Research questionAre age at last childbirth and number of children, as facets of female reproductive health, related to individual lifespan or familial longevity?DesignThis observational study... Show moreResearch questionAre age at last childbirth and number of children, as facets of female reproductive health, related to individual lifespan or familial longevity?DesignThis observational study included 10,255 female participants from a multigenerational historical cohort, the LINKing System for historical family reconstruction (LINKS), and 1258 female participants from 651 long-lived families in the Leiden Longevity Study (LLS). Age at last childbirth and number of children, as outcomes of reproductive success, were compared with individual and familial longevity using the LINKS dataset. In addition, the genetic predisposition in the form of a polygenic risk score (PRS) for age at menopause was studied in relation to familial longevity using the LLS dataset.ResultsFor each year increase in the age of the birth of the last child, a woman's lifespan increased by 0.06 years (22 days; P = 0.002). The yearly risk for having a last child was 9% lower in women who survived to the oldest 10% of their birth cohort (hazard ratio 0.91, 95% CI 0.86–0.95). Women who came from long-living families did not have a higher mean age of last childbirth. There was no significant association between familial longevity and genetic predisposition to age at menopause.ConclusionsFemale reproductive health associates with a longer lifespan. Familial longevity does not associate to extended reproductive health. Other factors in somatic maintenance that support a longer lifespan are likely to have an impact on reproductive health. Show less
The studies in this thesis jointly led to an evidence-based, expert-based and experience-based conceptualization of the challenging rehabilitation environment in five clusters. This... Show moreThe studies in this thesis jointly led to an evidence-based, expert-based and experience-based conceptualization of the challenging rehabilitation environment in five clusters. This conceptualization has been incorporated into the CREATE-tool, a team-self assessment tool that can be used to implement and evaluate the challenging rehabilitation environment in geriatric rehabilitation departments.This CREATE-tool is able to identify areas for improvement for the challenging rehabilitation environment at ward level and professionals are satisfied with the use of the tool. Show less
Over the past decade, the abundance of high-throughput omics approaches coupled with the use of machine learning techniques, has made it possible to investigate the full molecular complexity of... Show moreOver the past decade, the abundance of high-throughput omics approaches coupled with the use of machine learning techniques, has made it possible to investigate the full molecular complexity of health and aging. The primary forcus of this thesis was to study and improve biological aging prediction. To achieve this we developed, evaluated, and deployed state-of-the-art models predicting different aspects of human health risks by employing multiple omics measurement, with a particular attention given to 1H-NMR metabolomics. Availability, affordability, interpretability, and robustness of the 1H-NMR metabolomics platform by Nightingale Health makes it a powerful tool with implications in the risk prediction of common diseases. We explored this research line in epidemiological settings within the BBMRI-nl consortium, which incorporates 28 cohorts with various specific characteristics. Hence, we took advantage of the wide range of health statuses when examining the extensive BBMRI datasets, investigated specific subgroups such as elderly or night-working individuals respectively recruited for the Leiden Longevity Study (LLS) and LIFELINES, and even explored the potential complementarity and interaction of different omics (e.g., 1H-NMR metabolomics, DNA methylome) available within the subset known as BIOS Consortium. Show less
Geurkink, T.H.; Overbeek, C.L.; Marang-van de Mheen, P.J.; Nagels, J.; Nelissen, R.G.H.H.; Groot, J.H. de 2023
Purpose: This study aimed to quantify the extent to which age was associated with joint position sense (JPS) of the asymptomatic shoulder as measured by joint position reproduction (JPR) tasks and... Show morePurpose: This study aimed to quantify the extent to which age was associated with joint position sense (JPS) of the asymptomatic shoulder as measured by joint position reproduction (JPR) tasks and assess the reproducibility of these tasks. Methods: 120 Asymptomatic participants aged 18-70 years each performed 10 JPR-tasks. Both contralateral and ipsilateral JPR-tasks were evaluated on accuracy of JPR under active-and passive conditions at two levels within the shoulder forward flexion trajectory. Each task was performed three times. In a subgroup of 40 participants, the reproducibility of JPR-tasks was assessed one week after initial measurement. Reproducibility of JPR-tasks was evaluated by both reliability (intra-class correlation coefficients (ICC's)) and agreement (standard error of measurement (SEM)) measures. Results: Age was not associated with increased JPR-errors for any of the contralateral or ipsilateral JPR-tasks. ICC's ranged between 0.63 and 0.80 for contralateral JPR-tasks, and from 0.32 to 0.48 for ipsilateral tasks, except for one ipsilateral task where the reliability was similar to contralateral tasks (0.79). The SEM was comparable and small for all JPR-tasks, ranging between 1.1 and 2.1. Conclusion: No age-related decline in JPS of the asymptomatic shoulder was found, and good agreement between test and re-test measurements for all JPR-tasks as indicated by the small SEM. Show less
Geurkink, T.H.; Overbeek, C.L.; Marang-van de Mheen, P.J.; Nagels, J.; Nelissen, R.G.H.H.; Groot, J.H. de 2023
PurposeThis study aimed to quantify the extent to which age was associated with joint position sense (JPS) of the asymptomatic shoulder as measured by joint position reproduction (JPR) tasks and... Show morePurposeThis study aimed to quantify the extent to which age was associated with joint position sense (JPS) of the asymptomatic shoulder as measured by joint position reproduction (JPR) tasks and assess the reproducibility of these tasks.Methods120 Asymptomatic participants aged 18–70 years each performed 10 JPR-tasks. Both contralateral and ipsilateral JPR-tasks were evaluated on accuracy of JPR under active- and passive conditions at two levels within the shoulder forward flexion trajectory. Each task was performed three times. In a subgroup of 40 participants, the reproducibility of JPR-tasks was assessed one week after initial measurement. Reproducibility of JPR-tasks was evaluated by both reliability (intra-class correlation coefficients (ICC’s)) and agreement (standard error of measurement (SEM)) measures.ResultsAge was not associated with increased JPR-errors for any of the contralateral or ipsilateral JPR-tasks. ICC’s ranged between 0.63 and 0.80 for contralateral JPR-tasks, and from 0.32 to 0.48 for ipsilateral tasks, except for one ipsilateral task where the reliability was similar to contralateral tasks (0.79). The SEM was comparable and small for all JPR-tasks, ranging between 1.1 and 2.1.ConclusionNo age-related decline in JPS of the asymptomatic shoulder was found, and good agreement between test and re-test measurements for all JPR-tasks as indicated by the small SEM. Show less
Geurkink, T.H.; Overbeek, C.L.; Marang-van de Mheen, P.J.; Nagels, J.; Nelissen, R.G.H.H.; Groot, J.H. de 2023
Purpose: This study aimed to quantify the extent to which age was associated with joint position sense (JPS) of the asymptomatic shoulder as measured by joint position reproduction (JPR) tasks and... Show morePurpose: This study aimed to quantify the extent to which age was associated with joint position sense (JPS) of the asymptomatic shoulder as measured by joint position reproduction (JPR) tasks and assess the reproducibility of these tasks.Methods: 120 Asymptomatic participants aged 18-70 years each performed 10 JPR-tasks. Both contralateral and ipsilateral JPR-tasks were evaluated on accuracy of JPR under active-and passive conditions at two levels within the shoulder forward flexion trajectory. Each task was performed three times. In a subgroup of 40 participants, the reproducibility of JPR-tasks was assessed one week after initial measurement. Reproducibility of JPR-tasks was evaluated by both reliability (intra-class correlation coefficients (ICC's)) and agreement (standard error of measurement (SEM)) measures. Results: Age was not associated with increased JPR-errors for any of the contralateral or ipsilateral JPR-tasks. ICC's ranged between 0.63 and 0.80 for contralateral JPR-tasks, and from 0.32 to 0.48 for ipsilateral tasks, except for one ipsilateral task where the reliability was similar to contralateral tasks (0.79). The SEM was comparable and small for all JPR-tasks, ranging between 1.1 and 2.1.onclusion: No age-related decline in JPS of the asymptomatic shoulder was found, and good agreement between test and re-test measurements for all JPR-tasks as indicated by the small SEM. Show less
In the young and healthy shoulder, cranially directed forces during abduction are counteracted by co-contraction of the rotator cuff muscles. In this way, it is prevented that the humerus moves... Show moreIn the young and healthy shoulder, cranially directed forces during abduction are counteracted by co-contraction of the rotator cuff muscles. In this way, it is prevented that the humerus moves cranially towards the acromion, thus entrapping subacromial tissues. During ageing however, shoulder tissues are subject to marked degeneration, which particularly concerns the rotator cuff muscles. This may have two consequences. First, due to reduced contribution of the upper parts of the rotator cuff to the abduction movement, the deltoid has to compensate, which results in a more cranially, instead of mediocranially directed force. Second, reduced stabilising force by the rotator cuff may jeopardise counteraction of cranial deltoid forces. These changes could lead to cranialisation of the humerus with painful compression of subacromial tissues, as observed in patients with Subacromial Pain Syndrome (SAPS). Previous studies have shown that by co-contraction of arm adductors, humeral-head depression may be accomplished, for the purpose of unloading subacromial tissues. In this thesis, we investigated the role of adductor co-contraction in the ageing asymptomatic population and in patients with SAPS. This has resulted in eight scientific publications with which the fundaments for evidence-based therapy in SAPS have been built, with as cornerstone training of adductor co-contraction. Show less
Currently immunomodulatory compounds are under investigation for use in patients with cardiovascular disease, caused by atherosclerosis. These trials, using recurrent cardiovascular events as... Show moreCurrently immunomodulatory compounds are under investigation for use in patients with cardiovascular disease, caused by atherosclerosis. These trials, using recurrent cardiovascular events as endpoint, require enrollment of large patient groups. We investigated the effect of key risk factors for atherosclerosis development, ageing and smoking, on the immune system, with the objective to identify biomarkers differentiating between human populations, and potentially serving as endpoints for future phase 1B trials with immunomodulatory compounds. Blood was collected from young healthy volunteers (aged 18-25 years, n=30), young smokers (18-25 years, n=20), elderly healthy volunteers (>60 years, n=20), heavy smokers (>45 years, 15 packyears, n=11) and patients with stable coronary artery disease (CAD) (>60 years, n=27). Circulating immune cell subsets were characterized by flow cytometry, and collected plasma was evaluated by proteomics (Olink). Clear ageing effects were observed, mostly illustrated by a lower level in CD8+ and naïve CD4+ and CD8+ T cells, with an increase in CD4+ and CD8+ effector memory T cells in elderly healthy volunteers compared to young healthy volunteers. Heavy smokers showed a more inflammatory cellular phenotype, especially a shift in Th1/Th2 ratio: higher Th1 and lower Th2 percentages compared to young healthy volunteers. A significant decrease in circulating atheroprotective oxLDL-specific IgM was found in patients with CAD compared to young healthy volunteers. Elevated pro-inflammatory and chemotactic proteins TREM1 and CCL11 were observed in elderly volunteers compared to young volunteers. In addition, heavy smokers had an increase in pro-inflammatory cytokine IL-6 and lysosomal protein LAMP3. These data show that ageing and smoking are associated with an inflammatory immunophenotype, and that heavy smokers or aged individuals may serve as potential populations for future clinical trials investigating immunomodulatory drugs targeted for cardiovascular disease. Show less
Background Health-related quality of life (HRQoL) is an important outcome measure when considering medical treatment; however, the impact of polypharmacy on trajectories of HRQoL over time is... Show moreBackground Health-related quality of life (HRQoL) is an important outcome measure when considering medical treatment; however, the impact of polypharmacy on trajectories of HRQoL over time is unknown. This study aimed to investigate the association between polypharmacy status and trajectories of HRQoL in older adults. Methods A longitudinal cohort study of 2181 community-dwelling adults, 65 years and older, who participated in the 2013 to 2017 waves of the Household Income and Labour Dynamics in Australia (HILDA) Survey. Polypharmacy was defined as the regular use of >= 5 prescription medications. Polypharmacy status was categorised into no polypharmacy, in 2013 only (baseline only polypharmacy), in 2017 only (incident polypharmacy) or at both time points (persistent polypharmacy). HRQoL was assessed through the SF-36 questionnaire generating two summary scores: physical component summary (PCS) and mental component summary (MCS). Linear mixed-effects models stratified according to polypharmacy status and change in comorbidities were used to assess trajectories of HRQoL. Results Older adults with persistent polypharmacy had lowest scores for HRQoL measures from 2013 to 2017. After adjusting for all covariates, those with incident polypharmacy had the steepest annual decline in both the PCS and MCS: - 0.86 in PCS and - 0.76 in MCS for those with decreasing or stable comorbidities, and - 1.20 in PCS and - 0.75 in MCS for those with increasing comorbidities. Conclusions Polypharmacy was associated with poorer HRQoL, even after adjusting for confounders. Incident polypharmacy was found to be associated with a clinically important decline in HRQoL and this should be considered when prescribing additional medication to older adults. Show less
Introduction: Although increased cholesterol level has been acknowledged as a risk factor for dementia, evidence synthesis based on published data has yielded mixed results. This is especially... Show moreIntroduction: Although increased cholesterol level has been acknowledged as a risk factor for dementia, evidence synthesis based on published data has yielded mixed results. This is especially relevant in older adults where individual studies report non-linear relationships between cholesterol and cognition and, in some cases, find higher cholesterol associated with a lower risk of subsequent cognitive decline or dementia. Prior evidence synthesis based on published results has not allowed us to focus on older adults or to standardize analyses across studies. Given our ageing population, an increased risk of dementia in older adults, and the need for proportionate treatment in this age group, an individual participant data (IPD) meta-analysis is timely. Method: We combined data from 8 studies and over 21,000 participants aged 60 years and over in a 2-stage IPD to examine the relationship between total, high-density, and low-density lipoprotein (HDL and LDL) cholesterol and subsequent incident dementia or cognitive decline, with the latter categorized using a reliable change index method. Results: Meta-analyses found no relationship between total, HDL, or LDL cholesterol (per millimoles per litre increase) and risk of cognitive decline in this older adult group averaging 76 years of age. For total cholesterol and cognitive decline: odds ratio (OR) 0.93 (95% confidence interval [CI] 0.86: 1.01) and for incident dementia: OR 1.01 [95% CI 0.89: 1.13]. This was not altered by rerunning the analyses separately for statin users and non-users or by the presence of an APOE e4 allele. Conclusion: There were no clear consistent relationships between cholesterol and cognitive decline or dementia in this older adult group, nor was there evidence of effect modification by statin use. Further work is needed in younger populations to understand the role of cholesterol across the life-course and to identify any relevant intervention points. This is especially important if modification of cholesterol is to be further evaluated for its potential influence on risk of cognitive decline or dementia. Show less
The shoulder joint is a frequent anatomic site of musculoskeletal pain. Most middle-aged adults with shoulder pain have been diagnosed with subacromial bursitis, or subacromial impingement syndrome... Show moreThe shoulder joint is a frequent anatomic site of musculoskeletal pain. Most middle-aged adults with shoulder pain have been diagnosed with subacromial bursitis, or subacromial impingement syndrome. Attrition underneath the acromion have been presumed to cause painful inflammation of subacromial tissues for years, but scientific evidence was limited. The real cause for subacromial pain is still unknown, which resulted in the diagnostic label “subacromial pain syndrome”. In this thesis, we focused on the effectiveness of acromioplasty in the treatment of patients with subacromial pain. We found no effect of acromioplasty over bursectomy alone on long-term shoulder pain and function. We also examined shoulder kinematics and muscle activation in patients with subacromial pain. We found an association between the size of rotator cuff tears as well as subacromial pain syndrome with shoulder kinematics, and described an increase in teres major muscle activity in subacromial pain syndrome. The project contributed to changed recommendations in guidelines regarding the treatment of subacromial pain syndrome. Our kinematic and biomechanical studies may create a biomechanical rationale for physiotherapeutic strategies targeted at the teres major muscle in the treatment of subacromial pain. Show less
Bacalini, M.G.; Reale, A.; Malavolta, M.; Ciccarone, F.; Moreno-Villanueva, M.; Dolle, M.E.T.; ... ; Zampieri, M. 2021
Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give... Show moreAgeing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated. 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
Purpose The tumour microenvironment in older patients is subject to changes. The tumour-stroma ratio (TSR) was evaluated in order to estimate the amount of intra-tumoural stroma and to evaluate the... Show morePurpose The tumour microenvironment in older patients is subject to changes. The tumour-stroma ratio (TSR) was evaluated in order to estimate the amount of intra-tumoural stroma and to evaluate the prognostic value of the TSR in older patients with breast cancer (>= 70 years). Methods Two retrospective cohorts, the FOCUS study (N = 619) and the Nottingham Breast Cancer series (N = 1793), were used for assessment of the TSR on haematoxylin and eosin stained tissue slides. Results The intra-tumoural stroma increases with age in the FOCUS study and the Nottingham Breast Cancer series (B 0.031, 95% CI 0.006-0.057, p = 0.016 and B 0.034, 95% CI 0.015-0.054, p < 0.001, respectively). Fifty-one per cent of the patients from the Nottingham Breast Cancer series < 40 years had a stroma-high tumour compared to 73% of the patients of >= 90 years from the FOCUS study. The TSR did not validate as an independent prognostic parameter in patients >= 70 years. Conclusions The intra-tumoural stroma increases with age. This might be the result of an activated tumour microenvironment. The TSR did not validate as an independent prognostic parameter in patients >= 70 years in contrast to young women with breast cancer as published previously. Show less
Luo, J.; Mills, K.; Cessie, S. le; Noordam, R.; Heemst, D. van 2020
Among other mechanisms, oxidative stress has been postulated to play an important role in the rate of ageing. Oxidative damage contributes to the hallmarks of ageing and essential components in... Show moreAmong other mechanisms, oxidative stress has been postulated to play an important role in the rate of ageing. Oxidative damage contributes to the hallmarks of ageing and essential components in pathological pathways which are thought to drive multiple age-related diseases. Nonetheless, results from studies testing the hypothesis of oxidative stress in ageing and diseases showed controversial results. While observational studies mainly found detrimental effects of high oxidative stress levels on disease status, randomized clinical trials examining the effect of antioxidant supplementation on disease status generally showed null effects. However, re-evaluations of these counterinitiative observations are required considering the lack of reliability and specificity of traditionally used biomarkers for measuring oxidative stress. To facilitate these re-evaluations, this review summarizes the basic knowledge of oxidative stress and the present findings regarding the role of oxidative damage in ageing and age-related diseases. Meanwhile, two approaches are highlighted, namely proper participants selection, together with the development of reliable biomarkers. We propose that oxidized vitamin E metabolites may be used to accurately monitor individual functional antioxidant level, which might serve as promising key solutions for future elucidating the impact of oxidative stress on ageing and age-related diseases. Show less
Maintenance and repair is of key importance for the proper functioning of cells, tissues, and integrated physiology. We hypothesize that the balance between investments in growth, development, and... Show moreMaintenance and repair is of key importance for the proper functioning of cells, tissues, and integrated physiology. We hypothesize that the balance between investments in growth, development, and reproduction versus maintenance and repair is regulated by the brain. Specifically (the interplay of) hormones of the different hypothalamic-pituitary-target gland axes seem to be key regulators in constantly adjusting this balance to its optimal state. This thesis describes the associations between familial longevity and hormones of different hypothalamic-pituitary-target gland axes. In Chapter 2, the question is addressed whether circulating insulin-like growth factor 1 (IGF‐1) axis parameters associate with old age survival and functional status in nonagenarians from the LLS. In Chapter 3, we use growth hormone (GH) concentrations measured every 10 min over 24 h to derive and compare GH secretion parameters between offspring of long-lived families and their partners. In Chapter 4, we investigate the association between hypothalamic-pituitary-gonadal axis parameters and familial longevity. In Chapter 5, we use 24-h time series data of pituitary hormones to investigate how changes in the different hormonal axes are correlated with each other over time. In Chapter 6, we determine the circadian rhythm of bone turnover markers in healthy older subjects. Show less
Introduction: The ageing process can be influenced by different dietary patterns and dietary factors.Aim: To analyse the association of dietary factors, which include the Mediterranean diet... Show moreIntroduction: The ageing process can be influenced by different dietary patterns and dietary factors.Aim: To analyse the association of dietary factors, which include the Mediterranean diet adherence, the compliance with the "Sociedad Espanola de Nutricion Comunitaria" food portion recommendations, and the intake of different food groups, with the secreted form of the alpha-Klotho gene (S-Klotho as an anti-ageing marker) in middle-aged sedentary adults.Methods: A total of 74 (39 women) middle-aged sedentary adults participated in the study. Dietary factors were assessed with a food frequency questionnaire and the PREDIMED questionnaire. The S-Klotho plasma levels were measured using a soluble alpha-Klotho ELISA assay kit.Results: We observed: (i) a negative association between the adherence to the Mediterranean diet and the S-Klotho plasma levels (beta = - 53.219; R-2 = 0.078; P = 0.020), (ii) a higher intake of wine (> 7 glasses/week), was associated with lower S-Klotho plasma levels (P = 0.039), and (iii) a positive association between nuts portion intake and the S-Klotho plasma levels (beta = 26.087; R-2 = 0.070; P = 0.029). All the associations disappeared after controlling for lean mass index (LMI) (all P > 0.05).Conclusion: Our study suggests that, although dietary factors could be related to S-Klotho plasma levels in middle-aged sedentary adults, LMI is the main determinant in this regard. Show less
Kolk, A.; Zwaal, P. van der; Thomassen, B.J.W.; Kamp, E.W.C. van de; Stijnen, T.; Groot, J.H. de; Nelissen, R.G.H.H. 2018
