The thesis describes the study design and primary outcomes of two challenge studies: one with recombinant human thyroid-stimulating hormone, and the other with triiodothyronine, in members of the... Show moreThe thesis describes the study design and primary outcomes of two challenge studies: one with recombinant human thyroid-stimulating hormone, and the other with triiodothyronine, in members of the Leiden Longevity Study. Show less
Plant architecture has distinct forms in different plant species, but also within a species the finalarchitecture of a plant is determined by its gradual development and changes therein induced by... Show morePlant architecture has distinct forms in different plant species, but also within a species the finalarchitecture of a plant is determined by its gradual development and changes therein induced by environmental conditions during the plant’s life cycle. Higher plants have the ability tocontinually produce new organs and tissues during their lifetime. This unique ability is provided by pools of stem cells organized in so-called meristems. Primary meristems located at apices, of the plant body are involved in elongation of the main plant axes, whereas secondary meristems in lateral positions play a role in branching and axis thickening. First chapter is reviewing the current advances in our understanding of the molecular mechanisms that regulate plant meristems and their developmental phase transitions in Arabidopsis thaliana. AT-HOOK MOTIF NUCLEAR LOCALIZED (AHL) gene family is introduced in chapter 1,and that of family member AHL15 described and studied more in detail in chapter 2. In chapter 3 we identified a new branch of the ageing pathway in Arabidopsis, in which the longevity-promoting AHL15 protein represses ageing independent of miR156/157. Chapter 4 of this thesis focuses on AHL15's effect on Arabidopsis vascular cambium activity and secondary growth. Analysis showed that in an ahl15 loss-of-function mutant, interfascicular secondary growth is significantly reduced. Show less
Throughout this thesis, human aging and its relation to health are studied in the context of two parallel though complementary lines of research: biomarkers and genetics. The search for informative... Show moreThroughout this thesis, human aging and its relation to health are studied in the context of two parallel though complementary lines of research: biomarkers and genetics. The search for informative biomarkers of aging focuses on easy accessible and quantifiable substances of the body that can be used to predict the early signs of deteriorating health, prior to the development of overt age-related disease. The challenge in this field is to translate the molecular changes captured by omics platforms to the age-associated deterioration observed at the whole body-level. In this thesis, new integrative methodology was developed that lead to the identification of gene expression networks that serve as biomarkers for aging and mortality. The second part of this thesis is aimed at identifying genetic determinants that predispose to a decelerated rate of aging and an extension of life span. Using whole genome sequencing data created in 218 nonagenarians of the Leiden Longevity Study we observed that a long life is not necessarily hampered by potentially premalignant somatic mutations in either TET2 or DNMT3A. In addition, genetic variation at chr13q34 attenuating the thyroid function, may be beneficial at middle age, but seems to contribute causally to increased mortality above 90 years. Show less
Although both ICD and CRT have proven to be an effective treatment strategy for selected patients in large clinical trials, many issues of the effects of defibrillator treatment in routine clinical... Show moreAlthough both ICD and CRT have proven to be an effective treatment strategy for selected patients in large clinical trials, many issues of the effects of defibrillator treatment in routine clinical practice remain unclear. In the current thesis, some of these unresolved questions are clarified based on data from a large cohort of ICD and CRT-D patients with long-term follow-up in routine clinical practice. In the first part the thesis was specifically focused on clinical aspects such as pocket related complications, the mode of death, ventricular arrhythmias and the suitability for subcutaneous device implantation in ICD recipients. In the second part the thesis was focused on socio-economic implications of ICD therapy such as the cost-effectiveness of ICD therapy, device longevity and an evidence-based approach regarding driving restrictions in ICD patients. In addition, the last chapter focused on the development and implementation of criteria that allow better identification of high risk patients and to limit the number of defibrillator implants in patients who will not benefit Show less
This thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In... Show moreThis thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In the first part, we describe evidence for enhanced glucose metabolism in long-lived families. Middle-aged individuals predisposed to longevity were characterized by enhande insulin action at the level of the skeletal muscle, lower accumulation of intramyocellular lipids and lower nocturnal glucose levels. These results have provided the biological basis upon which health-promoting intervention in older age may be funded. In the second part, we have shonw that an internet-based intervention is effective at increasing physical activity and improving health in an older population. Furthermore, increasing total daily physical activity in sedentary elderly was shown to lead to better metabolic health. 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 prediction of coronary heart disease (CHD) risk is currently based on traditional risk factors (TRFs) like age, sex, lipid levels, blood pressure. Here we investigated, using the CAREMA cohort,... Show moreThe prediction of coronary heart disease (CHD) risk is currently based on traditional risk factors (TRFs) like age, sex, lipid levels, blood pressure. Here we investigated, using the CAREMA cohort, whether this prediction can potentially be improved by applying a metabolomics approach and by including information on single nucleotide polymorphisms (SNPs) previously reported to be relevant for cardiovascular disease risk. Based on the results described in this thesis it can be concluded that a metabolomics profile generated by 1H-NMR spectroscopy when combined with age and sex could mark individuals at high risk for cardiovascular disease. The performance of that method was comparable to a score based on TRFs. It was also found that a weighted genetic risk score based 29 SNPs associated with CHD marginally improved CHD risk prediction. In the Leiden Longevity Study it was examined if comprehensive lipid profiles could mark metabolic health in middle-aged individuals. We found that male metabolic health was characterized by LDL particle size and female metabolic health was characterized by triglyceride levels. Finally it was observed that an increased delta-5 desaturase activity was protective against CHD. This effect was mainly observed in AA carriers of a SNP located in FADS1 Show less
The aim of this thesis was to identify in the human blood transcriptome, relevant pathways and potential biomarker profiles that associate with chronological age and discriminate between __healthy... Show moreThe aim of this thesis was to identify in the human blood transcriptome, relevant pathways and potential biomarker profiles that associate with chronological age and discriminate between __healthy agers__ from long-lived families and normative ageing controls. Such profiles may harbor determinants of the biological ageing rate. We studied genome-wide gene expression profiles in blood of members of the Leiden Longevity Study (LLS) and replicated our findings by extended sampling within the unique LLS cohort. The findings of the exploratory analysis prompted us to investigate multiple genes in the IL7R and MTOR pathways for association with familial longevity. The results obtained by examining mRNA from blood samples brought us to study mTOR protein levels and signalling in primary skin fibroblasts from the corresponding donors in the LLS. Finally, to discover robust, biologically relevant gene networks as markers of chronological ageing in larger sample sizes, we performed an explorative network-based meta-analysis on large publicly available transcriptomic datasets. We have identified several networks, pathways and candidate genes potentially marking the biological age and the rate of ageing Show less
This thesis investigated the effect of several risk factors on objectively assessed disease progression (renal function decline and time until the start of renal replacement therapy) and... Show moreThis thesis investigated the effect of several risk factors on objectively assessed disease progression (renal function decline and time until the start of renal replacement therapy) and subjectively assessed disease progression (disease-related symptoms and health-related quality of life) in patients with chronic kidney disease on specialized pre-dialysis care. Furthermore, we explored (un)known mechanisms that may determine renal function decline in pre-dialysis patients. The conclusions are: low blood pressure, low proteinuria levels, and low cholesterol levels are associated with a slower objectively assessed disease progression. However, in elderly patients low blood pressure is a marker for an earlier start of renal replacement therapy. Concerning subjectively assessed disease progression, only in young patients treated with anemia-medication, high hemoglobin levels are associated with a better health-relate d quality of life. Furthermore, symptoms increase and health-related quality of life decreases during pre-dialysis care. Therefore, these markers are good candidates for defining the optimal moment to start with dialysis. This thesis also showed that black patients experience a faster renal function decline than white patients. A possible explanation could be the stronger negative consequences of diabetes mellitus in black patients. Finally, at middle-age, renal function is higher in longevity families, revealing possible new genetic mechanisms. Show less
The findings presented in this thesis fit the hypothesis that optimism is associated with enhanced mental well-being and longevity, but also that levels of optimism within a certain person are... Show moreThe findings presented in this thesis fit the hypothesis that optimism is associated with enhanced mental well-being and longevity, but also that levels of optimism within a certain person are rather stable over time and resistant to change. However, this stability of optimism does not necessarily imply that no fluctuations in optimism are possible. Certain positive or negative life events are likely to provoke small (but temporary) changes in optimism. But it is possible that dispositional optimism can hardly be learned and that only little changes are possible in an otherwise relatively stable personality trait. Thoughtfully designed future clinical and epidemiologic studies are required to explore the potential benefits of optimism. But it certainly would not hurt __ and it might put a smile on your face__ to see the glass half full. 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
Markers for longevity, which reflect the health condition and predict healthspan are extremely scarce. Such markers are, however, valuable in aging research. Protein N-glycosylation is an important... Show moreMarkers for longevity, which reflect the health condition and predict healthspan are extremely scarce. Such markers are, however, valuable in aging research. Protein N-glycosylation is an important post-translational modification, which has been shown to be altered in several pathological conditions. N-glycosylation patters therefore reflect an individual__s health state, and have therefore the potential to become candidate biomarkers for healthspan. To investigate familial longevity, large sample cohorts are necessary, and since no high-throughput analysis methods were available to facilitate Large scale N-glycan analysis, several methods, comprising HPLC-FL, CGE-LIF and MALDI-MS have been developed. These methods were applied to samples from the Leiden Longevity Study. Several changes in N-glycosylation patterns associated with familial longevity were observed in this thesis. As the predictive value of these markers is rather low, it has to be concluded that multiple markers are needed for the prediction of complex phenotypes like familial longevity. It is anticipated that __ apart from allowing more detailed insight in the processes underlying aging and longevity- the developed methodology will as well be of considerable value to other fields of biomedical research. Show less
Sustainability challenges raised by built environment development are two-folds: on the inflow side these include resource depletion and emission problems due to material production (pre-use); on... Show moreSustainability challenges raised by built environment development are two-folds: on the inflow side these include resource depletion and emission problems due to material production (pre-use); on the outflow side they include problems of construction and demolition waste (after-use). Understanding how the future construction inflow and demolition outflow will develop is essential for early recognition of these problems. A traditional approach is through extrapolation, which is risky because changes of trends may occur. A Dynamic Material Flow Analysis approach, based on the Law of Mass Preservation, provides a better framework for long-term projection. The challenge is to understand the dynamics of the built environment stocks. It is especially true for the emerging countries, where the combined influences of rapid economic development and urbanization have to be considered but are yet rarely investigated. This thesis develops the currently available approaches by including general socio-economic and specific urbanization-driven factors in China. Case studies on Chinese housing stock dynamics indicate: demolition activities in Chinese cities will continue to grow throughout the rest of the 21st century; a shrinking demand for residential steel may be expected over the next few decades, which may lead to a decrease in global steel consumption of up to 10%. 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
The general aim of the work described in this thesis is to help explain the variation in ageing by using the life history framework of B. anynana. Each chapter focuses on a different aspect of the... Show moreThe general aim of the work described in this thesis is to help explain the variation in ageing by using the life history framework of B. anynana. Each chapter focuses on a different aspect of the life history, together giving a complete picture of the origins of variation in ageing in this species. A central theme to every chapter is the relative influence of genes, the environment, and how they related to plasticity. A summarising discussion of all chapters, and a perspective on how the ideas in this thesis will contribute to ageing research in the future is also included. Show less
Genetic factors play an important role in the regulation of human life span but the exact pathways remain to be elucidated, however they may be interrelated with the regulation of human... Show moreGenetic factors play an important role in the regulation of human life span but the exact pathways remain to be elucidated, however they may be interrelated with the regulation of human reproduction. It is argued that an innate cytokine profile supportive of Th1-type T cells favors survival of infectious diseases (with longevity as the ultimate), but women with this profile are found less likely to have successful pregnancies (progeny). The probability of a normal fertility was found to increase more than 10-fold when the innate cytokine profile was characterized by high IL-10 (Th-2 cytokine) and low TNF- (Th-1 cytokine) responsiveness. The IL10 –2849 AA genotype was found to be associated with a decreased fertility and fecundity (time to pregnancy) in females, possibly due to the lower expected IL10 responsiveness. Rheumatoid arthritis (RA) is an example of a Th-1 mediated disease. It was found that the phenotype of joint destruction in RA was associated with the phenotype of reported miscarriages, suggesting common genetic risk factors for each of these two traits, possibly through the innate Th-1/Th-2 phenotype. Factor V Leiden (FVL) is a point mutation in the factor V gene generating a 7-fold increase in incidence of deep vein thrombosis. Specific advantages of the FVL mutation in early pregnancy (implantation) might balance its potentially harmful effects later in life and explain the remarkably high prevalence of this mutation in the general population. Show less
