Rozprawy doktorskie na temat „Ageing”

B-vitamin deficiency may contribute to age-related diseases. Low/deficient vitamin B 12 status is of particular concern in older people despite the fact that intakes of B 12 typically far exceed current recommendations. Pernicious anaemia accounts for a very small proportion of low/deficient status, however, a much more prevalent problem is food-bound vitamin B 12 malabsorption. Proton pump inhibitor [PPI] drugs are acid suppressant drugs which reduce gastric acid secretion [hypochlorhydria] and could thus potentially reduce the absorption of food-bound vitamin B 12. Using an experimental model of hypochlorhydria, the current results showed no evidence of vitamin B 12 depletion as a result of short-term PPI administration. Long-term PPI usage was however shown to be associated with an increased risk of vitamin B 12 deficiency but this appeared to be alleviated by the regular consumption of foods fortified with the vitamin, with a 19% prevalence of vitamin B 12 deficiency found in long-term PPI users who were non-consumers compared to a 2% prevalence in consumers. Overall the results highlight the importance of fortified food consumption in maintaining vitamin B 12 status, particularly in those at risk of food bound malabsorption owing to PPI usage. This thesis also demonstrated that low dose vitamin B 12 (1μg/d) supplementation can significantly increase vitamin B 12 status both in healthy people and in long-term PPl users. Of note, the investigation of vitamin B 12 biomarker responses to vitamin B 12 depletion and repletion study presented in this thesis indicated that holotranscobalamin (holoTC) was a more sensitive biomarker of vitamin B 12 status and responded quicker to changes in vitamin B 12 status than the more conventional biomarker, serum total B 12. One of the most important findings of this thesis was that low vitamin B6 status was associated with a 6-fold increased risk of cognitive decline in a cohort of healthy older adults investigated over a 4 year period. This largely overlooked B- vitamin may have an important role to play in maintenance of cognitive function in healthy ageing.

Older adults are worse than young adults at perceiving emotions in others. However, it is unclear why these age-related differences in emotion perception exist. The studies presented in this thesis investigated the cognitive, emotional and motivational factors influencing age differences in emotion perception. Study 1 revealed no age differences in mood congruence effects: sad faces were rated as more sad when participants experienced negative mood. In contrast, Study 2 demonstrated that sad mood impaired recognition accuracy for sad faces. Together, findings suggested that different methods of assessing emotion perception engage the use of discrete processing strategies. These mood influences on emotion perception are similar in young and older adults. Studies 3 and 4 investigated age differences in emotion perception tasks which are more realistic and contextualised than still photographs of facial expressions. Older adults were worse than young at recognising emotions from silent dynamic displays; however, older adults outperformed young in a film task that displayed emotional information in multiple modalities (Study 3). Study 4 suggested that the provision of vocal information was particularly beneficial to older adults. Furthermore, vocabulary mediated the relationship between age and performance on the contextual film task. However, age-related deficits in decoding basic emotions were established in a separate multi-modal video-based task. In addition, age differences in the perception of neutral expressions were also examined. Neutral expressions were interpreted as displaying positive emotions by older adults. Using a dual-task paradigm, Study 5 suggested that working memory processes are involved in decoding emotions. However, age-related declines in working memory were not driving age effects in emotion perception. Neuropsychological, motivational and cognitive explanations for these results are evaluated. Implications of these findings for older adults' social functioning are discussed.

Age is associated with the development of multi-system function loss including the musculoskeletal, immune and cardiovascular system, as well as body composition changes. These age-related alterations lead to frailty development and disease progression, reducing quality of life. A major lifestyle change occurring in later years is reduced physical activity levels. This thesis sought to examine the associations between physical activity and multi-system function loss in a cohort of elderly individuals, and to better understand the neural mechanisms underpinning the circulatory responses to exercise. It was observed that high daily physical activity levels attenuate some but not all of the age-related changes in elderly individuals. High physical activity was associated with superior physical functioning, lower total body fat and visceral adiposity, and plasma plasminogen activator inhibitor 1 (PAI-1) concentrations. Left ventricular (LV) diastolic function was negatively associated with mean arterial pressure (MAP) and visceral adiposity, suggesting that elderly individuals with higher MAP and visceral adiposity may have inferior LV diastolic function. In terms of neural mechanisms related to circulatory responses to exercise, in models of metaboreflex over-activity whereby BP is elevated as observed in heart failure patients, left atrial systolic function is enhanced in order to maintain end-diastolic volume and SV.

Partially crystalline polycaprolactone stored at different temperatures well above the glass transition temperature is found to age with the development of further crystallinity and an increase in melting point, yield stress and elastic modulus with time. The changes in mechanical properties are accounted for by the increased crystallinity, and the increase in melting point to an increase in lamellae thickness. Over the temperature range studied, the rate of ageing increase with temperature and the dependence of stem length on the square root of storage time observed are both consistent with diffusion control and inconsistent with nucleation control. It is concluded that partially crystalline polycaprolactone ages by a continuation of the crystallisation at a rate determined by the storage temperature and by the mechanism occurring prior to ageing.

Les homéoprotéines sont des facteurs de transcription morphogénétiques qui ont des fonctions cellulaire et non cellulaire-autonomes. Par exemple, En1 et En2 (Engrailed/En) sont importants pour le développement des neurones dopaminergiques du mésencéphale (mDA) et cruciaux pour leur maintien chez l'adulte. Les souris En1+/- présentent une dégénération progressive et spécifique des neurones mDA de la Substantia Nigra pars compacta (SNpc), rappelant la maladie de Parkinson. De plus, l'infusion d'En dans plusieurs modèles de la maladie sauve ces neurones. Dans le modèle MPTP, cela passe par l'augmentation de la traduction d'une sous-unité du complexe 1 de la mitochondrie, Ndufs1. Le but de ma thèse était de trouver d'autres mécanismes neuro-protecteurs d'En. En étudiant les souris En1+/-, nous avons montré que la neurodégénérescence est accompagnée de cassures d'ADN et d'une relaxation de la chromatine. Dans un modèle de fort stress oxydatif, on trouve un phénotype similaire mais accéléré, qui est guéri par En. L'amélioration de ces marqueurs majeurs du vieillissement après l'injection d'En renforce l'idée qu'il est un facteur anti-âge prometteur dans le traitement de la maladie de Parkinson. Les LINEs sont des rétrotransposons qui ont la capacité de se propager dans le génome, via un mécanisme de copier/coller. Bien que longtemps considérés comme silencieux, nous avons montré qu'ils sont exprimés dans la SNpc et suractivés par un fort stress oxydatif, entrainant cassures d'ADN et neurodégénération. Leur répression transcriptionnelle ou épigénétique par En pourrait expliquer l'activité protectrice de cette protéine dans des modèles de stress oxydatif progressifs ou forts
Homeoproteins are morphogenetic transcription factors, which have cell and non-cell autonomous functions. For example, En1 and En2, collectively Engrailed (En), are important for midbrain dopaminergic (mDA) neuron development and crucial for their adult maintenance. En1+/- mice display a selective and progressive degeneration of the mDA neurons of the Substantia Nigra pars compacta (SNpc), reminiscent of Parkinson disease (PD). Furthermore, En infusion in the SNpc saves neurons in several models of the disease. In the case of MPTP, En-mediated neuroprotection partially necessitates its ability to upregulate the translation of Ndufs1, a subunit of the mitochondrial Complex I. The main aim of my thesis was to study additional neuroprotective pathways mediated by En. We first studied En1+/- mice and showed that neurodegeneration was accompanied by increased DNA damage and chromatin relaxation. In an acute oxidative stress model, similar but accelerated phenotypes were seen, which were antagonized by En injection. The En-mediated positive impact on these key hallmarks of ageing lends weight to the idea that En is a promising anti-ageing factor, possibly useful in the treatment of PD. Long interspersed nuclear elements (LINE-1) are a class of retrotransposons with the ability to multiply in the genome. Although considered silent, they are expressed in mouse mDA neurons and their expression is increased by an acute oxidative stress, leading to DNA damage and degeneration. Their direct repression by En allows us to propose that their transcriptional and/or epigenetic silencing explains part of En protective activity in mouse models of acute and progressive oxidative stress

Bone age assessment (BAA) is a task performed daily by paediatricians in hospitalsworldwide. The main reasons for BAA to be performed are: fi�rstly, diagnosis of growth disorders through monitoring skeletal development; secondly, prediction of final adult height; and fi�nally, verifi�cation of age claims. Manually predicting bone age from radiographs is a di�fficult and time consuming task. This thesis investigates bone age assessment and why automating the process will help. A review of previous automated bone age assessment systems is undertaken and we investigate why none of these systems have gained widespread acceptance. We propose a new automated method for bone age assessment, ASMA (Automated Skeletal Maturity Assessment). The basic premise of the approach is to automatically extract descriptive shape features that capture the human expertise in forming bone age estimates. The algorithm consists of the following six modularised stages: hand segmentation; hand segmentation classifi�cation; bone segmentation; feature extraction; bone segmentation classifi�cation; bone age prediction. We demonstrate that ASMA performs at least as well as other automated systems and that models constructed on just three bones are as accurate at predicting age as expert human assessors using the standard technique. We also investigate the importance of ethnicity and gender in skeletal development. Our conclusion is that the feature based system of separating the image processing from the age modelling is the best approach, since it off�ers flexibility and transparency, and produces accurate estimates.

With a globally ageing population diseases associated with this natural process are becoming major issues worldwide. Research into the process of ageing and its concomitant issues is rapidly expanding; the need for new tools and models to investigate this rapidly expanding arena of research is paramount. The discovery of a spontaneous mutation in the AS rat strain which introduces a premature stop mutation into the gene encoding protein kinase C γ (PKCγ) lead to the development of a model for one such age related disorder, Parkinson's disease. Consequently, this model has been selected to investigate age related changes in specific areas of the brain (the cerebellum, basal ganglia, cerebral cortex and brainstem). These regions were selected because they have previously been shown to demonstrate changes with age (cerebellum, cerebral cortex and basal Ganglia), they show differences between the AS and AS/AGU strains (basal ganglia) or they show differences in PKCγ knockout models (cerebellum). The Brainstem was selected as it shows little change due to age and shows no differences in PKCγ knockouts or AS/AGU rats. This study used established qPCR methods to measure a validated biomarker of ageing, CDKN2A (the transcript for p16^INK4a) in the brains of these rats to determine whether this model is in fact a genuine model for accelerated ageing. This thesis demonstrates that CDKN2A expression, in combination with senescence-associated β-galactosidase staining, provides clear evidence of accelerated ageing in the brains of AS/AGU rats when compared with the parent AS strain. These investigations were furthered by an investigation of members of the Sirtuin family of proteins. The changes in expression of these Sirtuins indicates that there may be increased levels of cellular stress, disruption of metabolism and DNA damage in the AS/AGU rats, this would be congruent with the accelerated ageing phenotype present in this strain. Furthermore, the levels of these Sirtuins were in line with the predictions from the MTR trinity in regards to the accelerated ageing phenotype. Whilst some of the changes in senescence and metabolic disruption may be attributable to the PKCγ mutation in the AS/AGU rats, it would appear that there is some element of accelerated ageing that is independent of this mutation.

With advancing age, many cognitive faculties deteriorate, and navigation abilities may be among those most affected. The majority of previous work investigating navigation impairments in ageing has focused on allocentric processing, attributing deficits to hippocampal dysfunction. However, real-world navigation is dependent upon numerous different strategies, as well as the ability to flexibly switch between them. Outside the context of navigation, it has been demonstrated that strategy switching, thought to be coordinated by regions of prefrontal cortex and the locus coeruleus-noradrenergic system, is also susceptible to the effects of ageing. Deficits in navigational strategy switching, and prefrontal or noradrenergic dysfunction, are therefore also likely to contribute to age-related navigation impairments. The work presented in this thesis aimed to explore age-related impairments in strategy switching within the context of navigation, and the underlying neural mechanisms in terms of a prefrontal-noradrenergic model of switching. The studies presented in Chapter Three assessed the use of allocentric and egocentric navigational strategies by young and older people. Older participants tended to use an egocentric strategy where an allocentric strategy was required, possibly due to a difficulty in switching to the appropriate allocentric strategy. In Chapter Four, I provide an account of two studies directly assessing navigational strategy switching, using two different tasks based in virtual reality. The first study utilised a virtual adaptation of the plus maze task, involving switching between an allocentric place strategy and an egocentric response strategy, and demonstrated that older participants were specifically impaired at switching to the place strategy. The second study used a more realistic task set in a virtual town environment, which involved switching from an egocentric route-following strategy to an allocentric wayfinding strategy, and also demonstrated an age-related deficit in switching to an allocentric strategy. In Chapter Five, I begin to explore the mechanisms underlying impaired navigational strategy switching in ageing. Firstly, I describe a further behavioural study that used variants of the virtual plus maze and a navigational gambling task to demonstrate a contribution of impaired decision making to the deficit in switching to an allocentric strategy. This indicates that the deficit can be attributed, at least in part, to prefrontal dysfunction. A second study presented in the same chapter demonstrated that practising orienteering does not protect against decline in navigational strategy switching ability with ageing. Chapter Six provides an account of my direct assessment of the neural bases of navigational strategy switching using functional magnetic resonance imaging. In young subjects, I found some evidence in support of the roles of prefrontal regions in navigational strategy switching. However, I was unable to complete development of a task suitable for assessing age differences in functional activation of brain regions involved in navigational strategy switching. The final experimental study, included in Chapter Seven, assessed pupil size and heart rate as physiological correlates of noradrenergic activity during performance of the virtual plus maze. Both young and old participants demonstrated a noradrenergic response to all strategy changes, suggesting that impairments are more likely attributable to dysfunction of prefrontal cortex than of the locus coeruleus, although some subtle effects suggested that noradrenergic dysfunction does have some effect on navigational strategy switching deficits. In the same chapter, I report the results of a meta-analysis of data from five of the preceding studies, suggesting that deficits in both strategy switching and allocentric processing combine to produce a greater impairment in switching to an allocentric strategy. The main finding of this series of studies is that navigational strategy switching is impaired in ageing, which may contribute to the more widely reported difficulties that older people have with navigation. My work also provides evidence in support of a prefrontal-noradrenergic model of navigational strategy switching, and suggests that dysfunction of prefrontal cortex and, to a lesser extent, the locus coeruleus-noradrenergic system is responsible for decline in navigational strategy switching ability with ageing. In conclusion, this thesis draws attention to the important role of deficient executive processing and dysfunction of extra-hippocampal brain regions in age-related navigation impairments.

Atrial Fibrillation (AF) is rare amongst young people whilst epidemic in the elderly. Whilst much is known about the pathophysiology of AF, the mechanisms underlying the vulnerability to AF amongst older people in incompletely understood. Young (< 18 months, first quintile of life) and old (> 8 years, last quintile of life) Welsh mountain sheep were used to investigate changes in atrial electrophysiology with age. Old sheep were more vulnerable to induced AF than young sheep. On the surface ECG, p-wave duration increased with age suggesting increasing atrial size. The corrected sinus node recovery time increased with age, suggesting deteriorating sinus node function. These findings confirmed the validity of sheep as a model for human ageing. In isolated atrial myocytes, action potentials (APs) were recorded using the perforated patch clamp technique. AP duration increased with age, and an increase in AP amplitude was also seen at the lowest stimulation rates. Right atrial AP durations were prolonged compared to those from left atrial myocytes, and the inter-atrial difference was similar between old and young. However, when right atrial monophasic APs were recorded from anaesthetised sheep in vivo, no difference in AP duration was seen between age groups. Alternans occurred at lower stimulation rates in old compared to young myocytes and was of greater magnitude. These age-related differences were present in isolated myocytes and in vivo. Alternans mechanisms were explored by simultaneously recording APs and intracellular calcium concentration. Atrial alternans was driven by alternans of Ca2+ cycling at low stimulation rates. However, despite disabling Ca2+ cycling using thapsigargin, alternans could still be elicited from myocytes during rapid stimulation. Right atrial conduction velocity (CV) was assessed in vivo and found to increase with age. A key determinant of CV, the Na+ current INa was investigated using the whole cell patch clamp technique. INa increased with age in left atrial myocytes and recovered faster from inactivation. Protein expression was investigated using Western blotting. Expression of the Na+ channel α-subunit did not change with age. The gap junction protein Cx43 was expressed less in older subjects, but Cx40 expression was similar. This work has cast light on several aspects of atrial electrophysiology in which the effects of age have not been thoroughly investigated. The longer cellular APs seen with age decrease the wavelength of potential re-entrant circuits which could be seen as protective against AF. However, AP prolongation is also associated with afterdepolarisations which could serve to trigger AF. The increase in alternans behaviour may set the stage for wavebreak, leading to re-entrant circuit formation. The increase in CV was surprising and might be seen as protective against AF as it increases arrhythmia wavelength, and is likely to be caused by the increased INa.

Mestrado em Economia Monetária e Financeira
O envelhecimento da população altera a dinâmica das principais variáveis macroeconómicas com implicações para a condução da política monetária e estabilidade dos preços. O presente trabalho pretende analisar as principais tendências demográficas e de que forma influenciam o ambiente económico onde a política monetária é conduzida, causando direta ou indiretamente movimentos indesejados nas taxas de inflação. Recorrendo a uma técnica polinomial, estimamos a relação empírica entre a estrutura etária e a inflação para um painel de 24 países da OCDE durante o período 1961-2014. Encontramos uma correlação significativa entre demografia e inflação, consistente com a hipótese de que um aumento da população ativa causa pressões deflacionistas, enquanto uma maior parcela de dependentes e reformados está associada a taxas de inflação mais elevadas. Os resultados sugerem que o potencial impacto do processo de envelhecimento a nível global sobre a inflação deve ser tido em conta nas decisões de política monetária.
The ongoing demographic changes can affect the dynamic of economics in several ways, with implications for the conduct of monetary policy and price stability. This paper analyses the future prospects on demographic changes and how they are expected to influence the macroeconomic environment where monetary policy is conducted, which can directly or indirectly generate unwanted inflation dynamics. By adopting a polynomial technique, an estimation is carried out to determine the relationship between the age structure and inflation in a panel of 24 OECD countries over the 1961-2014 period. A significant correlation is found between demography and inflation, consistent with the hypothesis that an increase in the share of working-age population causes deflationary pressures, while a larger scale of dependents and young retirees are associated with higher inflation rates. The results suggest that the potential impact of the global ageing process on inflation should be taken into consideration in the decision making processes of monetary policy.

This thesis is concerned with the age-related changes in working memory (WM), and the inter-individual differences in cognitive and neural mechanisms that correspond to healthy versus poor ageing of WM function. The first half of this thesis focusses on the age-related decline in WM and whether preserved top-down attentional control could mitigate such deficits. In Chapter 2, I present a functional MRI study showing that older adults reliably recruit brain networks that subserve cognitive control, which work in concert with the task relevant sensory areas during effective selective WM. In Chapter 3, I show that older adults retain flexible control over WM representations, and this ability corresponded to the reliable recruitment of neural signals of orienting attention qualitatively similar to those observed in younger adults. Magnetoencephalographic recordings showed that the neural dynamics during orienting attention within WM was predictive of good performance, demonstrating that the more efficient the process of orienting within WM to select the target item, the better the memory representation can be preserved for upcoming behaviour. In the second half of this thesis, I explored whether WM for affective content has a special status in healthy ageing. In Chapter 4, I developed an emotional WM precision task to measure WM abilities for emotional content appropriate for elderly adults. In Chapter 5, I tested a group of young and older adults on WM and perceptual-matching abilities for emotional faces. The results suggest that older adults show a general impairment in task performance, but possibly with some preservation in the ability to maintain emotional content in WM. There were marked differences in how the emotional information was processed between age groups, in which older adults have a tendency to represent negative stimuli as less negative than younger adults in perception and WM, and tended to show a positive interpretation of the valence of more ambiguous emotional stimuli. In Chapter 6, I summarise the findings presented in this thesis, discuss the implications of the key findings, and consider some suggestions for future studies that aim to elucidate the mechanisms of WM in healthy ageing.

This thesis presents investigations of field-aged composite silicone rubber insulators, which have been deployed for 15 years on a 400 k V transmission line in a coastal region of the UK. Extensive measurements of their hydrophobicity, as detennined by contact angle, are given along with a description of their appearance. The hydrophobicity change varies from the low voltage end to the high voltage end with the lowest contact angles being found in the middle of the string. The sheds also aged differently around their circumference and this was reflected in discoloration differences on different sides of the insulator, in addition to hydrophobicity changes. Leakage current and surface discharge measurements carried out in the laboratory are also presented. Material analysis shows cracking and oxidation of the surface. Ageing effects were far from uniform over each shed, the greatest oxidation being on the top surfaces of the sheds on the south side: Microscopy, EDX and FTIR were found to be the most useful and effective tools for analysis of these polymeric insulators. The measurements of the various parameters over the whole surface of the insulators are found to be consistent with each other and can be interpreted in tenns of the chemistry of ageing and the longer term performance of the specific insulators in question. Two distinct types of ageing are identified. The role of solar radiation appears critical. It is suggested that wind direction, which is very consistent in the region concerned, may also be an important consideration. It is concluded that a possibility exists of an accelerated reduction in performance because of the non-uniformities observed. The asymmetry adds to the complexity of any model generated, and must be considered if the longer term operation of the insulator is to be forecast.

This study may be divided into two sections which cover different aspects of the reproducibility problems encountered in HPLC. In the first, the study has involved the separation of basic drugs, on different manufacturer's reversed-phase columns in conjunction with an acid buffered acetonitrile/water gradient. The retention reproducibility of each drug was assessed and compared on the basis of the retention index scale of 1-nitroalkanes. The effect of changing gradient run time on the reproducibility of the retention values of the 1-nitroalkanes was demonstrated on reversed-phases of different makers. The optimisation of initial isocratic composition of organic (acetonitrile) was carried out and its effect on the reproducibility of retention of basic drugs was evaluated. The effect of a premixed eluent on the retention reproducibility of selected basic drugs with time intervals between injections was demonstrated. The same method was further extended with or without using helium gas with small flow. The prediction of dwell volume and its effect on retention reproducibility was evaluated. Determination of retention times changes for selected aqueous basic solutes against eluent with different pH values on Capcell ODS column was studied. Applicability of each reversed-phases (Cl8) for the separation of basic analytes was demonstrated. In the second section, a number of different unbonded (bare) silicas were studied in terms of surface analysis using of solid state cross-polarisation (CP) magic angle spinning (MAS) NMR and Fourier Transform (FT) Diffuse Reflectance Infrared Spectra (DRIFT-IR) data. It is believed that silica material used for HPLC separation with eluent undergoes an ageing process with acidic (at pH:2–3) and basic eluents (higher than pH:8). To examine this process more clearly, some basic analytes were selected to evaluate each of the accelerated ageing process followed by showing the final surface properties by the method most commonly used such as solid-state NMR and FT-IR along with BET surface analyser.

Electrical insulation is known to age when under electrical stress. One cause of this is thought to relate to the movement and build up of charge within the insulation. The emission of a low level of light from polymeric materials when under electrical stressing is shown to occur before the onset of currently detectable material degradation. This light is termed electroluminescence (EL)and under an ac electric field is thought to relate to the interaction of charge in close proximity to the electrode-polymer interface. Understanding the cause of this light emission gives a very high resolution way of monitoring charge interaction and its influence on material ageing. This report presents the improvement to a system to measure changes in EL emission during the cycle of the applied field (point on wave measurements) under various electric fields. To investigate the relationship between EL and ageing, 100 �m, low-density polyethylene (LDPE) films were ultraviolet (UV) aged in 3 and 7 day intervals up to 17 days. The samples were aged in both air and nitrogen environments to separate the affect of photo-oxidation from photo irradiation reactions on charge movement. Changes as a result of ageing were characterised in terms of optical, chemical and electrical properties. These were investigated using ultraviolet and visible (UV-Vis) and Fourier transform infrared (FTIR) spectroscopy, ac ramp breakdown measurements and dielectric spectroscopy. The accumulation of space charge (SC) was then investigated using the pulsed electro acoustic (PEA) technique. This collection of results were used to explain changes in EL in terms of intensity and phase difference. A model using the bipolar charge recombination theory was then developed using trends shown in the characterising measurements to explain changes in EL. Results support the use of EL as a tool to investigate changes in charge movement very near the electrode-polymer interface.

Impulse over-voltage is a common phenomenon in electric power systems. A switching impulse is created by a switching surge or local fault while a lightning impulse is due to direct lightning strike to high voltage plant such as an overhead line. Both impulse events create travelling waves in the system, damaging insulation components and equipment. This work is concerned with the hypothesis that lightning impulses can lead to accelerated ageing of extruded polymeric cables. The results show that there may well be a reduction in electric field strength of the insulation of a power cable that experiences a lot of impressed lightning impulse over-voltages. Pre-designed shaped polyethylene material sample discs have been manufactured using a mould tool. The samples then have been electrically aged using an impulse generator. A real-time software based monitoring tool has been designed to control the impulse wave-shape and process the measurement data. Sets of identical lightning impulses were applied to samples and this was then followed by ramped AC breakdown tests. The obtained results were analyzed using the Weibull distribution to identify any differences in lifetime between aged and un-aged samples. This thesis also provides insight into the dominant ageing processes through the analysis of dielectric spectroscopy and space charge measurement data. In order to quantify the effects of dielectric ageing due to impressed lighting impulse over voltages, experiments have also been undertaken using samples that have been aged under UV light and thermally. Analysis of obtained results reveals that mechanisms of these two ageing processes are significantly different from the mechanisms due to lightning impulse ageing

The majority of local areas in the UK are faced with an ageing population. Popular retirement destinations in coastal and more rural areas are particularly affected. The thesis aims to find out how local areas strategically tackle these demographic shifts. The British government has issued strategic guidance for local areas, but as yet little is known about how actual responses look. The literature has largely focused on good practice compilations. Consequently, the thesis attempts to analyse in depth local areas’ experiences in planning for an ageing population. The main research question is: How do local actors in the UK plan for population ageing? A grounded theory approach has been chosen to develop theoretical concepts from empirical data. Local governance and collective learning are used as sensitising concepts, i.e. wider theoretical perspectives. Due to the state of research and the aim to gather detailed knowledge regarding the planning for an ageing population in local areas, a qualitative research design has been chosen. More precisely, it is a multiple case study design, covering the three heterogeneous cases North Tyneside, Poole and Wealden. Empirical data has been assembled from qualitative interviews with local experts and documents such as local strategies or minutes of meetings. The results are threefold. Firstly, local governance arrangements are analysed. This covers the identification of involved actors, their action orientations and interactions. As approaches in planning for an ageing population differ across organisations, a typology of individual actors is developed. Moreover, it is observed that and analysed how traditional hierarchical steering by public bodies is complemented by more network-like forms of governance, for example multi-organisational older people’s partnerships. Secondly, local learning processes in planning for an ageing population are reconstructed. Four phases are differentiated: setting the agenda for the topic of ageing and older people followed by building up knowledge on the subject and collective learning in a narrower sense and, finally, strategy-making. Interrelations between governance arrangements and collective learning are analysed, particularly with respect to different forms of learning in different types of older people’s partnerships. Finally, central challenges and perspectives arising from the analysis of governance arrangements and learning processes are discussed. On the one hand, these pertain to the cross-cutting nature of ageing, on the other hand they are due to the ambivalent influence from national government on local areas. Ageing affects various spheres of local steering activity. Among the main implications for local areas in the UK are the continuous search for responsibility and the struggle to broaden the agenda beyond health and care. This has led to experimenting with governance structures, intensifying involvement of older people and developing inter-agency older people strategies and others as catalysts for further development. The strong influence from central government on local steering advances local reactions to ageing but provokes superficial and unsustainable answers at the same time. Overall, the thesis provides in-depth empirical knowledge on local planning for an ageing population. The theoretical lenses local governance and collective learning have been used to generalise from the practical experiences in the three case study areas. The thesis concludes with recommendations for practitioners locally and at the national level. These refer inter alia to local governance arrangements which come up to the issue’s cross-cuttingness and to national guidance and regulation which could facilitate their introduction or modification.:Figures and tables.......................................................................................................11 List of Abbreviations...................................................................................................13 1 Introduction..........................................................................................................15 1.1 Rationale and aims of the research.............................................................15 1.2 Study design...............................................................................................18 1.3 Thesis structure...........................................................................................20 2 Planning for an ageing population – a UK-wide overview...................................23 2.1 The UK’s ageing population........................................................................23 2.2 Local governance and planning in transition................................................30 2.3 Reactions to ageing in the UK.....................................................................38 2.4 Questions raised.........................................................................................46 3 Conceptual framework.........................................................................................49 3.1 Local planning for an ageing population – linked to various research areas.............................................................................................49 3.2 Grounded theory perspective......................................................................53 3.3 Sensitising concepts....................................................................................55 3.3.1 Local governance..................................................................................56 3.3.2 Collective learning.................................................................................62 3.4 Presuppositions guiding the analysis............................................................67 4 Research design and methods..............................................................................71 4.1 Overall research design................................................................................71 4.2 Exploratory interviews – national level.........................................................74 4.3 Sampling procedures...................................................................................75 4.3.1 Sampling of case study areas.................................................................76 4.3.2 Sampling of interviewees.......................................................................79 4.4 Data collection............................................................................................81 4.5 Data analysis...............................................................................................83 5 The case study areas.............................................................................................89 5.1 North Tyneside............................................................................................90 5.1.1 North Tyneside in profile.......................................................................90 5.1.2 Planning for an ageing population in North Tyneside............................91 5.2 Poole...........................................................................................................94 5.2.1 Poole in profile......................................................................................94 5.2.2 Planning for an ageing population in Poole...........................................96 5.3 Wealden/East Sussex...................................................................................98 5.3.1 Wealden/East Sussex in profile..............................................................98 5.3.2 Planning for an ageing population in Wealden/East Sussex.................100 5.4 Summary and arising questions.................................................................103 6 Local governance and planning for an ageing population...................................105 6.1 The involved actors...................................................................................105 6.1.1 Actors belonging to the public sector..................................................106 6.1.2 Actors belonging to the private sector.................................................116 6.1.3 Actors belonging to the voluntary and community sector....................117 6.1.4 Connecting the sectors: The Local Strategic Partnership......................122 6.2 A typology of actors..................................................................................125 6.3 Governance arrangements: from working in silos to partnerships...............130 6.4 Summary...................................................................................................139 7 Local learning processes in planning for an ageing population..........................141 7.1 Setting the ageing agenda.........................................................................143 7.1.1 Awareness of the ageing population...................................................143 7.1.2 From awareness to action....................................................................146 7.2 Building up knowledge of ageing..............................................................149 7.2.1 Basing planning on (demographic) evidence.......................................149 7.2.2 Older people’s participation.................................................................155 7.2.3 Reacting to stimuli from national government.....................................158 7.3 Collective learning to plan for an ageing population..................................160 7.3.1 Collective learning in the local area.....................................................160 7.3.2 Learning in older people’s partnerships................................................164 7.4 Strategy-making for an ageing population.................................................171 7.4.1 Local strategies for dealing with population ageing.............................171 7.4.2 National trends reflected in local strategies..........................................178 7.4.3 The functions of strategies and strategy-making.................................187 7.5 Summary...................................................................................................191 8 Central challenges and perspectives in planning for an ageing population........193 8.1 The cross-cutting nature of ageing............................................................193 8.1.1 Searching for responsibility..................................................................194 8.1.2 Struggling to broaden the agenda.......................................................195 8.1.3 Experimenting with governance structures..........................................196 8.1.4 Involving older people.........................................................................197 8.1.5 Using strategies as catalysts................................................................198 8.2 Ambivalent influence from national government.......................................199 8.2.1 Influence via funding, instruments, targets and supervision.................200 8.2.2 Skipping the regional level..................................................................203 8.2.3 National government stimulating local areas to plan for an ageing population...............................................................................204 8.2.4 Local areas’ superficial reactions to national government influence......205 8.3 Regional and local challenges and perspectives..........................................207 9 Discussion of the results and implications..........................................................209 9.1 Summary of results....................................................................................209 9.2 Reflection of the results and the research design with respect to the state of research..............................................................................213 9.2.1 Discussion of the results......................................................................214 9.2.2 Discussion of the research design........................................................217 9.3 Open questions and need for further research...........................................219 9.4 Recommended action................................................................................221 9.5 Looking beyond the UK.............................................................................228 Literature..................................................................................................................231 Appendix..................................................................................................................251 A Interviewees and their positions..........................................................................251 B Exemplary e-mail to get into contact with potential interviewee and accompanying project outline..............................................................................252 C Interview guideline..............................................................................................254 D Transcription rules according to GAT 2 (modified)...............................................259
Die Mehrzahl britischer Gemeinden ist mit einer alternden Bevölkerung konfrontiert. Küstengebiete und ländliche Räume sind besonders betroffen, da sie als Altersruhesitz bevorzugt werden. Ziel der Dissertation ist es, den strategischen Umgang der Gemeinden mit diesen demographischen Veränderungen zu beleuchten. Die britische Nationalregierung gibt den Gemeinden strategische Leitlinien vor, allerdings ist wenig darüber bekannt, wie die lokalen Ansätze tatsächlich aussehen. Bisher wurden vor allem Good Practice Sammlungen zum Thema veröffentlicht. Vor diesem Hintergrund beschäftigt sich die Dissertation detailliert mit der Stadtentwicklung für eine alternde Bevölkerung in solchen Gemeinden, die in sich zwar mit der Bevölkerungsalterung beschäftigen, aber nicht als Good Practice klassifiziert werden können. Die Hauptforschungsfrage ist: Wie planen lokale Akteure für eine alternde Bevölkerung? Die Arbeit folgt einem Grounded Theory Ansatz, der darauf zielt, theoretische Konzepte aus den empirischen Daten zu entwickeln. Lokale Governance und kollektives Lernen dienen als sensibilisierende Konzepte, d.h. weitergefasste theoretische Perspektiven. Aufgrund des Forschungsstandes und des Ziels, detailliertes Wissen über die Stadtentwicklung für eine alternde Bevölkerung zu gewinnen, folgt die Arbeit einem qualitativen Forschungsdesign. In den drei heterogenen Fallstudiengemeinden North Tyneside, Poole und Wealden wurden insbesondere qualitative Interviews mit lokalen Experten durchgeführt und Dokumente wie Strategiepapiere und Sitzungsprotokolle ausgewertet. Die Ergebnisse umfassen drei Themenbereiche. Zunächst werden lokale Governanceformen analysiert, was die Identifikation der beteiligten Akteure, ihre Handlungsorientierungen und Interaktionen umfasst. Da Ansätze zum Umgang mit der alternden Bevölkerung sich stark zwischen individuellen Akteuren unterscheiden, wurde auf dieser Basis eine Akteurstypologie erstellt. Darüber hinaus wird analysiert wie traditionale Steuerungsansätze staatlicher Akteure durch netzwerkartige Governanceformen ergänzt werden. Bedeutendstes Beispiel sind Arbeitsgruppen, in denen Akteure verschiedener Organisationen und Sektoren zusammenkommen, um Ansätze zum Umgang mit Senioren und der Bevölkerungsalterung zu entwickeln. Anschließend werden lokale Lernprozesse in der Planung für eine alternde Bevölkerung rekonstruiert. Dabei werden vier Phasen unterschieden: Agenda-Setting, Wissensaufbau, kollektives Lernen im engeren Sinne und Strategieerstellung. Es werden die Wechselwirkungen zwischen Governanceformen und kollektivem Lernen analysiert, insbesondere bezüglich der Lernformen in verschiedenen Typen von Arbeitsgruppen. Schließlich werden Herausforderungen und Perspektiven der Stadtentwicklung für eine alternde Bevölkerung diskutiert, die aus der Analyse von Governanceformen und Lernprozessen hervorgehen. Einerseits beziehen diese sich auf den Querschnittcharakter des Themas Alterung, andererseits auf den ambivalenten Einfluss der Nationalregierung. Die Alterung betrifft verschiedenste Bereiche lokaler Steuerung. Dies führt zu einer anhaltenden Suche nach lokalen Verantwortungsträgern und zu Schwierigkeiten, die Agenda über Gesundheit und Pflege Älterer hinaus zu erweitern. Darüber hinaus hat der Querschnittcharakter ein Experimentieren mit Governanceformen angeregt, sowie die Schaffung von mehr Partizipationsmöglichkeiten für ältere Bürger und die Erstellung ressortübergreifender lokaler Alterungsstrategien. Die starken Eingriffe der Nationalregierung in lokale Steuerungstätigkeiten befördern einerseits die Auseinandersetzung mit der Alterung, andererseits führen sie auch zu oberflächlichen und wenig nachhaltigen Reaktionen. Insgesamt bietet die Dissertation detailliertes empirisches Wissen zur Stadtentwicklung für eine alternde Bevölkerung. Die theoretischen Perspektiven lokale Governance und kollektives Lernen wurden genutzt um generalisierbare Ergebnisse aus den Erfahrungen in den drei Fallstudiengemeinden zu gewinnen. Abschließend werden Handlungsempfehlungen für Praktiker auf der lokalen und nationalen Ebene abgeleitet.:Figures and tables.......................................................................................................11 List of Abbreviations...................................................................................................13 1 Introduction..........................................................................................................15 1.1 Rationale and aims of the research.............................................................15 1.2 Study design...............................................................................................18 1.3 Thesis structure...........................................................................................20 2 Planning for an ageing population – a UK-wide overview...................................23 2.1 The UK’s ageing population........................................................................23 2.2 Local governance and planning in transition................................................30 2.3 Reactions to ageing in the UK.....................................................................38 2.4 Questions raised.........................................................................................46 3 Conceptual framework.........................................................................................49 3.1 Local planning for an ageing population – linked to various research areas.............................................................................................49 3.2 Grounded theory perspective......................................................................53 3.3 Sensitising concepts....................................................................................55 3.3.1 Local governance..................................................................................56 3.3.2 Collective learning.................................................................................62 3.4 Presuppositions guiding the analysis............................................................67 4 Research design and methods..............................................................................71 4.1 Overall research design................................................................................71 4.2 Exploratory interviews – national level.........................................................74 4.3 Sampling procedures...................................................................................75 4.3.1 Sampling of case study areas.................................................................76 4.3.2 Sampling of interviewees.......................................................................79 4.4 Data collection............................................................................................81 4.5 Data analysis...............................................................................................83 5 The case study areas.............................................................................................89 5.1 North Tyneside............................................................................................90 5.1.1 North Tyneside in profile.......................................................................90 5.1.2 Planning for an ageing population in North Tyneside............................91 5.2 Poole...........................................................................................................94 5.2.1 Poole in profile......................................................................................94 5.2.2 Planning for an ageing population in Poole...........................................96 5.3 Wealden/East Sussex...................................................................................98 5.3.1 Wealden/East Sussex in profile..............................................................98 5.3.2 Planning for an ageing population in Wealden/East Sussex.................100 5.4 Summary and arising questions.................................................................103 6 Local governance and planning for an ageing population...................................105 6.1 The involved actors...................................................................................105 6.1.1 Actors belonging to the public sector..................................................106 6.1.2 Actors belonging to the private sector.................................................116 6.1.3 Actors belonging to the voluntary and community sector....................117 6.1.4 Connecting the sectors: The Local Strategic Partnership......................122 6.2 A typology of actors..................................................................................125 6.3 Governance arrangements: from working in silos to partnerships...............130 6.4 Summary...................................................................................................139 7 Local learning processes in planning for an ageing population..........................141 7.1 Setting the ageing agenda.........................................................................143 7.1.1 Awareness of the ageing population...................................................143 7.1.2 From awareness to action....................................................................146 7.2 Building up knowledge of ageing..............................................................149 7.2.1 Basing planning on (demographic) evidence.......................................149 7.2.2 Older people’s participation.................................................................155 7.2.3 Reacting to stimuli from national government.....................................158 7.3 Collective learning to plan for an ageing population..................................160 7.3.1 Collective learning in the local area.....................................................160 7.3.2 Learning in older people’s partnerships................................................164 7.4 Strategy-making for an ageing population.................................................171 7.4.1 Local strategies for dealing with population ageing.............................171 7.4.2 National trends reflected in local strategies..........................................178 7.4.3 The functions of strategies and strategy-making.................................187 7.5 Summary...................................................................................................191 8 Central challenges and perspectives in planning for an ageing population........193 8.1 The cross-cutting nature of ageing............................................................193 8.1.1 Searching for responsibility..................................................................194 8.1.2 Struggling to broaden the agenda.......................................................195 8.1.3 Experimenting with governance structures..........................................196 8.1.4 Involving older people.........................................................................197 8.1.5 Using strategies as catalysts................................................................198 8.2 Ambivalent influence from national government.......................................199 8.2.1 Influence via funding, instruments, targets and supervision.................200 8.2.2 Skipping the regional level..................................................................203 8.2.3 National government stimulating local areas to plan for an ageing population...............................................................................204 8.2.4 Local areas’ superficial reactions to national government influence......205 8.3 Regional and local challenges and perspectives..........................................207 9 Discussion of the results and implications..........................................................209 9.1 Summary of results....................................................................................209 9.2 Reflection of the results and the research design with respect to the state of research..............................................................................213 9.2.1 Discussion of the results......................................................................214 9.2.2 Discussion of the research design........................................................217 9.3 Open questions and need for further research...........................................219 9.4 Recommended action................................................................................221 9.5 Looking beyond the UK.............................................................................228 Literature..................................................................................................................231 Appendix..................................................................................................................251 A Interviewees and their positions..........................................................................251 B Exemplary e-mail to get into contact with potential interviewee and accompanying project outline..............................................................................252 C Interview guideline..............................................................................................254 D Transcription rules according to GAT 2 (modified)...............................................259

With advancing age there is a progressive decline in the function of the heart. In humans reductions in stroke volume and cardiac output occurs often resulting in cardiac disease and subsequent death. The pathology found in the heart due to advancing age is attributed to a reduction in cardiomyocytes which causes cardiac dysfunction and heart disease, leading to heart failure. Zebrafish are a valuable tool in studying ageing and heart disease. As zebrafish age they gradually senesce. This is similar to humans and other mammals. However the response of the zebrafish heart to ageing has not been explored. The zebrafish heart changes due to ageing, with increased fibrosis and ventricular wall thickness. I have established new assays to measure proliferation and apoptosis in zebrafish cardiomyocytes using multiplexing of thymidine analogues and cleaved caspase 3, respectively. Using these developed assays it was discovered that these changes may be caused by an observed increase in cardiomyocyte apoptosis. This was coupled with no change in cardiomyocyte proliferation. These changes may be mediated by an increase in natriuretic peptide expression. In response to exercise, cardiomyocyte proliferation increases signalled by increased gata4, nkx2.5, tbx5, and mef2c expression and a reduction of natriuretic peptide expression. In the long term these genetic and cellular changes in the heart in response to exercise may slow some of the pathological changes observed in the heart.

Elevated free fatty acids (FFA) are a feature of ageing and a risk factor for metabolic disorders such as cardiovascular disease (CVD) and type-2 diabetes (T2D). Elevated FFA contribute to insulin resistance, production of inflammatory cytokines and expression of adhesion molecules on immune cells and endothelial cells, risk factors for CVD and T2D. Molecular mechanisms of FFA effects on monocyte function and how FFA phenotype is affected by healthy ageing remain poorly understood. This thesis evaluated the effects of the two major FFA in plasma, oleate and palmitate on monocyte viability, cell surface antigen expression, and inflammatory activation in THP-1 monocytes. Palmitate but not oleate increased cell surface expression of CD11b and CD36 after 24h, independent of mitochondrial superoxide, but dependent on de novo synthesis of ceramides. LPS-mediated cytokine production in THP-1 monocytes was enhanced and decreased following incubation with palmitate and oleate respectively. In a model of monocyte-macrophage differentiation, palmitate induced a pro-inflammatory macrophage phenotype which required de novo ceramide synthesis, whilst oleate reduced cytokine secretion, producing a macrophage with enhanced clearance apoptotic cells. Plasma fatty acid analysis in young and mid-life populations revealed age-related increases in both the SFA and MUFA classes, especially the medium and very long chain C14 and C24 fatty acids, which were accompanied by increases in the estimated activities of desaturase enzymes. Changes were independently correlated with increased PBMC CD11b, plasma TNF-a and insulin resistance. In conclusion, the pro-atherogenic phenotype, enhanced LPS responses in monocytes, and pro-inflammatory macrophage in the presence of palmitate but not oleate is reliant upon de novo ceramide synthesis. Age-related increases in inflammation, cell surface integrin expression are related to increases in both the MUFA and SFA fatty acids, which in part may be explained by altered de novo fatty acid synthesis.