantial research into the cellular biology of apoptosis and its role in various diseases such as cancer and diabetes. Surprisingly, given this background, there has only been limited research into ageing and apoptosis in Australia. Darby (Royal Melbourne Institute of Technology University) has been analysing apoptosis in wound sections from unhealed wounds in older humans and more recently in collaboration with Khalil correlating the extent of apoptosis with neuronal NO synthase in wound sections (Darby et al., 2002). There has only been limited research into telomeres and genetics of ageing in Australia. There is currently no specific and continuing caloric restricted animal colony in Australia, and this has essentially prohibited Australian research in this important domain. In the past, Everitt established an ageing Wistar male rat colony including caloric restricted and hypophysectomized rats. His research examined extensively the relationship between ageing and endocrine function (Everitt and Meites, 1989) and ageing and collagen strength and cross-linkage (Everitt, 1971). NARI has established an ageing rat colony for the past 15 years that have been successfully used for ageing studies with striking correlation with data from human studies. This colony has been recently utilised to study the effect of oxidative stress prevention on decelerating both primary and secondary ageing processes but calorie restriction studies have not been undertaken.
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4. Other ageing research There is always considerable overlap between research into diseases of ageing, health care services and research in experimental gerontology. In Australia, there are many research groups with established records in age-related diseases such as osteoporosis, dementia, cancer and cardiovascular disease. Several examples are given of Australian research into diseases of ageing and health care where it is clear that a major focus of the research has been ageing and the research is occurring primarily in a geriatric or gerontological research organisation. Australia has a strong record in dementia research. Research on the structure of beta-amyloid was contributed to substantially by Australian workers led by Masters (Masters et al., 1985). The molecular and pathological determinants of Alzheimer’s disease and related dementias are now a focus for several major ageing research groups in Melbourne (Masters, Khalil), Sydney (Broe, Halliday, Kril) and Perth (Flicker, Almeida) amongst others. The Biology Research Team at the NARI was one of the first groups in the world to raise the possibility that betaamyloid is directly neurotoxic via vascular related mechanisms. Their concept that vascular effects of beta-amyloid could be detected in the peripheral microcirculation is new. Khalil’s group uses a unique system to investigate the vascular activity of betaamyloid, a system that utilises skin microvasculature in vivo. This raised the possibility that circulating beta-amyloid could alter their peripheral endothelial cell function and resulted in a novel non-invasive skin test for early diagnosis of Alzheimer’s disease (Khalil et al., 1996; Poliviou and Khalil, 1998). Ageing remains the most important risk factor for atherosclerosis. A new hypothesis has been put forward by the CERA and NARI (in collaboration with Professor Fraser at the University of Otago, New Zealand) that age-related changes in the liver predispose to atherosclerosis. These ageing changes have been called pseudocapillarisation (Le Couteur et al., 2001) and prevent the passage of chylomicron remnants from the blood to the liver cells (Le Couteur et al., 2002a,b). Furthermore, the structural changes can, in part, be reproduced by oxidative stress (Cogger et al., 2001). Age-related pseudocapillarisation of the liver and other ageing liver changes has been proposed to provide a
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mechanistic link between primary ageing processes (oxidative stress), age-related changes in physiological function (the capacity of the liver to clear endogenous and exogenous substrates including chylomicron remnants) and age-related disease (atherosclerosis, neurotoxic diseases such as Parkinson’s disease, adverse drug reactions). The Blue Mountain Eye Study led by Mitchell and Cumming has prospectively studied over 3000 older people for five years and found that cataracts and visual impairment were predictors of mortality (Wang et al., 2001). The Blue Mountain Eye Study has provided insight into the relationship between ageing, age-related diseases of the eye such as macular degeneration and cataracts, and broader aspects of ageing such as falls, self-rated health (Wang et al., 2000) and driving (Gilhorta et al., 2001). The study also identified behavioural issues such as smoking and diet that impact on eye disease in older people (Cumming et al., 2000). McCarty and colleagues (Centre for Eye Research Australia) are studying the effects of ageing on the eye. It is of interest that they have also reported that mild visual impairment in older people predicts mortality and could be considered a biomarker of ageing (Taylor et al., 2000). With respect to the effects of ageing on endocrine function, Handelsman’s group (ANZAC Research Institute) are investigating the effects of age-related changes in androgens on muscle function, activity and quality of life in older men as well as cardiovascular and prostate disease (Ly et al., 2001). Cuneo and colleagues (University of Queensland) have investigated the role of growth hormone deficiency in ageing including muscle strength and quality of life (Cuneo et al., 1998). Falls have also become a focus for clinical ageing research in Australia. Led by Lord, Cameron and Cumming, a large research consortium has been researching the risk factors for falls in older people and the benefits of interventions such as physical therapy, hip protectors, footwear, home modifications and correction of visual disturbances (Cumming, 1998; Menz and Lord, 1999; Cameron et al., 2001). One special population in Australia with respect to ageing are our Indigenous Peoples. Aboriginal and Torres Strait Islanders form about 2% of the total Australian population. Over the period 1997 –1999, the life expectancy at birth for Indigenous males was 56 years and females, 63 years. By comparison, life
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expectancy in the total Australian population for males was 76 years and females, 82 years (Edwards and Madden, 2001). This extraordinary disparity in life expectancy reflects a higher incidence and earlier onset of circulatory disease, cancer, renal failure and diabetes mellitus (Gracey and Veroni, 1995). Aboriginal and Torres Strait Islanders are poorly represented in ageing research because this group has shorter lifespan and there are few older people, in chronological terms, for investigation. This population may be important for future research because their poor health outcome may be the result of premature ageing secondary to genetic, environmental factors and societal factors. The Menzies Institute directed by O’Dea is leading research into the understanding of the health of Indigenous People. Much remains to be done in this important area of ageing research in the future. There are a number of centres in Australia undertaking research on ageing where the primary emphasis is on other than basic biological research but that increasingly incorporate biomarker data in a multidimensional approach. This research includes a number of successful longitudinal studies of ageing such as the Australian Longitudinal Study of Ageing in Adelaide, Dubbo Epidemiological Studies, Sydney Older Persons Study, Health Behaviours and Outcomes Study in Melbourne, Australian Women’s Health Study, Health Status of Older People Project, Perth Elderly Cohort, Blue Mountains Eye Study, and The Melbourne Collaborative Cohort Study (ECHNIDAS). Apart from those centres and institutes identified above Australian states presently have a number of Centres concerned generally with ageing research on a broader perspective. These are discussed briefly below. In Victoria, the Lincoln Gerontology Centre for Education and Research (La Trobe University)—www. latrobe.edu.au/aipc/lgc has specific projects on health behaviour and healthy retirement. The Alma Unit on Women and Ageing (Victorian University of Technology)—www.vu.edu.au/menu.cfm?menu_id ¼ 255 was inspired by a private individual who was concerned by the lack of information on older women and ageing. It specializes in qualitative research and women’s experiences of ageing. In South Australia, the Centre on Ageing Studies (Flinders University)—www.cas.flinders.edu.au directed by Gary Andrews is a multidisciplinary
centre for population-based research on ageing. It is a WHO Collaborating Centre for Research on Epidemiology of Ageing and is the base for the Australian Longitudinal Study of Ageing. This is a multidimensional panel study with 2000 Adelaide residents aged 70 years and over at baseline, which has continued thus far for 9 years. (Andrews et al., 1989; Andrews et al., 2002) In addition the Centre has been responsible for a series of cross-national studies in Asia and the Middle East under the auspices of WHO, UNFPA and the UN. The Centre also hosts and maintains the South Australian Network for Research on Ageing (SANRA)—www.cas.flinders.edu.au/ sanra a statewide network of researchers and research interests that maintains a directory on current research, publishes a regular newsletter and commissions occasional papers runs workshops on all aspects of ageing research as well as providing consultative services and facilitating collaborative projects. In Western Australia, the Positive Ageing Foundation of Australia (previously the Positive Ageing Centre)—www.positiveageing.com.au was established with the mission of improving the lives of older people, and is engaged in programs involving working with older persons in development of elder friendly products, research and advocacy. The Centre actively networks among researchers, practitioners, older persons and their respective organisations. The recently established Freemasons Centre for Research into Aged Care Services (Curtin University)—www. curtin.edu.au/health/research/cracs/ is embarking upon a multi-disciplinary research agenda with a primary focus on aged care and well-being. In New South Wales, the Health and Ageing Research Programme, led by Kendig, (University of Sydney) is supported by University infrastructure funds and supports a wide network of clinical, biomedical, and social researchers. The benefits of exercise on healthy ageing have been a particular focus for this research (Fiatarone-Singh). The Research Centre on Ageing and Retirement (University of NSW)—www.arts.unsw. edu.au/ageing/ also facilitates a multidisciplinary perspective to major academic research studies. The Garvan Institute based at St. Vincent’s Hospital in Sydney—www.garvan.org.au/garvan.asp, though not primarily focused on ageing research has a major epidemiological, genetic, clinical and hormonal series of studies on osteoporosis.
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In Queensland, the Healthy Ageing Unit (University of Queensland) has investigated carers, older workers, falls prevention, older drivers and end of life decision-making. The unit is now part of a newly established Australasian Centre on Ageing—www.uq. edu.au/cfha/ that is following a broad research agenda including biological ageing research focusing on oxidative stress and cardiovascular disease.
5. The future Despite being a small nation, Australia has a very strong record in biomedical research particularly in the fields of disease-based research and health care. As such, there has been substantial research into diseases of ageing (e.g. dementia, osteoporosis, falls) and health services for older people. More recently there has been growing recognition of the importance of basic research into the biology of ageing, evidenced by the formation of the Australian Society for Cellular and Molecular Gerontology and the recent interest in the NHMRC, Australia’s major government funding body for biomedical research, in ageing biology. Opportunities are now emerging for multidimensional and multidisciplinary research that integrates basic biological, biomedical, health, psychological, social and behavioural perspectives. There is a crucial need to further encourage a multidisciplinary approach to research into ageing. Indeed, such a multifactorial phenomenon requires a holistic and integrated approach to adequately deal with the complex of age related issues.
Acknowledgements We would like to thank the Consortium Members of the Scoping Study on Ageing Research funded by the National Health and Medical Research Council of Australia for valuable input into the information provided in this paper.
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