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Background: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. Methods: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (

IntroductionResistance exercise has been shown to improve muscle health in older adults and is recommended as a front-line treatment for many health conditions, including sarcopenia and frailty. However, despite considerable research detailing the potential benefits of resistance exercise programmes, little is known about how older adults recover from individual exercise sessions. This scoping review will examine the current evidence surrounding the acute post-exercise effects of resistance exercise and the exercise recovery process in older adults to inform future research and exercise prescription guidelines for older adults.Methods and analysisThe methodological framework of Arksey and O’Malley (2005) will be applied for this scoping review. A systematic search of five online databases and the hand-searching of reference lists of identified articles will be used to identify relevant papers. Studies that aim to measure exercise-induced muscle damage or exercise recovery following a resistance exercise session in participants aged 65 years and over will be included. Qualitative and quantitative data from relevant studies will be presented in a tabular format. Results will be summarised in narrative format. Key findings will be discussed concerning resistance exercise prescription in older adults.DisseminationThis review will be used to direct further research surrounding the exercise recovery process from resistance exercise in older adults and will also aid in designing specific exercise prescription guidelines for an older population. Findings will be relevant to researchers, clinicians, health workers and policy-makers and disseminated through publications and presentations.

Correction: Volume: 48 Issue: 4 Article Number: UNSP 601 DOI: 10.1093/ageing/afz046 Background in 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) published a sarcopenia definition that aimed to foster advances in identifying and caring for people with sarcopenia. In early 2018, the Working Group met again (EWGSOP2) to update the original definition in order to reflect scientific and clinical evidence that has built over the last decade. This paper presents our updated findings. Objectives to increase consistency of research design, clinical diagnoses and ultimately, care for people with sarcopenia. Recommendations sarcopenia is a muscle disease (muscle failure) rooted in adverse muscle changes that accrue across a lifetime; sarcopenia is common among adults of older age but can also occur earlier in life. In this updated consensus paper on sarcopenia, EWGSOP2: (1) focuses on low muscle strength as a key characteristic of sarcopenia, uses detection of low muscle quantity and quality to confirm the sarcopenia diagnosis, and identifies poor physical performance as indicative of severe sarcopenia; (2) updates the clinical algorithm that can be used for sarcopenia case-finding, diagnosis and confirmation, and severity determination and (3) provides clear cut-off points for measurements of variables that identify and characterise sarcopenia. Conclusions EWGSOP2's updated recommendations aim to increase awareness of sarcopenia and its risk. With these new recommendations, EWGSOP2 calls for healthcare professionals who treat patients at risk for sarcopenia to take actions that will promote early detection and treatment. We also encourage more research in the field of sarcopenia in order to prevent or delay adverse health outcomes that incur a heavy burden for patients and healthcare systems.

© 2019 The Author(s). Academic geriatric medicine activity lags behind the scale of clinical activity in the specialty. A meeting of UK academic geriatricians was convened in March 2018 to consider causes and solutions to this problem. The meeting highlighted a lack of research-Active clinicians, a perception that research is not central to the practice of geriatric medicine and a failure to translate discovery science to clinical studies. Solutions proposed included better support for early-career clinical researchers, schemes to encourage non-University clinicians to be research-Active, wider collaboration with organ specialists to broaden the funding envelope, and the need to co-produce research programmes with end-users. Solutions to grow academic geriatric medicine are essential if we are to provide the best care for the growing older population.

Background: weak grip strength is a key component of sarcopenia and is associated with subsequent disability and mortality. We have recently established life course normative data for grip strength in Great Britain, but it is unclear whether the cut points we derived for weak grip strength are suitable for use in other settings. Our objective was to investigate differences in grip strength by world region using our data as a reference standard. Methods: we searched MEDLINE and EMBASE for reporting age- and gender-stratified normative data for grip strength. We extracted each item of normative data and converted it on to a Z-score scale relative to our British centiles. We performed meta-regression to pool the Z-scores and compare them by world region. Findings: our search returned 806 abstracts. Sixty papers met inclusion criteria and reported on 63 different samples. Seven UN regions were represented, although most samples (n = 44) were based in developed regions. We extracted 726 normative data items relating to 96,537 grip strength observations. Normative data from developed regions were broadly similar to our British centiles, with a pooled Z-score 0.12 SDs (95% CI: 0.07, 0.17) above the corresponding British centiles. By comparison, normative data from developing regions were clearly lower, with a pooled Z-score of −0.85 SDs (95% CI: −0.94, −0.76). Interpretation: our findings support the use of our British grip strength centiles and their associated cut points in consensus definitions for sarcopenia and frailty across developed regions, but highlight the need for different cut points in developing regions.

BACKGROUND: Concerns about the degree of compassion in health care have become a focus for national and international attention. However, existing research on compassionate care interventions provides scant evidence of effectiveness or the contexts in which effectiveness is achievable.\ud OBJECTIVES: To assess the feasibility of implementing Creating Learning Environments for Compassionate Care programme (CLECC) in acute hospital settings and evaluating its impact on patient care.\ud DESIGN: Pilot cluster randomised controlled trial (CRT) and associated process and economic evaluations.\ud SETTING: Six inpatient ward nursing teams (clusters) in two English NHS hospitals randomised to intervention (n=4) or control (n=2)\ud PARTICIPANTS: 639 patients, 211 staff, 188 visitors.\ud INTERVENTION: CLECC, a workplace educational intervention focused on developing sustainable leadership and work-team practices (dialogue, reflective learning, mutual support) theorised to support the delivery of compassionate care. Control: no planned staff team-based educational activity.\ud MAIN OUTCOME MEASURES: Quality of Interaction Schedule (QuIS) for staff-patient interactions; patient-reported evaluations of emotional care in hospital (PEECH); nurse-reported empathy (Jefferson Scale of Empathy).\ud DATA SOURCES: structured observations of staff-patient interactions; patient, visitor and staff questionnaires and qualitative interviews; qualitative observations of CLECC activities.\ud RESULTS: CRT: Pilot proceeded as planned and randomisation was acceptable to teams. There was evidence of contamination between wards in the same hospital. QuIS performed well achieving a 93% recruitment rate with 25% of patient sample cognitively impaired. At follow-up there were more positive (78% versus 74%) and less negative (8% versus 11%) QuIS ratings for intervention wards versus control wards. 63% of intervention ward patients scored lowest (i.e. more negative) scores on PEECH connection subscale, compared with 79% of control group patients. These differences, while supported by the qualitative findings, are not statistically significant. No statistically significant differences in nursing empathy were observed, although response rates to staff questionnaire were low (36%). Process evaluation: The CLECC intervention is feasible to implement in practice with medical and surgical nursing teams in acute care hospitals. We found strong evidence of good staff participation in some CLECC activities and staff reported benefits throughout its introductory period and beyond. Further impact and sustainability were limited by the focus on changing ward team behaviours rather than wider system restructuring. Economic evaluation: We also identified the costs associated with using CLECC and recommend that an impact inventory be used in any future study.\ud LIMITATIONS: Findings are not generalizable outside of hospital nursing teams and this feasibility work is not powered to detect differences due to CLECC.\ud CONCLUSIONS: Use of experimental methods is feasible. The use of structured observation of staff-patient interaction quality is a promising primary outcome that is inclusive of patient groups often excluded from research but further validation is required. Further development of the CLECC intervention should focus on ensuring it is adequately supported by resources, norms and relationships in the wider system by, for instance, improving the cognitive participation of senior nurse managers.

Objectives To characterise the descriptive epidemiology of insomnia in mid-life and explore the relative importance of different occupational risk factors for insomnia in older workers.Methods A questionnaire was mailed to all adults aged 50-64 years registered with 24 English general practices. Insomnia was defined as having at least one of four problems with sleep severely in the past 3 months. Subjects were also asked about employment conditions, feelings concerning work, and their health. Associations were assessed by logistic regression and population attributable fractions (PAF) calculated.Results: Analysis was based on 8067 respondents (5470 in paid work). Insomnia was reported by 18.8% of subjects, being commoner in women, smokers, obese individuals, those living alone, and those in financial hardship, and less prevalent in the educated, those in South-East England, and those with friendships and leisure-time pursuits. Occupational risk factors included unemployment, shift working, lack of control and support at work, job insecurity, job dissatisfaction and several of its determinants (lacking a sense of achievement, feeling unappreciated, having difficult work colleagues, feeling unfairly criticised). Population burden of insomnia was associated more strongly with difficulties in coping with work demands, job insecurity, difficult colleagues, and lack of friendships at work (PAF 15-33%) than shift work and lack of autonomy or support (PAF 5-7%). It was strongly associated with seven measures of poorer self-assessed health. ConclusionsEmployment policies aimed at tackling insomnia in older workers may benefit from focussing particularly on job-person fit, job security and relationships in the workplace. Summary – What is new Job demands, lack of support and choice, job stress and shift working have been the main occupational risk factors for insomnia considered in previous research. Our findings suggest that these contribute less to the population burden of insomnia in older workers than other workplace factors such as inability to cope at work, job insecurity, having difficult colleagues and lacking work friendships.

Background: Low protein intake has been linked to reduced muscle strength and physical performance in older adults but little is known about how it may affect muscle health and subsequent functional decline in the very old (aged 85+), who are at enhanced risk of malnutrition and loss of muscle mass and strength. Aims: To investigate the associations between low protein intake, defined as the intake of

Background The UK population is ageing; improved understanding of risk factors for hospital admission is required. Linkage of the Hertfordshire Cohort Study (HCS) with Hospital Episode Statistics (HES) data has created a multiple-failure survival dataset detailing the characteristics of 2,997 individuals at baseline (1998–2004, average age 66 years) and their hospital admissions (regarded as ‘failure events’) over a 10 year follow-up. Analysis of risk factors using logistic regression or time to first event Cox modelling wastes information as an individual’s admissions after their first are disregarded. Sophisticated analysis techniques are established to examine risk factors for admission in such datasets but are not commonly implemented. Methods We review analysis techniques for multiple-failure survival datasets (logistic regression; time to first event Cox modelling; and the Andersen and Gill [AG] and Prentice, Williams and Peterson Total Time [PWP-TT] multiple-failure models), outline their implementation in Stata, and compare their results in an analysis of housing tenure (a marker of socioeconomic position) as a risk factor for different types of hospital admission (any; emergency; elective; >7 days). The AG and PWP-TT models include full admissions histories in the analysis of risk factors for admission and account for within-subject correlation of failure times. The PWP-TT model is also stratified on the number of previous failure events, allowing an individual’s baseline risk of admission to increase with their number of previous admissions. Results All models yielded broadly similar results: not owner-occupying one’s home was associated with increased risk of hospital admission. Estimated effect sizes were smaller from the PWP-TT model in comparison with other models owing to it having accounted for an increase in risk of admission with number of previous admissions. For example, hazard ratios [HR] from time to first event Cox models were 1.67(95 % CI: 1.36,2.04) and 1.63(95 % CI:1.36,1.95) for not owner-occupying one’s home in relation to risk of emergency admission or death among women and men respectively; corresponding HRs from the PWP-TT model were 1.34(95 % CI:1.15,1.56) for women and 1.23(95 % CI:1.07,1.41) for men. Conclusion The PWP-TT model may be implemented using routine statistical software and is recommended for the analysis of multiple-failure survival datasets which detail repeated hospital admissions among older people.

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90+years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score=- 0.02; 95% CI=- 0.05 to 0.02; p value=0.3; n=18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.

Sarcopenia, the loss of muscle mass and function with age, is highly relevant to clinical practice as it has been associated with a wide range of ageing outcomes including disability and shorter survival times. As such it is now a major focus for research and drug discovery. There has been recent progress in the development of consensus definitions for the diagnosis of sarcopenia, taking the form of measurements of muscle mass and strength or physical performance. These definitions form potential inclusion criteria for use in trials, although the optimum choice of outcome measures is less clear. Prevalence estimates using these new definitions vary, although they suggest that sarcopenia is a common (approximately 13% from one study) clinical problem in older people. A range of lifestyle factors have been investigated in regard to the development of this condition, and progressive resistance training is the most well-established intervention so far. There is also marked research interest in the role of diet, although so far the value of supplementation is less clear. Other potential treatments for sarcopenia include the angiotensin-converting enzyme inhibitors, with some evidence that they can improve physical performance in older people. Future research directions include an increased understanding of the molecular and cellular mechanisms of sarcopenia and the use of a life course approach to explore the possibility of earlier intervention and prevention.

Sarcopenia, the loss of muscle mass and function with age, is highly relevant to clinical practice as it has been associated with a wide range of ageing outcomes including disability and shorter survival times. As such it is now a major focus for research and drug discovery. There has been recent progress in the development of consensus definitions for the diagnosis of sarcopenia, taking the form of measurements of muscle mass and strength or physical performance. These definitions form potential inclusion criteria for use in trials, although the optimum choice of outcome measures is less clear. Prevalence estimates using these new definitions vary, although they suggest that sarcopenia is a common (approximately 13% from one study) clinical problem in older people. A range of lifestyle factors have been investigated in regard to the development of this condition, and progressive resistance training is the most well-established intervention so far. There is also marked research interest in the role of diet, although so far the value of supplementation is less clear. Other potential treatments for sarcopenia include the angiotensin-converting enzyme inhibitors, with some evidence that they can improve physical performance in older people. Future research directions include an increased understanding of the molecular and cellular mechanisms of sarcopenia and the use of a life course approach to explore the possibility of earlier intervention and prevention. A sarcopenia, definida como a perda de função e massa muscular que ocorrem com a idade, é altamente relevante para a prática clínica, pois está associada a vários desfechos negativos, incluindo diminuição da funcionalidade e da sobrevida. Houve recente progresso no desenvolvimento de definições para o diagnóstico da sarcopenia, e estas atualmente se compõem tanto de medidas de massa e força muscular quanto do desempenho físico. Essas definições são potencialmente úteis como critérios de inclusão em pesquisas científicas, todavia a escolha de desfechos é menos clara. As estimativas de prevalência utilizando essas novas definições variam, mas elas sugerem que a sarcopenia é um problema clínico comum (cerca de 13% a partir de um estudo) em pessoas idosas. Uma série de fatores de estilo de vida foi investigada em relação ao desenvolvimento dessa condição, e o treinamento de resistência progressiva é a intervenção mais bem estabelecida até o momento. A intervenção dietética também foi aventada como um fator modificável, embora menos clara que a anterior. Outros tratamentos potenciais para sarcopenia incluem os inibidores da enzima conversora de angiotensina, com alguma evidência de que eles podem melhorar o desempenho físico em idosos. Pesquisas futuras que abordem uma maior compreensão dos mecanismos moleculares e celulares da sarcopenia, além de abordagens precoces que possam vir a modificar o surgimento da sarcopenia, são necessárias.

Background: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

Introduction:\ud \ud Epidemiological studies have shown that weaker grip strength in later life is associated with disability, morbidity, and mortality. Grip strength is a key component of the sarcopenia and frailty phenotypes and yet it is unclear how individual measurements should be interpreted. Our objective was to produce cross-sectional centile values for grip strength across the life course. A secondary objective was to examine the impact of different aspects of measurement protocol.\ud \ud Methods:\ud \ud We combined 60,803 observations from 49,964 participants (26,687 female) of 12 general population studies in Great Britain. We produced centile curves for ages 4 to 90 and investigated the prevalence of weak grip, defined as strength at least 2.5 SDs below the gender-specific peak mean. We carried out a series of sensitivity analyses to assess the impact of dynamometer type and measurement position (seated or standing).\ud \ud Results:\ud \ud Our results suggested three overall periods: an increase to peak in early adult life, maintenance through to midlife, and decline from midlife onwards. Males were on average stronger than females from adolescence onwards: males’ peak median grip was 51 kg between ages 29 and 39, compared to 31 kg in females between ages 26 and 42. Weak grip strength, defined as strength at least 2.5 SDs below the gender-specific peak mean, increased sharply with age, reaching a prevalence of 23% in males and 27% in females by age 80. Sensitivity analyses suggested our findings were robust to differences in dynamometer type and measurement position.\ud \ud Conclusion:\ud \ud This is the first study to provide normative data for grip strength across the life course. These centile values have the potential to inform the clinical assessment of grip strength which is recognised as an important part of the identification of people with sarcopenia and frailty.

BACKGROUND: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory.METHODS: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression.RESULTS: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error.CONCLUSIONS: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required. Background: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions: Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

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

Relationships between birthweight and grip strength throughout the life course 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 4 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 univariable analyses, both parents' grip strengths were significantly associated with that of the child (r = 0.17, P0.001 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 fathers (r = 0.17, P0.001). In the multivariable 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 each parent is associated with that of the 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 life course.

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the 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 (also known as 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.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

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.

Cross-sectional studies show that older people with better cognition tend to walk faster. Whether this association reflects an influence of fluid cognition upon walking speed, vice versa, a bidirectional relationship or the effect of common causes is unclear. We used linear mixed effects models to examine the dynamic relationship between usual walking speed and fluid cognition, as measured by executive function, verbal memory and processing speed, in 2,654 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. There was a bidirectional relationship between walking speed and fluid cognition. After adjusting for age and sex, better performance on executive function, memory and processing speed was associated with less yearly decline in walking speed over the 6-year follow-up period; faster walking speed was associated with less yearly decline in each cognitive domain; and less yearly decline in each cognitive domain was associated with less yearly decline in walking speed. Effect sizes were small. After further adjustment for other covariates, effect sizes were attenuated but most remained statistically significant. We found some evidence that walking speed and the fluid cognitive domains of executive function and processing speed may change in parallel with increasing age. Investigation of the association between walking speed and cognition earlier in life is needed to better understand the origins of this relation and inform the development and timing of interventions.

The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits. Electronic supplementary material The online version of this article (doi:10.1007/s11357-014-9673-9) contains supplementary material, which is available to authorized users.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Includes abstract. Includes bibliographical references.