In this paper, we assess the role of policies aimed at regulating the number and age structure of elections on the size and age structure of five European Academies of Sciences. We show the recent pace of ageing and the degree of variation in policies across them and discuss the implications of different policies on the size and age structure of academies. We also illustrate the potential effect of different election regimes (regimens? types?) (fixed vs. linked) and age structures of elections (younger vs. older) by contrasting the steady-state dynamics of different projections of Full Members in each academy into 2070 and measuring the size and age-compositional effect of changing a given policy relative to a status quo policy scenario. Our findings suggest that academies with linked intake (i.e., where the size of the academy below a certain age is fixed and the number of elections is set to the number of members becoming that age) may be a more efficient approach to curb growth without suffering any aging trade-offs relative to the faster growth of academies electing a fixed number of members per year. We further discuss the implications of our results in the context of stable populations open to migration.

As one of the most promising pathways in the transition period towards the low carbon economy, a large scale implementation of electric vehicles (EV) is expected in the near future. Concentration of EV charging in a small area or within a short time will dramatically affect the load demand profile, especially the peak load in the distribution network. As a result, distribution transformers are facing hazards of shortened lifetime due to extra loads, and direct failures caused by potential overloads. Considering the large number of distribution transformers and the massive investment involved, the adaptability of the population of distribution transformers under future EV scenarios should be assessed. In this thesis, an assessment strategy for the future adaptability of distribution transformer population under EV scenarios is introduced. Assessing the adaptability is to understand the impact of the hot-spot temperature, loss-of-life, expected lifetime and failure probability of each individual in the distribution transformer population. Determination of hot-spot temperature of distribution transformers is essential for the assessment. In order to achieve accurate prediction of hot-spot temperatures under EV scenarios, thermal parameters should be refined for individual distribution transformers so that their thermal characteristics can be reflected more accurately than using the generic values recommended for all distribution transformers in the IEC loading guide. Two methods for the refinement are proposed in this thesis. One method is to curve-fit hot-spot temperatures measured in the extended heat run test; and the other is to calculate each parameter with developed equations in the loading guide with standard heat run test results. The assessment strategy is introduced and demonstrated on a group of selected distribution transformers from the population under three EV scenarios, i.e. Business as usual (BAU), High-range and Extreme-range scenarios, which represent 0%, 32% and 58.9% EV penetration levels respectively. Results show that EV charging would be less concerned on the acceleration of thermal ageing than the direct failure due to breakdown caused by decrease of dielectric strength in an event of bubbling. Since the peak load and hot-spot temperature under EV scenarios only last for a short time and would be compensated by low values during the rest time of a day, which eventually leads to a moderate thermal ageing. Occasionally, severe over-ageing can be caused by extremely high hot-spot temperatures, and the lifetime will be reduced to an unacceptable level. However, on such occasions, hot-spot temperatures would be high enough to trigger bubbling and reduce the dielectric strength of transformer's insulation system to a level that is incapable of undertaking the voltage stress, which eventually causes breakdown of transformers. In terms of the failure probability, results show that no distribution transformers are facing failure risks due to bubbling under BAU scenario. Failure starts under High-range scenario. If transformers possessing a failure probability over 50% are identified as high risk, then 13% of investigated transformers are at high risk under High-range scenario, while it increases to 39% under Extreme-range scenario. It is found that the failure probability is dominantly controlled by the peak load, other factors such as transformer age and installation conditions are less influential. A threshold peak load of around 1.5 p.u. is observed that distinguishes transformers in high risk from others under Extreme-range scenario. This observation could be applied to assist the asset management under future EV scenarios that the peak load of distribution transformers should be restricted below 1.5 p.u. to prevent potential failure due to bubbling.

Increasing age is the single biggest independent risk factor for cardiovascular disease, which is in turn the leading cause of morbidity and mortality worldwide. Ageing is associated with hypertension and metabolic changes which all increase the risk of the development of cardiovascular disease. In young, healthy individuals, perivascular adipose tissue (PVAT) secretes factors that can influence vascular contractility, exerting a net anti-contractile effect against numerous vasoconstrictors including the thromboxane A2 mimetic U46619 and α1-adrenoceptor phenylephrine. Whilst it is known that dysfunction in PVAT can contribute to obesity-related hypertension, little is known whether similar dysfunction occurs with ageing. In young Wistar rats, wire myography and pharmacological studies showed that the anti-contractile effect of PVAT in the presence of U46619 is dependent on both PVAT-derived nitric oxide and prostaglandins, whereas the anti-contractile effect in the presence of phenylephrine is nitric oxide independent. This finding was supported by Western blot experiments that showed increased phosphorylation of endothelial nitric oxide synthase (eNOS) in PVAT following U46619 incubation, but not phenylephrine. In the Wistar rat model of ageing used, wire myograph studies revealed that the PVAT anti-contractile effect in the presence of phenylephrine is preserved at 24 months of age, but in in the presence of U46619 is lost. Furthermore PVAT from aged animals had a deleterious effect on endothelial function, suggesting changes in its secreted factors. These changes are accompanied by alterations in the expression and activation of key enzymes in the nitric oxide synthesis pathway within the PVAT as measured by Western blot, as well as alterations in cardiometabolic phenotype including hypertension, hyperglycaemia and insulin resistance. Taken together these findings suggest that previously unidentified age-related PVAT dysfunction may contribute to age-related hypertension and thus may provide a potential therapeutic target for future study.

The aim of my work was to identify additional genetic and non-genetic factors influencing female reproductive ageing in humans. Although approximately 50% of population variation in age at menopause is due to genetics, less than 3% of variation had been accounted for by common genetic variants. Of non-genetic risk factors, only smoking had consistently been found to have a strong effect on age of menopause. In the wider context of female reproduction, our understanding of the role of genetics in determining sex hormone levels was limited. By combining the results of research in these different areas, I hoped to improve our knowledge of the biology of female reproductive ageing. Chapter 1 is an introduction in which I discuss the biology of menopause, describe relationships with health and present current knowledge regarding non-genetic and genetic risk factors influencing menopause age. Chapter 2 is an analysis of the associations between non-genetic risk factors occurring in early life with early menopause. We identified an association between multiple births and early menopause, connecting events pre-birth, when the oocyte pool is formed, with reproductive ageing in later life. Chapter 3 is a genome-wide association study to identify genetic variants associated with levels of nine sex hormone related phenotypes. We highlighted loci of relevance to reproductive function, which suggested overlaps in the genetic basis of hormone regulation. Chapter 4 is a genome-wide association study of menstrual cycle length. We showed that a common genetic variant related to follicle stimulating hormone levels and age at menopause is associated with several reproductive traits including length of menstrual cycle. Chapter 5 is an investigation of the relationship between differences in length of normal FMR1 triplet repeat alleles and timing of menopause. We found no association between the length of normal FMR1 alleles and timing of menopause, contradicting the results of smaller studies and replicating a null result in another large study. Chapter 6 is large genome-wide meta-analysis to identify common and low-frequency genetic variants associated with age at menopause. We identified 44 regions containing 54 independent common signals and two rare missense alleles of large effect. Finally, in Chapter 7 I evaluate how this work has benefitted our knowledge of female reproductive ageing and describe directions for future research.

Human brain structure can be measured across the lifecourse (“in vivo”) with magnetic resonance imaging (MRI). MRI data are often used to create “atlases” and statistical models of brain structure across the lifecourse. These methods may define how brain structure changes through life and support diagnoses of increasingly common, yet still fatal, age-related neurodegenerative diseases. As diseases such as Alzheimer’s (AD) cast an ever growing shadow over our ageing population, it is vitally important to robustly define changes which are normal for age and those which are pathological. This work therefore assessed existing MR brain image data, atlases, and statistical models. These assessments led me to propose novel methods for accurately defining the distributions and boundaries of normal ageing and pathological brain structure. A systematic review found that there were fewer than 100 appropriately tested normal subjects aged ≥60 years openly available worldwide. These subjects did not have the range of MRI sequences required to effectively characterise the features of brain ageing. The majority of brain image atlases identified in this review were found to contain data from few or no subjects aged ≥60 years and were in a limited range of MRI sequences. All of these atlases were created with parametric (mean-based) statistics that require the assumptions of equal variance and Gaussian distributions. When these assumptions are not met, mean-based atlases and models may not well represent the distributions and boundaries of brain structure. I tested these assumptions and found that they were not met in whole brain, subregional, and voxel-based models of ~580 subjects from across the lifecourse (0- 90 years). I then implemented novel whole brain, subregional, and voxel-based statistics, e.g. percentile rank atlases and nonparametric effect size estimates. The equivalent parametric statistics led to errors in classification and inflated effects by up to 45% in normal ageing-AD comparisons. I conclude that more MR brain image data, age appropriate atlases, and nonparametric statistical models are needed to define the true limits of normal brain structure. Accurate definition of these limits will ultimately improve diagnoses, treatment, and outcome of neurodegenerative disease.

Introduction: Factors that influence atrioventricular (AV) nodal conduction are complex and not well understood. Multiple studies have been performed to explain the mechanisms responsible for AV nodal conduction but the AV node (AVN) remains a "riddle". With ageing there is an increase in the incidence of AV nodal dysfunction leading to AV block. Methodology: I have performed electrophysiological (EP) and immunohistochemistry experiments on male Wistar-Hanover rats aged 3 months (equivalent to 20 year old humans; n=24) and 2 years (equivalent to 70 year old humans; n=15). AH interval, Wenkebach cycle length (WCL) and AV node effective refractory period (AVNERP) were measured. I used cesium (Cs+ = 2 mM) to block HCN channels responsible for the funny current "If " (and therefore the membrane clock), and ryanodine (2 μM) to block RyR2 channels responsible for Ca2+ release from the sarcoplasmic reticulum (and therefore the Ca2+ clock) in the two age groups. Protein expression in each group (from n=9 young and n=8 old rats) from different regions of the AV conduction axis: inferior nodal extension (INE), compact node (CN), proximal penetrating bundle (PPB) and distal penetrating or His bundle (His) were studied using immunofluorescence and confocal microscopy. The expression of the gap junction channels Cx43 and Cx40 and ion channel’s including HCN4 (responsible for If current), Nav1.5 (major cardiac Na+ channel responsible for INa) and Cav1.3 (L-type Ca2+ channel), and calcium handling proteins, RyR2 and SERCA 2a (involved in Ca2+ release and reuptake from cardiac sarcoplasmic reticulum, SR) were studied. Semi-quantitative signal intensity of these channels was measured using Volocity software. Structural characteristics of the tissue were studied using histology (Masson’s trichome stain and picrosirius red stain for collagen). Statistical analysis was performed with Prism 6.0. Electrophysiological measurements were performed using Spike2.Results: Without drugs to block the If current and Ca2+ release from the SR, there was a significant prolongation of the AH interval (P<0.005), WCL (P<0.005) and AVNERP (P<0.001) with ageing. In young rats (but not old rats), Cs+ prolonged the AH interval (P<0.001), WCL (P<0.01) and AVNERP (P<0.01). Ryanodine prolonged the AH interval (P<0.01) and WCL (P<0.01) in young and old rats. Immunofluorescence revealed that with ageing: Cx43 is downregulated in the PPB and His (P<0.05); Cx40 is upregulated in the INE and CN (P<0.05); HCN4 is downregulated in the His bundle (P=0.05); Nav1.5 is downregulated in the CN and PB (P<0.05); RyR2 is downregulated in the CN and PPB (P<0.05); SERCA2a and Cav1.3 is upregulated in the PPB (P<0.05). Histology confirmed that with ageing that the cells of CN, PPB and His are more loosely packed and irregularly arranged. There is cellular hypertrophy, decrease in the number of nuclei and increase in the collagen content with ageing. The clinical study has shown that elderly patients with syncope and cardiac conduction system disease are at risk of high mortality and recurrent transient loss of consciousness. Conclusion: For the first time, we have shown that both HCN and RyR2 channels play an important role in AV nodal conduction. With ageing the expression of HCN4 and the role of If in AV nodal conduction decreases, whereas the role of Ca2+ clock in AV nodal conduction was unchanged, although the expression of RyR2 and SERCA2a changes. The clinical study suggests that AV nodal disease is associated with significant morbidity and higher mortality among elderly patients who present with transient loss of consciousness.

With increasing age, aspects of the innate and adaptive immune systems show functional decline. In the skin this is associated with an increased incidence of epidermal malignancies and infections, a decreased incidence of contact allergy, and the development of autoimmunity. The mechanisms underlying these clinical effects in aged skin are poorly understood. Langerhans’ cells (LCs), which are members of the wider family of dendritic cells (DCs), reside in the epidermis where they act as sentinels of the immune system by processing and presenting antigen and inducing T cell responses. Previous investigations have suggested that the number of epidermal LCs is reduced, and that the motility of LCs is impaired in aged skin. A series of investigations was performed to characterise the mechanistic basis for the reduced frequency and restricted mobility of epidermal LCs in the skin of the elderly. Initially LC-like cells were cultured from circulating monocyte precursors and characterised using flow cytometry. The ability of precursors to differentiate into LC-like cells was not impaired in the aged; furthermore there were no age-associated differences in expression of markers of LC activation at baseline or upon stimulation. The phenotype of epidermal LCs was assessed using flow cytometric analysis of epidermal cell suspensions and did not appear altered in aged individuals. In addition, using the same techniques with dermal cell suspensions the dermal DC population was not altered with age. Langerhans’ cell migration from epidermal explants prepared from the skin of aged individuals was impaired but could be restored with exogenous interleukin (IL)-1β. There was no age-related reduction in the epidermal levels of IL-1β or caspase-1 (IL-1β converting enzyme which converts pro-IL-1β to the active form) or the expression of the IL-1 receptor I (IL-1RI), to account for this observation. However, the amount of IL-1 receptor antagonist was reduced in aged skin suggesting a change in the overall local cytokine balance. Based on previous reports that topical retinoic acid (RA) can increase cutaneous IL-1 production, a 4-day patch test assay was performed using 0.025% all-trans RA cream to explore whether this could restore LC migration in the aged. There was no effect on LC migration from epidermal explants prepared after treatment with RA in the aged.These data demonstrate that changes in LC function in the elderly may not be associated with changes in systemic DC biology. Age related changes in the cutaneous microenvironment are likely to be more relevant.

Polymer electrolyte membrane fuel cell (PEMFC) stacks require sealing around the perimeter of the cells to prevent the gases inside the cell from leaking. Elastomeric materials are commonly used for this purpose. The overall performance and durability of the fuel cell is heavily dependent on the long-term stability of the gasket. In this study, the degradation of three elastomeric gasket materials (silicone rubber, commercial EPDM and a developed EPDM 2 compound) in an accelerated ageing environment was investigated. The change in properties and structure of a silicone rubber gasket caused by use in a real fuel cell was studied and compared to the changes in the same silicone rubber gasket material brought about by accelerated aging. The accelerated aging conditions were chosen to relate to the PEM fuel cell environment, but with more extreme conditions of elevated temperature (140°C) and greater acidity. Three accelerated ageing media were used. The first one was dilute sulphuric acid solution with the pH values of 1, 2 and 4. Secondly, Nafion® membrane suspended in water was used for accelerated ageing at a pH 3 to 4. Finally, diluted trifluoroacetic acid (TFA) solution of pH 3.3 was chosen. Weight change and the tensile properties of the aged gasket samples were measured. In addition, compression set behaviour of the elastomeric seal materials was investigated in order to evaluate their potential sealing performance in PEM fuel cells. The results showed that acid hydrolysis was the most likely mechanism of silicone rubber degradation and that similar degradation occurred under both real fuel cell and accelerated aging conditions. The effect of TFA solution on silicone rubber was more aggressive than sulphuric acid and Nafion® solutions with the same acidity (pH value) suggesting that TFA accelerated the acid hydrolysis of silicone rubber. In addition, acid ageing in all three acidic solutions caused visible surface damage and a significant decrease in tensile strength of the silicone rubber material, but did not significantly affect the EPDM materials. EPDM 2 compound had a desirable (low) compression set value which was similar to silicone rubber and much better than the commercial EPDM. It also showed a very good performance in the fuel cell test rig conforming that it a potential replacement for silicone rubber in PEMFCs.

Ageing is a process correlated with cellular stress and increased risks of neurodegenerative diseases, in particular Alzheimer’s disease (AD), which is accompanied with severe cognitive and memory impairments. Both ageing and AD affect many brain regions and thus induce brain malfunctions. Among the brain regions, the entorhinal cortex (EC) has drawn more and more attentions due to its pivotal role in cognition and memory functions as well as its vulnerability to ageing process and AD neuropathology. Synaptic and neuronal degenerations, which are also manifest features of AD, occur in the EC during the ageing process and at the early stage of AD. In addition, both pathological hallmarks of AD, namely abnormal accumulation of β-amyloid (Aβ) and hyperphosphorlation of tau proteins, initially appear in the EC and then progress to other brain regions such as the hippocampus and the neocortex. Glial alterations in AD and ageing process have been considered as secondary event to neuronal changes. Nevertheless, accumulating evidence indicates the relevant and primary involvement of astroglia, which is responsible for brain homeostasis, in AD and ageing. In this thesis, we have focused on the astroglial alterations in the EC during the progression of AD in an animal model of the disease as well as in ageing process in non-transgenic control mice. We have used the triple transgenic mouse model of AD (3xTg-AD), which is the most relevant animal model of AD and resembles the spatiotemporal progression of human AD pathology. Our results revealed cytoskeletal atrophy of astrocytes in the EC of 3xTg-AD animals (Chapter 3), shown by significant decrease in GFAP surface and volume. This astroglial alteration began at very early age (1 month) and sustained till more advanced age (12 month). Moreover, Aβ plaques did not trigger astrogliosis, and there was rare presence of GFAP labelled astrocytes in the vicinity of Aβ deposition. This may reflect the relative indifference of astroglia in the EC and thus explain the susceptibility of the EC at the early stage of AD. To study whether astroglial atrophy in cytoskeleton compromise astrocytic function in glutamate homeostasis, we investigated the expression of glutamine synthetase (GS), which is specifically expressed in astrocytes and is critical for glutamate balance (Chapter 4). Our results showed constant GS expression and the density of GS positive astrocytes in the EC. However, dual labelling of GS and GFAP revealed 3 different subsets of astrocytes, being GS-, GFAP-, GS/GFAP- positive astrocytes. The morphology of GS-IR cells, measured by surface and volume, did not change in spite of the evident GFAP atrophy. Therefore, GFAP atrophy does not disturb glutamate homeostasis in the EC, suggesting diverse functional populations of astrocytes, which may show distinct responses during AD progression. In addition we also analysed astroglial changes during the ageing process in the EC and its major projection area, the hippocampus (Chapter 5). Astrocytes in the hippocampus exhibited prominent hypertrophy, shown by increased GFAP whereas entorhinal astrocytes in the EC had profound reduction in GFAP expression. This may implicate heterogeneous astrocytic responses to ageing in different brain regions. The general atrophy of astrocytes in the EC of 3xTg-AD mice and aged controls, suggests astroglial atrophy may results in reduced astrocytic coverage and modulation of synapses, accounting for the synaptic dysfunction in ageing and AD.

La recherche de critères de vieillissement des revêtements de protection sur le long terme est nécessaire dans de nombreuses configurations industrielles. Ce travail présente l'étude de l'évolution de l'élasticité de revêtements de peinture sur plaque métallique par réflectométrie ultrasonore pour détecter de façon non destructive l'endommagement induit lors de tests de vieillissement thermique accéléré. La modélisation du pouvoir réflecteur permet d'identifier, dans une certaine gamme de fréquence, un mode particulier dont la valeur de l'angle critique est préférentiellement sensible à la rigidité de la couche en bon accord avec les tests réalisés sur des revêtements de 100µm de peinture sur plaque d'acier. Cette méthode est appliquée sur des échantillons étuvés à 80°C et 110°C durant 4000 heures. En fonction de la température, la mesure quotidienne de la position de cet angle critique permet de suivre le temps nécessaire au séchage complet des revêtements suite à l'évaporation du solvant. Au-delà, les variations de cette position angulaire indiquent, pour les modules élastiques de la peinture, une légère augmentation de moins de 2%. L'altération de la structure chimique détectée par mesures de température de transition vitreuse et de concentration de certains marqueurs (FTIR) se traduit donc par des modifications faibles d'élasticité nécessitant une résolution angulaire inférieure à 0,1°. Pour mieux différencier la rigidité de ces échantillons suite au vieillissement thermique, la sensibilité nécessaire est obtenue en réalisant une excursion en température autour de l'ambiante de quelques °C durant les mesures de réflectométrie. / The determination of paint coating's ageing criteria after long term service is necessary in many industrial configurations. In this work, we have studied by ultrasonic reflectometry the evolution of the elasticity of paint coated on a metallic plate in order to detect in a non destructive way the damage induced by thermal accelerated ageing tests. The simulation of the reflection coefficient identifies a particular mode whose critical angle is preferentially sensitive to the elasticity of the paint layer in a particular range of frequency. This result is in agreement with experimental tests performed on 100 µm thick paint coated on a steel plate. These samples are heated at 80°C and 110°C during 4000 hours. The everyday measurement of the evolution of the critical angle allows the identification of the time necessary to reach the complete drying of the paint coating. This parameter depends on the heating temperature. The total variations of these critical angular positions indicate a small increase less than 2% of the paint's elasticity moduli. In parallel, the change of the chemical structure is detected by the measurement of the glass transition temperature and the concentration of some markers identified by FTIR. This chemical change is linked to a small variation of elasticity implying an angular resolution less than 0.1°. For an easier differentiation of the rigidity of these thermally aged coatings, an enhanced sensibility is obtained by changing the temperature during the reflectometry measurements.