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
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
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
In this thesis we aimed to get insight in how the methylome is established during development and subsequently degenerates during ageing using an integrative approach to the analysis of DNA... Show moreIn this thesis we aimed to get insight in how the methylome is established during development and subsequently degenerates during ageing using an integrative approach to the analysis of DNA methylation in conjunction with other levels of genomics data. The first two empirical chapters of this thesis describe the establishment and the maintenance of the epigenome during fetal development and in later life in multiple tissues. In the subsequent two chapters we investigated the loss of control over the methylome in blood and other tissues. Show less
Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories,... Show more Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories, morbidity and mortality. In the three parts of this thesis, we examined three interacting systems that have been identified as contributing to a slower pace of ageing, namely glucose/insulin metabolism (part I), the thyroid axis (part II), and the autonomic nervous system (part III). We found that familial longevity is associated with a stronger association of insulin parameters with microstructural brain parameters, and by higher TSH secretion, in the absence of differences in basal energy metabolism or differences in heart rate and its variability. Using specialized MRI techniques, we showed that subtle changes in microstructural brain parenchymal homogeneity in relation to insulin can be detected, even in brain tissue that appears normal on conventional MR imaging sequences. Insulin (rather than glucose), seemed to be a stronger indicator of micro- structural brain integrity in normo-glycemic older adults. Furthermore, intranasal application of insulin improved brain perfusion in parietal and occipital gray matter and in the thalamus of older adults. These results deepen our understanding of the physiological mechanisms and processes that underlie the ageing process. Show less
Human ageing is characterized by a gradual decline in cognitive and physical performance strongly determining someone’s functional abilities and quality of life. In this thesis, insights into... Show moreHuman ageing is characterized by a gradual decline in cognitive and physical performance strongly determining someone’s functional abilities and quality of life. In this thesis, insights into these age-related changes and most importantly their interactions are given, which might be suggestive for potential causal mechanisms and is required for the development of preventive and therapeutic paradigms. We focused on global and domain specific measures of cognitive and physical performance and assessed the interactions across different populations of calendar and biological age (range 45 to 90 years). For the assessment of physical performance, instrumented measures were introduced to assess their additional value. Across the entire age range, interactions between cognitive and physical performance were consistently found. The temporal relationship differed across age and domains, suggesting a specific rather than a general relationship. Because age-related changes were already observed from middle age, these results encourage the early and repeated assessment of cognitive and physical performance across different domains and development of age and domain specific interventions. Instrumented measures can be used for the identification of age-related changes and show promising results in providing additional insights into potential underlying determinants. This will enable the development of even more refined and patient specific interventions. Show less
With the increase in life expectancy, the prevalence of cognitive disorders is expected to rise the coming years. In this thesis we studied the association between blood pressure, cardiac... Show moreWith the increase in life expectancy, the prevalence of cognitive disorders is expected to rise the coming years. In this thesis we studied the association between blood pressure, cardiac biomarkers and cognitive function in 5800 people with mean age of 75 years. Furthermore, we investigated the feasibility to use smartphone technology to measure home blood pressure in 151 people during a 6 months follow-up period. We show that higher variability in blood pressure is associated with increased microdamage of the brain and worse cognitive function, independent of average blood pressure and use of blood pressure lowering medication. Furthermore, increased levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT), both markers of cardiac disease, are associated with worse cognitive function and steeper cognitive decline, independent of cardiovascular diseases or risks. Finally, we show that smartphone-based technology is a reliable and promising method with good adherence to measure blood pressure at home. This provides a possibility for implementation in large-scale studies and can potentially contribute to blood pressure reduction, eventually helping to prevent cognitive impairment. Show less
Current evidence on older adults is derived from population-based cohort studies and randomized controlled trials, which may not include frail individuals. Data are lacking on older outpatients, a... Show moreCurrent evidence on older adults is derived from population-based cohort studies and randomized controlled trials, which may not include frail individuals. Data are lacking on older outpatients, a potentially diverse population. Therefore, we initiated the Milan Geriatrics 75+ Cohort Study, a prospective hospital-based outpatient cohort study. Chapter 1 of this thesis provides a background on the controversies regarding the homeostasis of older adults. Chapter 2, 3 and 4 report findings from the Milan Geriatrics 75+ Cohort Study. Chapter 2 explores the association between blood pressure and cognition, and whether it varies according to age and functional status. Chapter 3 examines the relationship between blood pressure and mortality risk, and whether it varies according to functional and cognitive status. Chapter 4 investigates the association between thyroid status and mortality risk in euthyroid older adults, and whether it differs by sex and age. Chapter 5 and 6 report findings from the PROSPER cohort, which includes older adults at high cardiovascular risk. Chapter 5 presents new evidence on the association of heart rate and heart rate variability with functional decline. Chapter 6 analyses the relationship between blood pressure variability and functional decline. Chapter 7 summarises and discusses the main findings of this thesis. Show less
With increasing age, incidence and prevalence of cardiovascular disease increase. Many physicians face the dilemma whether or not to start preventive treatment in old age. To help physicians decide... Show moreWith increasing age, incidence and prevalence of cardiovascular disease increase. Many physicians face the dilemma whether or not to start preventive treatment in old age. To help physicians decide whether to advise preventive medication to their older patients, prediction of those at highest or lowest (relative) risk using (preferably) inexpensive and easy to use cardiovascular risk factors is important. However, in old age there is a lack of good cardiovascular risk predictors. This thesis shows that the use of multiple blood pressure measurements expressed in the variability (in diastolic blood pressure) or trends in blood pressure can identify older persons with high cardiovascular risk. It also shows that in the oldest old, the absence or presence of heart failure does not influence the prognostic value of low systolic blood pressure regarding risk of death. The serological biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) is found to be an interesting candidate in cardiovascular risk prediction in old age, especially in secondary prevention. In the oldest old, an increase in NT-proBNP still reflects increased risk of (cardiovascular) death, independent of decreasing renal function and is associated with incident heart failure and atrial fibrillation. Show less
The evolution of ageing is a field flush with misconceptions, misunderstandings, and hiatuses. In this thesis I address the most important misunderstanding and misconceptions, and develop new... Show moreThe evolution of ageing is a field flush with misconceptions, misunderstandings, and hiatuses. In this thesis I address the most important misunderstanding and misconceptions, and develop new theory to fill the gaps. This work directly leads to the restatement of the central question in the evolutionary theory of ageing. Rather than evaluating evolutionary forces in models that are at best weakly rooted in (patho-) physiological mechanisms, usually phrased in terms of __age-specific genes__ that are not further specified, as is the current practice, the most pressing question becomes why an organism cannot, or does not, do in itself what it is perfectly capable of doing outside itself in the form of reproduction, namely producing a perfectly healthy __young__ organism. Evolutionary forces cannot answer this question. If anything, this is a mechanistic question. I suggest investigating __the evolution of unretainability__: why and how has our form of life evolved, in which it is mechanistically impossible to bring ageing to a halt, and what are the responsible mechanistic constraints? Show less
