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2.  The developmental origins of sarcopenia: using peripheral quantitative computed tomography to assess muscle size in older people 
Background
A number of studies have shown strong graded positive relationships between size at birth and grip strength and estimates of muscle mass in older people. However no studies to date have included direct measures of muscle size.
Methods
We studied 313 men and 318 women born in Hertfordshire UK between 1931 and 1939 who were still resident there and had historical records of growth in early life. Information on lifestyle was collected and participants underwent peripheral quantitative computed tomography to directly measure forearm and calf muscle size.
Results
Birth weight was positively related to forearm muscle area in the men (r = 0.24 p < 0.0001) and women (r = 0.17 p =0.003). There were similar but weaker associations between birth weight and calf muscle area in the men (r=0.13, p=0.03) and in the women (r=0.17, p=0.004). These relationships were all attenuated by adjustment for adult size.
Conclusion
We present first evidence that directly measured muscle size in older men and women is associated with size at birth. This may reflect tracking of muscle size and is important because it suggests that benefit may be gained from taking a life course approach both to understanding the aetiology of sarcopenia and to developing effective interventions.
PMCID: PMC2652118  PMID: 18772471
3.  Falls, sarcopenia and growth in early life 
American journal of epidemiology  2006;164(7):665-671.
Recent studies have shown that people with poor early growth have an increased risk of sarcopenia. Sarcopenia is an important risk factor for falls but it is not known whether poor early growth is related to falls. We investigated this in the Hertfordshire Cohort Study where 2148 participants completed a falls history. Grip strength was used as a marker of sarcopenia. Birth weight, weight at one year and conditional infant growth were analysed in relation to falls history. The prevalence of any fall in the last year was 14.3% for men and 22.5% for women. Falls in the last year were inversely related to adult grip strength, height and walking speed in men and women as well as to lower conditional infant growth in men (OR 1.27 [95% CI 1.04, 1.56] per SD decrease in conditional infant growth, p=0.02). This association was attenuated after adjustment for grip strength. Our findings support an association between poor early growth and falls in older men which appears to be mediated partly through sarcopenia. The lack of relationship with birth weight suggests that postnatal rather than prenatal influences on muscle growth and development may be important for risk of falls in later life.
doi:10.1093/aje/kwj255
PMCID: PMC2062502  PMID: 16905644
Falls accidental; muscle skeletal; muscle development; frail older adults; geriatrics; epidemiology; cohort studies
4.  LOWER MATERNAL BODY CONDITION DURING PREGNANCY AFFECTS SKELETAL MUSCLE STRUCTURE AND GLUT-4 PROTEIN LEVELS BUT NOT GLUCOSE TOLERANCE IN MATURE ADULT SHEEP 
Sub-optimal maternal nutrition and body composition are implicated in metabolic disease risk in adult offspring. We hypothesized that modest disruption of glucose homeostasis previously observed in young adult sheep offspring from ewes of a lower body condition score (BCS) would deteriorate with age, due to changes in skeletal muscle structure and insulin signalling mechanisms. Ewes were fed to achieve a lower (L, n=10) or higher (H, n=14) BCS before and during pregnancy. Baseline plasma glucose, glucose tolerance and basal glucose uptake into isolated muscle strips was similar in male offspring at 210±4 weeks. Vastus total myofibre density (HBCS, 343±15; LBCS, 294±14 fibres/mm2, p<0.05) and fast myofibre density (HBCS, 226±10; LBCS 194±10 fibres/mm2, p<0.05), capillary to myofibre ratio (HBCS, 1.5±0.1; LBCS 1.2±0.1 capillary:myofibre, p<0.05) were lower in LBCS offspring. Vastus protein levels of Akt1 were lower (83±7% of HBCS, p<0.05), and total GLUT-4 was increased (157±6% of HBCS, p<0.001) in LBCS offspring, Despite the reduction in total myofibre density in LBCS offspring, glucose tolerance was normal in mature adult life. However such adaptations may lead to complications in metabolic control in an overabundant postnatal nutrient environment.
doi:10.1177/1933719113477494
PMCID: PMC3766346  PMID: 23420826
Glucose uptake; myofibres; type 2 diabetes; maternal body condition; skeletal muscle
5.  Quality of Life in Sarcopenia and Frailty 
Calcified tissue international  2013;93(2):101-120.
The reduced muscle mass and impaired muscle performance that defines sarcopenia in older individuals is associated with increased risk of physical limitation and a variety of chronic diseases. It may also contribute to clinical frailty.
A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities.
This review and report of an expert meeting, presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarises QoL concepts and specificities in older populations, examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability and argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade off study could be appropriate.
doi:10.1007/s00223-013-9758-y
PMCID: PMC3747610  PMID: 23828275
Age; aging; muscle weakness; quality of life; malnutrition
6.  Inflammatory markers and incident frailty in men and women: The English Longitudinal Study of Ageing 
Age (Dordrecht, Netherlands)  2013;35(6):10.1007/s11357-013-9528-9.
Cross-sectional studies show that higher blood concentrations of inflammatory markers tend to be more common in frail older people but longitudinal evidence that these inflammatory markers are risk factors for frailty is sparse and inconsistent. We investigated the prospective relation between baseline concentrations of the inflammatory markers C-reactive protein and fibrinogen and risk of incident frailty in 2146 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. The relationship between C-reactive protein and fibrinogen and risk of incident frailty differed significantly by sex (p for interaction terms <0.05). In age-adjusted logistic regression analyses, for a standard deviation increase in c-reactive protein or fibrinogen odds ratios (95% confidence intervals) for incident frailty in women were 1.69 (1.32, 2.17) and 1.39 (1.12, 1.72) respectively. Further adjustment for other potential confounding factors attenuated both these estimates. For an SD increase in CRP and fibrinogen the fully-adjusted odds ratio (95% confidence interval) for incident frailty in women was 1.27 (0.96, 1.69 and 1.31 (1.04, 1.67) respectively. Having a high concentration of both inflammatory markers was more strongly predictive of incident frailty than having a high concentration of either marker alone. In men, there were no significant associations between any of the inflammatory markers and risk of incident frailty. High concentrations of the inflammatory markers C-reactive protein and fibrinogen are more strongly predictive of incident frailty in women than in men. Further research is needed to understand the mechanisms underlying this sex difference.
doi:10.1007/s11357-013-9528-9
PMCID: PMC3751755  PMID: 23543263
frailty; inflammation; C-reactive protein; fibrinogen; longitudinal study
8.  Symptoms of anxiety or depression and risk of fracture in older people: The Hertfordshire Cohort Study 
Archives of osteoporosis  2012;7(0):59-65.
Background
Use of psychotropic drugs has been linked with an increased risk of fracture in older people, but there are indications that the conditions for which these drugs were prescribed may themselves influence fracture risk.
Aim
To investigate the relation between symptoms of anxiety and depression and risk of fracture in older people.
Design
Prospective cohort study.
Methods
1087 men and 1050 women aged 59-73 years completed the Hospital Anxiety and Depression Scale (HADS). Data on incident fracture during an average follow-up period of 5.6 years was collected through interview and a postal questionnaire.
Results
Compared to men with no or few symptoms of anxiety (score ≤7 on the HADS anxiety subscale), men with probable anxiety (score ≥11) had an increased risk of fracture: after adjustment for age and potential confounding factors, the odds ratio (OR) (95% confidence interval) was 4.03 (1.55, 10.5). Men with possible anxiety (score 8-10) did not have an increased risk of fracture: multivariate-adjusted OR was 1.04 (0.36, 3.03). There were no associations between levels of anxiety and fracture risk in women. Few men or women had probable depression at baseline (score ≥11 on the HADS depression subscale). Among men with possible depression (score 8-10) there was an increased risk of fracture that was of borderline significance: multivariate-adjusted OR 3.57 (0.99, 12.9). There was no association between possible depression and fracture risk in women.
Conclusions
High levels of anxiety in older men may increase their risk of fracture. Future research needs to replicate this finding in other populations and investigate the underlying mechanisms.
doi:10.1007/s11657-012-0080-5
PMCID: PMC3736098  PMID: 23225282
anxiety; depression; fracture
9.  How to get started with a systematic review in epidemiology: an introductory guide for early career researchers 
Archives of Public Health  2013;71(1):21.
Background
Systematic review is a powerful research tool which aims to identify and synthesize all evidence relevant to a research question. The approach taken is much like that used in a scientific experiment, with high priority given to the transparency and reproducibility of the methods used and to handling all evidence in a consistent manner.
Early career researchers may find themselves in a position where they decide to undertake a systematic review, for example it may form part or all of a PhD thesis. Those with no prior experience of systematic review may need considerable support and direction getting started with such a project. Here we set out in simple terms how to get started with a systematic review.
Discussion
Advice is given on matters such as developing a review protocol, searching using databases and other methods, data extraction, risk of bias assessment and data synthesis including meta-analysis. Signposts to further information and useful resources are also given.
Conclusion
A well-conducted systematic review benefits the scientific field by providing a summary of existing evidence and highlighting unanswered questions. For the individual, undertaking a systematic review is also a great opportunity to improve skills in critical appraisal and in synthesising evidence.
doi:10.1186/0778-7367-71-21
PMCID: PMC3844862  PMID: 23919540
Systematic review; Systematic review methods; Meta-analysis; Early career researchers; Evidence synthesis; Observational studies
10.  Evaluation of common genetic variants identified by GWAS for early onset and morbid obesity in population-based samples 
Background
Meta-analysis of case-control genome wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes.
Objective
We aimed to validate association of these variants with obesity-related traits in population-based samples.
Design
Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2 042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r2>0.8), with the odds of being overweight and obese, as well as with BMI, percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age2 in adults and for sex, age, age-group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods.
Results
We had 80% power to detect ORs of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P > 0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (beta=0.013 SD/allele, P =0.040), but not with any of the remaining obesity-related traits (P >0.3).
Conclusion
Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population.
doi:10.1038/ijo.2012.34
PMCID: PMC3680864  PMID: 22430306
Obesity-susceptibility loci; genome-wide association; morbid; early-onset; anthropometric traits; children and adolescents; population-based
11.  Telomere Length and Physical Performance at Older Ages: An Individual Participant Meta-Analysis 
PLoS ONE  2013;8(7):e69526.
Background
Telomeres are involved in cellular ageing and shorten with increasing age. If telomere length is a valuable biomarker of ageing, then telomere shortening should be associated with worse physical performance, an ageing trait, but evidence for such an association is lacking. The purpose of this study was to examine whether change in telomere length is associated with physical performance.
Methods
Using data from four UK adult cohorts (ages 53–80 years at baseline), we undertook cross-sectional and longitudinal analyses. We analysed each study separately and then used meta-analytic methods to pool the results. Physical performance was measured using walking and chair rise speed, standing balance time and grip strength. Telomere length was measured by quantitative real-time polymerase chain reaction (PCR) in whole blood at baseline and follow-up (time 1, time 2).
Results
Total sample sizes in meta-analyses ranged from 1,217 to 3,707. There was little evidence that telomere length was associated with walking speed, balance or grip strength, though weak associations were seen with chair rise speed and grip strength at baseline (p = 0.02 and 0.01 respectively). Faster chair rise speed at follow-up, was associated with a smaller decline in telomere length between time 1 and time 2 (standardised coefficient per SD increase 0.061, 95% CI 0.006, 0.115, p = 0.03) but this was consistent with chance (p = 0.08) after further adjustment.
Conclusions
Whereas shortening of leukocyte telomeres might be an important measure of cellular ageing, there is little evidence that it is a strong biomarker for physical performance.
doi:10.1371/journal.pone.0069526
PMCID: PMC3724915  PMID: 23922731
12.  Associations between grip strength of parents and their 4 year old children: findings from the Southampton Women’s Survey 
Summary
Relationships between birthweight and grip strength throughout the lifecourse suggest that early influences on the growth and development of muscle are important for long-term muscle function. However, little is known about parental influences on children’s grip strength. We have explored this in the Southampton Women’s Survey, a prospective general population cohort study from before conception through childhood. Grip strength was measured using a Jamar handgrip dynamometer in the mother at 19 weeks’ gestation and her partner, and in the child at age four years. Pre-pregnancy heights and weights were measured in the mothers; reported weights and measured heights were available for the fathers. Complete data on parents and children were available for 444 trios. In univariate analyses, both parents’ grip strengths were significantly associated with that of the child (r=0.17, p<0.001 for mothers, r=0.15, p=0.002 for fathers). These correlations were similar to that between the grip strength of the mothers and the father (r=0.17, P<0.001). In the multivariate model, after adjustment for child’s height and physical activity, the correlations with the child’s grip strength were attenuated, being 0.10 (P=0.02) and 0.11 (P=0.01) for mothers’ and fathers’ grip strength respectively. The findings show that grip strength of both parents is associated with that of their child, indicating that heritable influences and the shared family environment influence the development of muscle strength. This contributes to our understanding of the role of heritable and environmental factors on early muscle growth and development, which are important for muscle function across the lifecourse.
doi:10.1111/j.1365-3016.2011.01231.x
PMCID: PMC3685131  PMID: 22150705
muscle; grip strength; growth and development; genetic and environmental influences; height
13.  Association of diarrhoea in childhood with blood pressure and coronary heart disease in older age: analyses of two UK cohort studies 
Background
There is a suggestion that acute dehydration in childhood may lead to elevated blood pressure. We examined if episodes of diarrhoea in childhood, a recognized proxy for acute dehydration, were related to measured blood pressure and coronary heart disease in older adults.
Methods
Data were pooled from two prospective UK cohort studies (participants born 1920–39) in which episodes of diarrhoea were ascertained from health visitor records from birth until 5 years of age. Blood pressure and coronary heart disease were assessed during medical examination in men and women over 64 years of age. In total, 5203 men and women had data on diarrhoea in early life, adult blood pressure and a range of covariates; 4181 of these also had data on coronary heart disease status.
Results
The prevalence of diarrhoea in infancy (3.3%) and between 1 and 5 years (1.1%) was low. There was no relation of diarrhoea from either period (age- and sex-adjusted results for diarrhoea in infancy presented here) with measured blood pressure [coefficient for systolic; 95% CI (confidence interval): 0.44; −2.88–3.76] or coronary heart disease (Odds ratio, OR; 95% CI: 0.91; 0.54–1.54) in adulthood. There was a similar lack of association when hypertension was the outcome of interest. These observations were unchanged after adjustment for a range of covariates.
Conclusions
In the largest study to date to examine the relation, there was no evidence that diarrhoea in early life had an influence on measured blood pressure, hypertension or coronary heart disease in older adults.
doi:10.1093/ije/dym178
PMCID: PMC3660699  PMID: 18056131
blood pressure; children; diarrhoea; hypertension; coronary heart disease
14.  Intrahepatic Lipid Content and Insulin Resistance Are More Strongly Associated with Impaired NEFA Suppression after Oral Glucose Loading Than with Fasting NEFA Levels in Healthy Older Individuals 
Introduction. The mechanisms underlying the association between insulin resistance and intrahepatic lipid (IHL) accumulation are not completely understood. We sought to determine whether this association was explained by differences in fasting non-esterified fatty acid (NEFA) levels and/or NEFA suppression after oral glucose loading. Materials and Methods. We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 ± 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin, and NEFA levels measured over two hours. IHL was quantified with magnetic resonance spectroscopy. Insulin sensitivity was measured with the oral glucose insulin sensitivity (OGIS) model, the leptin: adiponectin ratio (LAR), and the homeostasis model assessment (HOMA). Results. Measures of insulin sensitivity were not associated with fasting NEFA levels, but OGIS was strongly associated with NEFA suppression at 30 minutes and strongly inversely associated with IHL. Moreover, LAR was strongly inversely associated with NEFA suppression and strongly associated with IHL. This latter association (beta = 1.11 [1.01, 1.21], P = 0.026) was explained by reduced NEFA suppression (P = 0.24 after adjustment). Conclusions. Impaired postprandial NEFA suppression, but not fasting NEFA, contributes to the strong and well-established association between whole body insulin resistance and liver fat accumulation.
doi:10.1155/2013/870487
PMCID: PMC3659510  PMID: 23737780
15.  Type of milk feeding in infancy and health behaviours in adult life: findings from the Hertfordshire Cohort Study 
The British journal of nutrition  2012;109(6):1114-1122.
A number of studies suggest that breastfeeding has beneficial effects on adult cardiovascular risk factors in adulthood, although the mechanisms involved are unknown. One possible explanation is that adults who were breastfed differ in their health behaviours. In a historical cohort, adult health behaviours were examined in relation to type of milk feeding in infancy. From 1931-1939, records were kept on all infants born in Hertfordshire, UK. Their type of milk feeding was summarised as breastfed only, breast & bottle-fed, or bottle-fed only. Information about adult health behaviours was collected from 3217 of these men and women when they were aged 59-73 years. Diet was assessed by administered food frequency questionnaire; the key dietary pattern was a ‘prudent’ pattern, that described compliance with ‘healthy’ eating recommendations. 60% of the men and women were breastfed, 31% were breast & bottle-fed, 9% were bottle-fed. Type of milk feeding did not differ according to social class at birth, and was not related to social class attained in adult life. There were no differences in smoking status, alcohol intake or reported physical activity according to type of milk feeding, but there were differences in the participants’ dietary patterns. In a multivariate model that included gender and infant weight gain, there were independent associations between type of feeding and prudent diet scores in adult life (P=0.009), such that higher scores were associated with being breast fed. These data support experimental findings that suggest that early dietary exposures can have lifelong influences on food choice.
doi:10.1017/S000711451200267X
PMCID: PMC3628663  PMID: 23021469
Breastfeeding; food choice; dietary patterns; health behaviours
16.  Prevalence and correlates of frailty among community-dwelling older men and women: findings from the Hertfordshire Cohort Study 
Age and ageing  2009;39(2):197-203.
Background
frailty, a multi-dimensional geriatric syndrome, confers a high risk for falls, disability, hospitalisation and mortality. The prevalence and correlates of frailty in the UK are unknown.
Methods
frailty, defined by Fried, was examined among community-dwelling young-old (64-74 years) men (n = 320) and women (n = 318) who participated in the Hertfordshire Cohort Study, UK.
Results
the prevalence of frailty was 8.5% among women and 4.1% among men (P = 0.02). Among men, older age (P = 0.009), younger age of leaving education (P = 0.05), not owning/mortgaging one’s home (odds ratio [OR] for frailty 3.45 [95% confidence interval {CI} 1.01-11.81], P = 0.05, in comparison with owner/mortgage occupiers) and reduced car availability (OR for frailty 3.57 per unit decrease in number of cars available [95% CI 1.32, 10.0], P = 0.01) were associated with increased odds of frailty. Among women, not owning/mortgaging one’s home (P = 0.02) was associated with frailty. With the exception of car availability among men (P = 0.03), all associations were non-significant (P > 0.05) after adjustment for co-morbidity.
Conclusions
frailty is not uncommon even among community-dwelling young-old men and women in the UK. There are social inequalities in frailty which appear to be mediated by co-morbidity.
doi:10.1093/ageing/afp204
PMCID: PMC3546311  PMID: 20007127
frailty; prevalence; older people; social inequalities; co-morbidity; elderly
17.  New horizons in the pathogenesis, diagnosis and management of sarcopenia 
Age and Ageing  2013;42(2):145-150.
Sarcopenia is the age-related loss of skeletal muscle mass and function. It is now recognised as a major clinical problem for older people and research in the area is expanding exponentially. One of the most important recent developments has been convergence in the operational definition of sarcopenia combining measures of muscle mass and strength or physical performance. This has been accompanied by considerable progress in understanding of pathogenesis from animal models of sarcopenia. Well-described risk factors include age, gender and levels of physical activity and this knowledge is now being translated into effective management strategies including resistance exercise with recent interest in the additional role of nutritional intervention. Sarcopenia is currently a major focus for drug discovery and development although there remains debate about the best primary outcome measure for trials, and various promising avenues to date have proved unsatisfactory. The concept of ‘new tricks for old drugs’ is, however, promising, for example, there is some evidence that the angiotensin-converting enzyme inhibitors may improve physical performance. Future directions will include a deeper understanding of the molecular and cellular mechanisms of sarcopenia and the application of a lifecourse approach to understanding aetiology as well as to informing the optimal timing of interventions.
doi:10.1093/ageing/afs191
PMCID: PMC3575121  PMID: 23315797
sarcopenia; skeletal muscle; ageing; pathogenesis; diagnosis; exercise; nutrition; drug treatment; life course; epidemiology; older people
18.  Southampton mealtime assistance study: design and methods 
BMC Geriatrics  2013;13:5.
Background
Malnutrition is common in older people in hospital and is associated with adverse clinical outcomes including increased mortality, morbidity and length of stay. This has raised concerns about the nutrition and diet of hospital in-patients. A number of factors may contribute to low dietary intakes in hospital, including acute illness and cognitive impairment among in-patients. The extent to which other factors influence intake such as a lack of help at mealtimes, for patients who require assistance with eating, is uncertain. This study aims to evaluate the effectiveness of using trained volunteer mealtime assistants to help patients on an acute medical ward for older people at mealtimes.
Methods/design
The study design is quasi-experimental with a before (year one) and after (year two) comparison of patients on the intervention ward and parallel comparison with patients on a control ward in the same department. The intervention in the second year was the provision of trained volunteer mealtime assistance to patients in the intervention ward. There were three components of data collection that were repeated in both years on both wards. The first (primary) outcome was patients’ dietary intake, collected as individual patient records and as ward-level balance data over 24 hour periods. The second was clinical outcome data assessed on admission and discharge from both wards, and 6 and 12 months after discharge. Finally qualitative data on the views and experience of patients, carers, staff and volunteers was collected through interviews and focus groups in both years to allow a mixed-method evaluation of the intervention.
Discussion
The study will describe the effect of provision of trained volunteer mealtime assistants on the dietary intake of older medical in-patients. The association between dietary intake and clinical outcomes including malnutrition risk, body composition, grip strength, length of hospital stay and mortality will also be determined. An important component of the study is the use of qualitative approaches to determine the views of patients, relatives, staff and volunteers on nutrition in hospital and the impact of mealtime assistance.
Trial registration
Trial registered with ClinicalTrials.gov NCTO1647204
doi:10.1186/1471-2318-13-5
PMCID: PMC3547699  PMID: 23294981
Nutrition; Older; Volunteer; Mealtime assistance; Dietary intake; Hospital
19.  Genetic markers of bone and joint health and physical capability in older adults: the HALCyon programme 
Bone  2013;52(1):278-285.
Background
Good bone and joint health is essential for the physical tasks of daily living and poorer indicators of physical capability in older adults have been associated with increased mortality rates. Genetic variants of indicators of bone and joint health may be associated with measures of physical capability.
Methods
As part of the Healthy Ageing across the Life Course (HALCyon) programme, men and women aged between 52 and 90 + years from six UK cohorts were genotyped for a polymorphism associated with serum calcium (rs1801725, CASR), two polymorphisms associated with bone mineral density (BMD) (rs2941740, ESR1 and rs9594759, RANKL) and one associated with osteoarthritis risk rs3815148 (COG5). Meta-analysis was used to pool within-study effects of the associations between each of the polymorphisms and measures of physical capability: grip strength, timed walk or get up and go, chair rises and standing balance.
Results
Few important associations were observed among the several tests. We found that carriers of the serum calcium-raising allele had poorer grip strength compared with non-carriers (pooled p = 0.05, n = 11,239) after adjusting for age and sex. Inconsistent results were observed for the two variants associated with BMD and we found no evidence for an association between rs3815148 (COG5) and any of the physical capability measures.
Conclusion
Our findings suggest elevated serum calcium levels may lead to lower grip strength, though this requires further replication. Our results do not provide evidence for a substantial influence of these variants in ESR1, RANKL and COG5 on physical capability in older adults.
Highlights
► We examined associations between bone-related genotypes and physical capability. ► We conducted a meta-analysis on 12,836 middle-age adults. ► We found CASR may be associated with grip strength. ► No substantial support for specific bone mineral density variants and physical capability.
doi:10.1016/j.bone.2012.10.004
PMCID: PMC3526776  PMID: 23072920
BMD, bone mineral density; OA, osteoarthritis; BMI, body mass index; SNP, single nucleotide polymorphism; CaPS, Caerphilly Prospective Study; ELSA, English Longitudinal Study of Ageing; HAS, Hertfordshire Ageing Study; HCS, Hertfordshire Cohort Study; LBC1921, The Lothian Birth Cohort 1921; NSHD, National Survey of Health and Development; HWE, Hardy–Weinberg equilibrium; WHR, waist–hip ratio; GWAS, genome-wide association studies; Aging; Grip strength; Calcium; Bone mineral density; Osteoarthritis
20.  Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages: An individual participant meta-analysis 
Psychoneuroendocrinology  2013;38(1):40-49.
Summary
The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50–92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from n = 2146 for associations between morning Cortisol Awakening Response and balance to n = 8448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.052, 95% confidence interval (CI) 0.029, 0.076, p < 0.001; age and gender adjusted) and a quicker chair rise time (standardised coefficient per SD increase −0.075, 95% CI −0.116, −0.034, p < 0.001; age and gender adjusted). There was little evidence of associations with balance or grip strength. Greater diurnal decline of the HPA axis is associated with better physical performance in later life. This may reflect a causal effect of the HPA axis on performance or that other ageing-related factors are associated with both reduced HPA reactivity and performance.
doi:10.1016/j.psyneuen.2012.04.016
PMCID: PMC3533133  PMID: 22658392
HPA axis; Physical capability; Healthy ageing
21.  ACTN3 genotype, athletic status and lifecourse physical capability: meta-analysis of the published literature and findings from nine studies 
Human mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (p-value=0.09, n=7672 in males; p-value=0.90, n=7839 in females), standing balance, timed get up and go or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
doi:10.1002/humu.21526
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
22.  ACTN3 Genotype, Athletic Status, and Life Course Physical Capability: Meta-Analysis of the Published Literature and Findings from Nine Studies 
Human Mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population. Hum Mutat 32:1–11, 2011. © 2011 Wiley-Liss, Inc.
doi:10.1002/humu.21526
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
23.  Absence of association of a SNP in the TERT-CLPTM1L locus with age-related phenotypes in a large multi-cohort study: the HALCyon program 
Aging cell  2011;10(3):520-532.
Summary
Background
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other ageing traits such as physical capability have not been reported.
Methods
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from 9 UK cohorts were genotyped for the single nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses.
Results
No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score=0.02, 95% CI: -0.01- 0.04, p-value=0.12, n=18,737), physical performance tests (e.g. pooled beta for grip strength=-0.02, 95% CI:-0.045- 0.006, p-value=0.14, n=11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment.
Conclusion
The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multi-cohort study suggests that whilst this SNP may be associated with cancer, it is not an important contributor to other markers of ageing.
doi:10.1111/j.1474-9726.2011.00687.x
PMCID: PMC3094481  PMID: 21332924
Aging; ageing; middle-aged; telomere; cognition; physical
24.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function 
Artigas, María Soler | Loth, Daan W | Wain, Louise V | Gharib, Sina A | Obeidat, Ma’en | Tang, Wenbo | Zhai, Guangju | Zhao, Jing Hua | Smith, Albert Vernon | Huffman, Jennifer E | Albrecht, Eva | Jackson, Catherine M | Evans, David M | Cadby, Gemma | Fornage, Myriam | Manichaikul, Ani | Lopez, Lorna M | Johnson, Toby | Aldrich, Melinda C | Aspelund, Thor | Barroso, Inês | Campbell, Harry | Cassano, Patricia A | Couper, David J | Eiriksdottir, Gudny | Franceschini, Nora | Garcia, Melissa | Gieger, Christian | Gislason, Gauti Kjartan | Grkovic, Ivica | Hammond, Christopher J | Hancock, Dana B | Harris, Tamara B | Ramasamy, Adaikalavan | Heckbert, Susan R | Heliövaara, Markku | Homuth, Georg | Hysi, Pirro G | James, Alan L | Jankovic, Stipan | Joubert, Bonnie R | Karrasch, Stefan | Klopp, Norman | Koch, Beate | Kritchevsky, Stephen B | Launer, Lenore J | Liu, Yongmei | Loehr, Laura R | Lohman, Kurt | Loos, Ruth JF | Lumley, Thomas | Al Balushi, Khalid A | Ang, Wei Q | Barr, R Graham | Beilby, John | Blakey, John D | Boban, Mladen | Boraska, Vesna | Brisman, Jonas | Britton, John R | Brusselle, Guy G | Cooper, Cyrus | Curjuric, Ivan | Dahgam, Santosh | Deary, Ian J | Ebrahim, Shah | Eijgelsheim, Mark | Francks, Clyde | Gaysina, Darya | Granell, Raquel | Gu, Xiangjun | Hankinson, John L | Hardy, Rebecca | Harris, Sarah E | Henderson, John | Henry, Amanda | Hingorani, Aroon D | Hofman, Albert | Holt, Patrick G | Hui, Jennie | Hunter, Michael L | Imboden, Medea | Jameson, Karen A | Kerr, Shona M | Kolcic, Ivana | Kronenberg, Florian | Liu, Jason Z | Marchini, Jonathan | McKeever, Tricia | Morris, Andrew D | Olin, Anna-Carin | Porteous, David J | Postma, Dirkje S | Rich, Stephen S | Ring, Susan M | Rivadeneira, Fernando | Rochat, Thierry | Sayer, Avan Aihie | Sayers, Ian | Sly, Peter D | Smith, George Davey | Sood, Akshay | Starr, John M | Uitterlinden, André G | Vonk, Judith M | Wannamethee, S Goya | Whincup, Peter H | Wijmenga, Cisca | Williams, O Dale | Wong, Andrew | Mangino, Massimo | Marciante, Kristin D | McArdle, Wendy L | Meibohm, Bernd | Morrison, Alanna C | North, Kari E | Omenaas, Ernst | Palmer, Lyle J | Pietiläinen, Kirsi H | Pin, Isabelle | Polašek, Ozren | Pouta, Anneli | Psaty, Bruce M | Hartikainen, Anna-Liisa | Rantanen, Taina | Ripatti, Samuli | Rotter, Jerome I | Rudan, Igor | Rudnicka, Alicja R | Schulz, Holger | Shin, So-Youn | Spector, Tim D | Surakka, Ida | Vitart, Veronique | Völzke, Henry | Wareham, Nicholas J | Warrington, Nicole M | Wichmann, H-Erich | Wild, Sarah H | Wilk, Jemma B | Wjst, Matthias | Wright, Alan F | Zgaga, Lina | Zemunik, Tatijana | Pennell, Craig E | Nyberg, Fredrik | Kuh, Diana | Holloway, John W | Boezen, H Marike | Lawlor, Debbie A | Morris, Richard W | Probst-Hensch, Nicole | Kaprio, Jaakko | Wilson, James F | Hayward, Caroline | Kähönen, Mika | Heinrich, Joachim | Musk, Arthur W | Jarvis, Deborah L | Gläser, Sven | Järvelin, Marjo-Riitta | Stricker, Bruno H Ch | Elliott, Paul | O’Connor, George T | Strachan, David P | London, Stephanie J | Hall, Ian P | Gudnason, Vilmundur | Tobin, Martin D
Nature Genetics  2011;43(11):1082-1090.
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
doi:10.1038/ng.941
PMCID: PMC3267376  PMID: 21946350
25.  Childhood Socioeconomic Position and Objectively Measured Physical Capability Levels in Adulthood: A Systematic Review and Meta-Analysis 
PLoS ONE  2011;6(1):e15564.
Background
Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood.
Methods and Findings
Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations.
Conclusions
Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.
doi:10.1371/journal.pone.0015564
PMCID: PMC3027621  PMID: 21297868

Results 1-25 (36)