The general aim of this thesis was to study the frequency, causes and consequences of pathologic brain aging specifically focusing on sub-clinical and clinical MRI manifestations of vascular (small... Show moreThe general aim of this thesis was to study the frequency, causes and consequences of pathologic brain aging specifically focusing on sub-clinical and clinical MRI manifestations of vascular (small vessel disease) and neurodegenerative (brain atrophy) disease. A second aim was to improve the accuracy of the tools to quantify brain tissue so to better reflect the imaging characteristics of older people. All data presented in this thesis are from the AGES-Reykjavik Study including 5764 elderly men and women. The data is based on cross-sectional and longitudinal assessments of the brain with MRI measures. Show less
Worldwide, life expectancy has increased, which also resulted in an increasing number of people reaching old age. With aging, several age-related diseases commonly occur, such as dementia,... Show moreWorldwide, life expectancy has increased, which also resulted in an increasing number of people reaching old age. With aging, several age-related diseases commonly occur, such as dementia, osteoporosis and cardiovascular disease. The occurence of these diseases with age is highly heterogeneous. The research described in this thesis assessed the role of thyroid hormones in the etiology of age-related diseases. Based on the results, variation in blood levels of thyroid hormones do not appear to play a major role in the development of cogniitve decline, osteoporosis, anemia, diabetes mellitus or cardiovascular disease. Therefore, we conclude that is unlikely that thyroid hormones are a modifiable risk factor in the aging process. Nevertheless, many other research questions remain regarding thyroid hormones and older individuals. Show less
The experimental research in this thesis aims to gain more understanding of how the SCN network is organized and what is needed for network changes. More specifically, this work focused on the... Show moreThe experimental research in this thesis aims to gain more understanding of how the SCN network is organized and what is needed for network changes. More specifically, this work focused on the potential role of GABA and the GABAeric E/I balance in SCN network plasticity. Communication and synchronization in the SCN are important for the generation of a strong and coherent output signal. Under certain conditions, like long photoperiod, the phases of the individual SCN cells are more dispersed over the 24 hour cycle as evidenced by measurements of electrical activity and clock gene expression. Aging is also known to affect the network organization of the SCN with deterioration in synchronization among the individual SCN neurons. In this thesis, I present work that contributes to research questions regarding the effect of light exposure and/or aging on several characteristics of SCN network plasticity. Show less
My research projects include the investigation of effects of different environmental factors on sleep and the circadian clock in the course of aging (such as light levels, exercise, diet and... Show moreMy research projects include the investigation of effects of different environmental factors on sleep and the circadian clock in the course of aging (such as light levels, exercise, diet and pharmacological substances including caffeine and diazepam). Investigating thebeneficial or adverse effects in the course of aging provides significant insights that could accelerate, hinder or ameliorate parts of the aging process allowing for a healthier and longer life span.Chronic consupmtion of high-caloric diet, eventually leading to obesity, alters the sleep homeostasis as well as the sleep architecture denoting a potentially enhanced aging phenotype.In addition to dietary preferences, light levels particularly at night significantly affect sleep and the sleep electroencephalogram across a wide age span, impactingthe sleep regulatory system as well as the brain integrity.Factors that induce beneficial effects include exercise and caffeine intake. Long-term exercise was able to lead to a younger brain phenotype across all ages while caffeine generally ameliorated sleep health. Show less
The subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known... Show moreThe subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness. One of the biggest risk factors for glaucoma is elevated eye pressure. Our study found that glaucoma may in fact be an autoimmune disorder. We found that the body’s own T cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore these T cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria that normally live in our body. This opens a new approach to prevent and treat glaucoma. Currently most treatments focus on lowering eye pressure. However, in many patients, the disease worsens even after intraocular pressure returns to normal. We showed that when we blocked these autoreactive T cells in the eye, not only does it diminish the loss of retinal ganglion cells and axons, but it also preserves retinal function. Show less
Thoracale epidurale anesthesie (TEA), ook wel ruggenprik genoemd, zorgt voor een uitstekende pijnstilling rondom operaties en wordt als zodanig veelvuldig toegepast binnen de cardiothoracale... Show moreThoracale epidurale anesthesie (TEA), ook wel ruggenprik genoemd, zorgt voor een uitstekende pijnstilling rondom operaties en wordt als zodanig veelvuldig toegepast binnen de cardiothoracale chirurgie. TEA heeft echter ook effecten op het hart en de bloedsomloop. Hoewel in fysiologische studies is aangetoond dat thoracale epidurale anesthesie gunstige effecten heeft op het hart, heeft zich dit in grote klinische studies niet vertaald in een betere uitkomst. Dit proefschrift beschrijft de anatomie en fysiologie van het hart tijdens TEA bij patiënten die een long ingreep ondergaan. Het doel van dit proefschrift is het bepalen van de bijwerkingen van TEA op het hart en de bloedsomloop waarbij deze effecten van TEA zowel tijdens rust als gedurende omstandigheden van stress (zoals tijdens operatie of inspanning) onderzocht werden. De resultaten van dit proefschrift tonen aan dat TEA de functie van de rechter hartkamer vermindert. Dit proefschrift toont ook aan dat de toename van de linker- en rechter kamerfunctie tijdens inspanning nauwelijks wordt beïnvloed door TEA. Leeftijd lijkt geen duidelijke invloed te hebben op de bijwerkingen van TEA. Het is nog niet duidelijk in hoeverre deze resultaten klinisch relevant zijn. Echter, de resultaten uit dit proefschrift zouden kunnen helpen bij het maken van weloverwogen besluiten rond het gebruik van TEA bij cardiothoracale chirurgie. Show less
The main objective of this thesis was to investigate the serotonergic and cholinergic neurotransmitter systems, and the way these are altered in older age and Alzheimer’s disease. For that purpose,... Show moreThe main objective of this thesis was to investigate the serotonergic and cholinergic neurotransmitter systems, and the way these are altered in older age and Alzheimer’s disease. For that purpose, the neuroimaging technique resting state fMRI (RS-fMRI) was used to measure whole brain functional connectivity with and without pharmacological stimulation. The first part of the thesis concerns two pharmacological RS-fMRI studies that were executed in young adults. Pharmacological challenge effects of two selective serotonin reuptake inhibitors (sertraline and citalopram) and a cholinesterase inhibitor (galantamine) on brain connectivity were examined to gain more insight into the underlying neurotransmitter systems and the mechanisms of drug action in the central nervous system. The second part of this thesis was aimed at discovering changes in brain connectivity and serotonergic and cholinergic system functioning in aging and Alzheimer’s disease, by comparing brain network connections and the pharmacological response of this measure between young and older adults and patients with Alzheimer’s disease. Show less
In this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of... Show moreIn this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of thrombosis in the elderly population, in order to advance our basic understanding of physiological age-related changes that increase the risk of venous thrombosis and which may ultimately lead to improved personalized interventions. In this chapter firstly background information will be provided on risk factors for venous thrombosis, focussing specifically on age as a risk factor. Secondly, the role of veins and venous valves in the development of venous thrombosis will be discussed and thirdly, global assays as a potential tool to identify patients at high risk for venous thrombosis will be considered. The study populations used in this thesis will discussed, and an outline of this thesis will be provided. Show less
The aim of this thesis is to investigate the role of chronic inflammation as well as acute inflammatory response on muscle aging. We conclude that high chronic inflammation is associated with low... Show moreThe aim of this thesis is to investigate the role of chronic inflammation as well as acute inflammatory response on muscle aging. We conclude that high chronic inflammation is associated with low muscle strength, while high acute pro-inflammatory response is associated with high muscle strength. Show less
This thesis describes to which extent the skin reflects the aging process, with a specific focus on cellular senescence. Since the first descriptions of the growth arrested state of... Show more This thesis describes to which extent the skin reflects the aging process, with a specific focus on cellular senescence. Since the first descriptions of the growth arrested state of fibroblasts upon multiple replication rounds, cellular senescence has now emerged as a promising target to regulate the aging process in vivo as well. Here, we study whether fibroblast senescence in vitro is associated with in vivo donor characteristics such as chronological age and prevalence of disease. We further describe in this thesis whether senescence in skin tissue (in situ) is associated with other histological skin characteristics and with in vivo donor characteristics. Show less
The aim of this thesis was to identify novel lifespan regulating loci that influence human longevity and population mortality. To this end, we performed two genome-wide association studies, one of... Show moreThe aim of this thesis was to identify novel lifespan regulating loci that influence human longevity and population mortality. To this end, we performed two genome-wide association studies, one of long-lived individuals from the family-based Leiden Longevity Study (LLS) and an extended one of long-lived individuals from multiple cohorts of European descent. Using the latter, we identified two genome-wide significant loci, the TOMM40/APOE/APOC1 locus and an intergenic locus on chromosome 5q33.3. In addition, our gene set analysis with the LLS data showed that genetic variation in genes involved in the insulin/IGF-1 signaling and telomere maintenance pathways is associated with human longevity. Since our genetic studies identified a limited number of longevity loci, we additionally examined whether leukocyte telomere length (LTL) could be used as a biomarker of healthy aging. We showed that LTL meets three of the four criteria for a biomarker of healthy aging in the LLS, i.e., LTL changes with chronological age and is associated with health, in this case immune-related parameters, and prospective mortality. To identify novel longevity loci, future research may benefit from a better definition of the healthy aging phenotype, combining study designs, and the use of novel methods and technologies, such as next-generation sequencing. Show less
The general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were... Show moreThe general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were MTI, tCBF and WSS measurements. The new markers we studied were cerebral microbleeds and iron accumulation in the basal ganglia. In chapter 2 we investigated whether MTI changes could be detected in the GM, WM or both in patients suffering from MCI or AD. Using MTI we found evidence for structural brain changes in both GM and WM of patients with MCI and AD. Furthermore, these MTI changes were related to cognitive impairment as expressed by the mini mental state examination (MMSE) score. These findings imply that cerebral changes can be detected in both GM and WM even before patients are clinically demented. The finding of MTI changes in the GM might relate to classical AD type pathology, whereas WM MTI changes could indicate concomitant vascular pathology. The findings in chapter 2 raised the question of how the MTI changes found in this study are distributed over the GM and WM. This was investigated in chapter 3. In this study we showed that brain damage, as detected by MTI, is widespread over the lobes in both AD and MCI patients whereas GM damage is more focally present in the temporal and frontal lobe of MCI patients. These findings are compatible with the knowledge that GM damage originates from the temporal lobe in AD. This interpretation is further supported by the observed independent association between temporal GM peak height and cognitive decline. MTI changes were found in all four lobes of the MCI patients investigated in this study and show the involvement of a diffuse process affecting the WM even before patients are clinically demented, a finding potentially explained by the presence of diffuse vascular pathology. Chapter 4 shows that the tCBF is strongly associated with parenchymal volume rather than age and, although much weaker, with the severity of WMHs. Although the association between tCBF and parenchyma volume seems straightforward, this finding has important implications for future studies. Volume flow measurements should be corrected for parenchymal volume ratherthan age in all future studies in which flow measurements are being used as a diagnostic tool. In addition, studies including elderly patients or patients with a pathological increase of WMHs, such as diabetic type II subjects, should also correct their tCBF measurements for WMH volumes. Chapter 5 shows that hemodynamic conditions of the carotid and basilar arteries, as expressed in lower WSS parameters, are worse in both MCI and AD compared to controls. In addition, the WSS parameters were found to correlate strongly with cognition. Again, this study is additional evidence for an important role of vascular pathology in the development of AD. In chapter 6, we found a high prevalence of microbleeds in a population of patients suffering from vascular disease or at high risk of developing this condition. Age, hypertension and WMH were the most important risk factors for microbleeds, especially when located in the cortico-subcortical junction and basal ganglia. Regarding the associations between the presence and location of microbleeds on the one hand and parameters of cognitive functioning on the other, chapter 7 shows that microbleeds located infratentorially are associated with impaired cognitive functioning in the aging population with increased vascular risk factors. This suggests that in elderly individuals microbleeds in the posterior fossa should be considered a sign of small vessel disease with potential functional consequences. The semi-quantative scale for scoring basal ganglia hypo-intensity on T2*- weighted imaging presented in chapter 8 was associated with markers of neurodegeneration. This study showed that low signal intensity of the caudate nucleus T2*-weighted MR is a frequent finding which is associated with more cerebral atrophy, a higher load of WMH and a higher load of invisible changes in both cortical GM and NAWM non-demented elderly. Furthermore, hypo- intensity limited to the globus pallidus and putamen was not associated with any of these parameters of neurodegeneration. In chapter 9 we present a method for automated detection and classification of hypo-intense regions on T2-weighted MR images of the basal ganglia. In this chapter we not only show an association between basal ganglia hypo-intensity and cardiovascular risk factors but also with measures of cognitive functioning. From this we conclude that hypo-intensity of the basal ganglia on T2-weighted MR is not only a radiological finding accompanying cerebral aging but also an independent marker of neurodegeneration. Show less
Temporal variation in abiotic and biotic variables such as temperature, rainfall, food availability or predation pressure profoundly affects the abilities of organisms to survive and reproduce... Show moreTemporal variation in abiotic and biotic variables such as temperature, rainfall, food availability or predation pressure profoundly affects the abilities of organisms to survive and reproduce successfully. Most organisms are remarkably flexible in the face of such heterogeneity in habitat quality, and display phenotypic plasticity in response to environmental variation, i.e. the production of alternative phenotypes from a single genotype, dependent on the experienced environment. The aftrotropical butterfly Bicyclus anynana expresses alternative adult life histories in its habitat's wet and dry seasons, including reproductive timing and lifespan. This thesis aims to increase insight into the hormonal and transcriptional patterns that underlie life history plasticity in B. anynana. The first question is how the environment experienced during development induces the two adult seasonal forms via conserved hormonal pathways. The second major question covered in this thesis is what transcriptional changes in the adult are associated with the seasonal forms, and how ageing differs between the seasons. Together, these data contribute to a better mechanistic understanding of plastic responses as adaptation to environmental variation, and provide starting points for research into mechanisms linking development and ageing in humans, and how events during early development can affect lifespan and human health. Show less
DNA damage, mutations and genomic instability are established driving forces of cancer and other age-related diseases. Mutations in tumor suppressor genes and oncogenes are very frequently found in... Show moreDNA damage, mutations and genomic instability are established driving forces of cancer and other age-related diseases. Mutations in tumor suppressor genes and oncogenes are very frequently found in tumors and genomic instability is the most common enabling characteristic of cancer. Aging is also believed to be enabled, amongst others, by genomic instability. DNA repair pathways, like the nucleotide excision repair (NER) pathway and cell cycle control (e.g. p53-dependent) processes are therefore vital to organisms, since these processes counteract or prevent genomic instability, and are thought to underlie, when affected, aging and age-related diseases like cancer. To unravel the functions, mechanisms and pathways involved in the onset of aging and age-related diseases we have investigated several mouse models deficient in either DNA repair (NER) capacity (Chapter 3, 4), cell cycle control (p53) (Chapter 6) or both (Chapter 5), and compared this to a wild type situation (Chapter 2). The use of mouse models enabled us to investigate cancer and aging in a controlled environment, minimizing possible confounding factors. Additionally, the mouse models can be useful as an alternative tool to identify genotoxic and non-genotoxic carcinogens that can be harmful to the society and the environment (Chapter 5). Show less
With the ever-increasing life expectancies of people, the prevalence of aging-related diseases is also increasing. We studied a unique cohort of people; offspring of nonagenarian siblings with the... Show moreWith the ever-increasing life expectancies of people, the prevalence of aging-related diseases is also increasing. We studied a unique cohort of people; offspring of nonagenarian siblings with the propensity for longevity were also recruited and compared to their partners, representing the general population. The offspring (~60 year old) already show lower prevalence of cardiovascular disease and diabetes. In the thesis __Cellular stress in vitro and longevity on vivo__ it is reported how cells (dermal fibroblasts) derived from these offspring were compared with cells from their partners. It was shown that they react differenly in vitro under both non stressed and under conditions of oxidative stress. Future research is warranted to further elucidate the genes involved in these differences. Show less
This thesis discusses the metabolic and endocrine characteristics of long-lived Dutch families. We found that familial longevity is marked by low thyroid function and preserved insulin senitivity.... Show moreThis thesis discusses the metabolic and endocrine characteristics of long-lived Dutch families. We found that familial longevity is marked by low thyroid function and preserved insulin senitivity. The second part of this thesis adresses the Gompertz law of mortality as an estimate of the rate of senescence Show less
Stress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid... Show moreStress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid receptors as nuclear transcription factors. The lack of the p66Shc gene reduces OS and increases lifespan in mice. Main aim of the study was to elucidate whether the interactions linking OS and the neuroendocrine system represent a crucial determinant of aging in p66Shc-/- mice. Thus, the contribution of p66Shc to behaviour and neuroendocrine regulations was assessed from early post-natal life to senescence. Mutant old mice were characterized by a slow-down in physical and emotional aging; adult subjects showed increased behavioural plasticity and lower emotionality associated to increased central levels of Brain-derived neurotrophic factor, reduced oxidative stress markers and greater resilience to stress-induced changes in the internal milieu. A role has been recently described for p66Shc in regulating energetic metabolism. Intriguingly, we found metabolic and emotional aspects to be strictly related and possibly mediated by maternal behaviour in these mutants. Our results shed light on the role played by OS and metabolism in longevity and emotionality/mood disorders and point to p66Shc as a candidate gene in the trade-off between fertility and lifespan. Show less
Lifespan in under genetic control. In this thesis we translated genes regulating lifespan in model organisms to humans. First we identified DAF-12 as a critical gene for lifespan regulation in the... Show moreLifespan in under genetic control. In this thesis we translated genes regulating lifespan in model organisms to humans. First we identified DAF-12 as a critical gene for lifespan regulation in the nematode worm C. elegans. Then we found that the Liver X Receptors and the Vitamin D Receptor are the most similar human proteins. We tested these genetic variation in these human genes in the Leiden 85-plus Study and found them to associate with with lifespan and cognitive decline respectively. Apolipoprotein E is a target gene of the Liver X Receptor. We found that plasma levels of apolipoprotein E associated with increased risk of cardiovascular mortality, cognitive decline and stroke in a manner independent of classical cardiovascular risk factors. Finally we reviewed the evidence from human candidate gene studies. We conclude that the use of model organisms provides useful directions for research into the genetics of human longevity. However, as the human signalling systems are more complex and our environment is different from that of model organisms, it is unclear to what extent results obtained in model organisms can be extrapolated to humans. Show less
In this thesis the reproducibility of new methods using MRI for measuring total cerebral blood flow and cerebrovascular reserve capacity was assessed. We used these methods to show that NO is an... Show moreIn this thesis the reproducibility of new methods using MRI for measuring total cerebral blood flow and cerebrovascular reserve capacity was assessed. We used these methods to show that NO is an important factor in the hypoxia induced vasodilatation of vessels in the brain. It was shown that basal total cerebral blood flow in the elderly, in contrary to the young, is dependent on the NO pathway. White matter hyperintensities are seen in almost every elderly subject. We showed that besides the white matter hyperintensities there are also change because of aging in the normal appearing white matter. This was demonstrated with the use of magnetization transfer imaging. The appearance of the white matter hyperintensities seems to be independent of the changes in the normal appearing white matter which gives rise to the idea that both entities have different aetiologies. Using this technique we also showed that not all white matter hyperintensities are the same but that differences exists between white matter hyperintensities periventricular and in the deep white matter. Also, differences between frontal and occipital located periventricular white matter hyperintensities exists. Finally, we found that cognitive decline in the elderly is associated with a diminished total cerebral blood flow. Show less
