Aging and age-related diseases have been linked to microbial dysbiosis with changes in blood bacterial DNA concentration. This condition may promote chronic low-grade inflammation, which can be... Show moreAging and age-related diseases have been linked to microbial dysbiosis with changes in blood bacterial DNA concentration. This condition may promote chronic low-grade inflammation, which can be further aggravated by antioxidant nutrient deficiency. Low plasma carotenoids are associated with an increased risk of inflammation and cellular damage and predict mortality. However, no evidence is yet available on the relationship between antioxidants and the blood bacterial DNA (BB-DNA). Therefore, this study aimed to compare BB-DNA from (a) GO (nonagenarian offspring), (b) age-matched controls (Randomly recruited Age-Stratified Individuals from the General population [RASIG]), and (c) spouses of GO (SGO) recruited in the MARK-AGE project, as well as to investigate the association between BB-DNA, behavior habits, Charlson Comorbidity Index (CCI), leucocyte subsets, and the circulating levels of some antioxidants and oxidative stress markers. BB-DNA was higher in RASIG than GO and SGO, whereas GO and SGO participants showed similar values. BB-DNA increased in smokers and males with CCI >= 2 compared with those with CCI <= 1 within RASIG. Moreover, BB-DNA was positively associated with lymphocyte, neutrophil, and monocyte counts, but not with self-reported dietary habits. Higher quartiles of BB-DNA were associated with low lutein and zeaxanthin and elevated malondialdehyde plasma concentrations in RASIG. BB-DNA was also positively correlated with nitric oxide levels. Herein, we provide evidence of a reduced BB-DNA in individuals from long-living families and their spouses, suggesting a decreased microbial dysbiosis and bacterial systemic translocation. BB-DNA was also associated with smoking, CCI, leukocyte subsets, and some redox biomarkers in older participants. Show less
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
Rodriguez-Girondo, M.; Berg, N. van den; Hof, M.H.; Beekman, M.; Slagboom, E. 2021
Background: Although human longevity tends to cluster within families, genetic studies on longevity have had limited success in identifying longevity loci. One of the main causes of this limited... Show moreBackground: Although human longevity tends to cluster within families, genetic studies on longevity have had limited success in identifying longevity loci. One of the main causes of this limited success is the selection of participants. Studies generally include sporadically long-lived individuals, i.e. individuals with the longevity phenotype but without a genetic predisposition for longevity. The inclusion of these individuals causes phenotype heterogeneity which results in power reduction and bias. A way to avoid sporadically long-lived individuals and reduce sample heterogeneity is to include family history of longevity as selection criterion using a longevity family score. A main challenge when developing family scores are the large differences in family size, because of real differences in sibship sizes or because of missing data.Methods: We discussed the statistical properties of two existing longevity family scores: the Family Longevity Selection Score (FLoSS) and the Longevity Relatives Count (LRC) score and we evaluated their performance dealing with differential family size. We proposed a new longevity family score, the mLRC score, an extension of the LRC based on random effects modeling, which is robust for family size and missing values. The performance of the new mLRC as selection tool was evaluated in an intensive simulation study and illustrated in a large real dataset, the Historical Sample of the Netherlands (HSN).Results: Empirical scores such as the FLOSS and LRC cannot properly deal with differential family size and missing data. Our simulation study showed that mLRC is not affected by family size and provides more accurate selections of long-lived families. The analysis of 1105 sibships of the Historical Sample of the Netherlands showed that the selection of long-lived individuals based on the mLRC score predicts excess survival in the validation set better than the selection based on the LRC score .Conclusions: Model-based score systems such as the mLRC score help to reduce heterogeneity in the selection of long-lived families. The power of future studies into the genetics of longevity can likely be improved and their bias reduced, by selecting long-lived cases using the mLRC. 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
Mourits, R.J.; Berg, N. van den; Rodriguez-Girondo, M.; Mandemakers, K.; Slagboom, P.E.; Beekman, M.; Janssens, A.A.P.O. 2020
Studies have shown that long-lived individuals seem to pass their survival advantage on to their offspring. Offspring of long-lived parents had a lifelong survival advantage over individuals... Show moreStudies have shown that long-lived individuals seem to pass their survival advantage on to their offspring. Offspring of long-lived parents had a lifelong survival advantage over individuals without long-lived parents, making them more likely to become long-lived themselves. We test whether the survival advantage enjoyed by offspring of long-lived individuals is explained by environmental factors. 101,577 individuals from 16,905 families in the 1812-1886 Zeeland cohort were followed over time. To prevent that certain families were overrepresented in our data, disjoint family trees were selected. Offspring was included if the age at death of both parents was known. Our analyses show that multiple familial resources are associated with survival within the first 5 years of life, with stronger maternal than paternal effects. However, between ages 5 and 100 both parents contribute equally to offspring's survival chances. After age 5, offspring of long-lived fathers and long-lived mothers had a 16-19% lower chance of dying at any given point in time than individuals without long-lived parents. This survival advantage is most likely genetic in nature, as it could not be explained by other, tested familial resources and is transmitted equally by fathers and mothers. Show less
Lee, S.J. van der; Conway, O.J.; Jansen, I.; Carrasquillo, M.M.; Kleineidam, L.; Akker, E. van den; ... ; GIFT Genetic Invest 2019
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
Purpose: The moving rectangle method is used to disentangle the contributions of rectangularization and life span extension to the increase in life expectancy. It requires the choice of an endpoint... Show morePurpose: The moving rectangle method is used to disentangle the contributions of rectangularization and life span extension to the increase in life expectancy. It requires the choice of an endpoint of the survival curve that approaches the maximum age at death. We examined the effect of choosing different end points on the outcomes of this method. Methods: For five developed countries, survival curves from age 50 years were constructed per calendar year from 1922 onward. Survival values of 0.1, 0.01, and 0.001 were chosen as end points of the survival curve, and the contributions of rectangularization and life span extension to the increase in life expectancy were calculated using the moving rectangle method. Results: The choice of different survival values as end points profoundly influenced the estimated contributions of rectangularization and life span extension to the increase in life expectancy. When choosing 0.001, rectangularization contributed most years, whereas when choosing 0.1, life span extension contributed most years. Conclusions: When the moving rectangle method is used to estimate the contributions of rectangularization and life span extension to the increase in life expectancy, its outcomes depend on the choice of the endpoint of the survival curve. 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
Kroft, L.J.M.; Bijl, N. van der; Grond, J. van der; Altmann-Schneider, I.; Slagboom, P.E.; Westendorp, R.G.J.; ... ; Craen, A.J.M. de 2014
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
