Microglia are the resident macrophages of the central nervous system (CNS) and, as key immune effector cells, form the first line of defence. Microglial cells also provide support for maintaining neuronal homeostasis and more generally normal brain physiology and cognitive function. It has been speculated that in order to support homeostasis, microglia adapt to a variety of brain microenvironments leading to regional phenotypic heterogeneity. To date this hypothesis lacks convincing empirical evidence, yet is critical to better understand microglial function in health and age-related neurodegenerative disease. In 2010 it was estimated that in the UK approximately 10 million people are over the age of 65, which is expected to double by 2050. Ageing is one of the strongest risk factors for neurodegenerative diseases such as Alzheimer’s and Parkinson‘s disease and growing evidence implicates neuroinflammatory mechansims that may involve microglial dysfunction in disease aetiology. The majority of age-related neurodegenerative diseases develop in a region-specific manner but the reasons are poorly understood. Accordingly, the work described in this thesis sought to determine the extent and nature of regional transcriptional heterogeneity of microglia and how this is affected by ageing. To examine the function and phenotype of these cells a technique for isolating pure microglia from the adult mouse brain was established. Microglia were consistently extracted by density-gradient and immunomagnetic cell separation. In vitro assays showed purified microglia retained key functional properties including phagocytosis, polarisation and production of pro-inflammatory cytokines in response to exogenous stimulation. Thus, freshly isolated microglia are not altered or dysfunctional during the extraction process and are likely to adequately represent the 'real' in vivo state. Genome-wide transcriptional network analysis of young adult mouse microglia from four discrete regions of the brain (cerebellum, cerebral cortex, hippocampus and striatum) uncovered regional heterogeneity in the microglial transcriptome driven particularly by bioenergetic and immunoregulatory functions. Transcriptional profiles of cerebellar and hippocampal microglia suggest a higher immune vigilance and alertness, which was supported by functional differences in the capability of microglia to phagocytose and control replication of bacteria. Region-dependent heterogeneity of microglia was largely consistent throughout the ageing process; however the region-specific phenotypes were more pronounced as age increased indicating region-dependent kinetics of microglial ageing. Collectively, the outcome of this study implies that microglia adapt to region-specific demands of brain tissue under steady-state conditions and are susceptible to ageing. Region was found to have a greater impact on microglial diversity than age. Overall, these findings will generate a substantial advance in our understanding of microglial function in the healthy brain and in age-related neurodegeneration.

This thesis presents novel investigations of three common ageing phenotypes in human population studies, using microarray technology to assess ‘transcriptome-wide’ expression in whole blood to identify mechanisms and biomarkers. Muscle strength is related to frailty and is predictive of disability in older persons. I assessed the association between transcript abundance in the InCHIANTI peripheral blood samples (N=695) and muscle strength. One gene (CEBPB) passed the multiple testing criteria, and is involved in macrophage-mediated repair of damaged muscle. I extended this work with a meta-analysis of over 7,781 individuals in four collaborating cohorts; expression of over 222 genes were significantly associated with strength, less than half of which have previously been linked to muscle in the literature. CEBPB did not replicate in these younger cohorts. I then performed the first human analysis of gene expression and cognitive function (and separately with decline in cognitive ability over nine years) in the InCHIANTI cohort (N=681), and one gene was identified; CCR2, a chemokine receptor. Evidence in mice has implicated this gene in the accumulation of β-amyloid and cognitive impairment. Finally, in a collaborative project with the Framingham Heart Study I studied age-related inflammation – another hallmark of ageing - using a novel approach to ‘transcriptome-wide’ analysis; each transcript was assessed for the proportion of the association between age and interleukin-6 (IL6) that it statistically mediated. Very few of the genes associated with IL6 alone also mediated the relationship with age. Findings include; SLC4A10, the strongest mediator, not previously linked to inflammation, and interleukin-1 beta and perforin, a cytokine and cytotoxic protein, respectively. These novel analyses highlight key molecular pathways associated with age-related phenotypes in whole blood and provide links between mouse models and humans. They provide biological insight and directions for future research.

This thesis investigates issues central to population ageing in Australia. A principal policy concern is financing the retirement incomes of an increasing number of aged retirees from a shrinking working age population. The investigation has two primary aims. The first is to measure the budgetary savings that alternative social security reforms may yield, and the implications of these reforms for the economic wellbeing of the elderly. The second is to examine how the aged can become more self sufficient through an exploration of the potential role of home equity conversion, an understanding of why the labour force participation of mature age Australians is low, and how labour force participation may be promoted as retirement approaches. A microsimulation model is employed to conduct empirical analyses in the context of the new tax system introduced in July 2000. The main microsimulation exercises include measurement of the impacts of potential social security reforms and home equity conversion on the economic well-being of the elderly, and estimation of work disincentive measures, that is, effective marginal tax rates and replacement rates. The Replacement rate estimates are then used in econometric models of labour force participation. Innovative approaches are developed to overcome methodological problems that have prevented the inclusion of replacement rates in previous models. The major findings are that reforms motivated by budgetary savings can have sizeable adverse impacts on the economic well-being of the elderly. Home equity conversion can promote financial independence, but significant risks are borne by elderly homeowners in those states and regions with less buoyant house prices. Blunt work incentives are experienced by specific mature age socio-economic groups, in particular persons whose partners’ incomes help to cushion their economic position on quitting employment. The replacement rate is found to have a significant impact on the participation decision of mature age persons.

Hur kan vi utveckla informationsteknik som passar äldre? Är sådan teknikspeciell, och i så fall hur och varför? Vad innebär det att vara äldre och delta iett sådant forskningsprojekt? Och när projektet är användardrivet och deäldre betraktas som de allra viktigaste deltagarna, vad innebär egentligendet?Det här är några exempel på de frågor som har lyfts i forskningsprojektetAGNES. Boken visar dels på erfarenheter av att skapa och driva ett projektmed syfte att bedriva användardriven teknikutveckling tillsammans medseniorer och representanter från näringsliv, kommun och universitetet. Delsvisar den på de äldres perspektiv på att ha deltagit i utveckling av nyinformationsteknik. / AGNES

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