The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults.

Small noncoding RNAs (sncRNAs) are implicated in age-associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarcopenia and IR. sncRNA expression including miRNAs, transfer RNAs (tRNAs), tRNA-associated fragments (tRFs), and piwi-interacting RNAs (piRNAs) was measured in serum from 21 healthy and 21 sarcopenic Hertfordshire Sarcopenia Study extension women matched for age (mean 78.9 years) and HOMA2-IR. Associations with age, sarcopenia and HOMA2-IR were examined and predicted gene targets and biological pathways characterized. Of the total sncRNA among healthy controls, piRNAs were most abundant (85.3%), followed by tRNAs (4.1%), miRNAs (2.7%), and tRFs (0.5%). Age was associated (FDR < 0.05) with 2 miRNAs, 58 tRNAs, and 14 tRFs, with chromatin organization, WNT signaling, and response to stress enriched among gene targets. Sarcopenia was nominally associated (p < .05) with 12 tRNAs, 3 tRFs, and 6 piRNAs, with target genes linked to cell proliferation and differentiation such as Notch Receptor 1 (NOTCH1), DISC1 scaffold protein (DISC1), and GLI family zinc finger-2 (GLI2). HOMA2-IR was nominally associated (p<0.05) with 6 miRNAs, 9 tRNAs, 1 tRF, and 19 piRNAs, linked with lysine degradation, circadian rhythm, and fatty acid biosynthesis pathways. These findings identify changes in circulating sncRNA expression in human serum associated with chronological age, sarcopenia, and IR. These may have clinical utility as circulating biomarkers of ageing and age-associated pathologies and provide novel targets for therapeutic intervention.

Primary and secondary care service use and costs associated with frailty in an ageing population: longitudinal analysis of an English primary care cohort of adults aged 50 and over, 2006-2017.

BACKGROUND: Frailty becomes more prevalent and healthcare needs increase with age. Information on the impact of frailty on population level use of health services and associated costs is needed to plan for ageing populations. AIM: To describe primary and secondary care service use and associated costs by electronic Frailty Index (eFI) category. DESIGN AND SETTING: Retrospective cohort using electronic health records. Participants aged ≥50 registered in primary care practices contributing to the Oxford Royal College of General Practitioners Research and Surveillance Centre, 2006-2017. METHODS: Primary and secondary care use (totals and means) were stratified by eFI category and age group. Standardised 2017 costs were used to calculate primary, secondary and overall costs. Generalised linear models explored associations between frailty, sociodemographic characteristics. Adjusted mean costs and cost ratios were produced. RESULTS: Individual mean annual use of primary and secondary care services increased with increasing frailty severity. Overall cohort care costs for were highest in mild frailty in all 12 years, followed by moderate and severe, although the proportion of the population with severe frailty can be expected to increase over time. After adjusting for sociodemographic factors, compared to the fit category, individual annual costs doubled in mild frailty, tripled in moderate and quadrupled in severe. CONCLUSIONS: Increasing levels of frailty are associated with an additional burden of individual service use. However, individuals with mild and moderate frailty contribute to higher overall costs. Earlier intervention may have the most potential to reduce service use and costs at population level.

The dynamics of frailty development and progression in older adults in primary care in England (2006-2017): a retrospective cohort profile.

BACKGROUND: Frailty is a common condition in older adults and has a major impact on patient outcomes and service use. Information on the prevalence in middle-aged adults and the patterns of progression of frailty at an individual and population level is scarce. To address this, a cohort was defined from a large primary care database in England to describe the epidemiology of frailty and understand the dynamics of frailty within individuals and across the population. This article describes the structure of the dataset, cohort characteristics and planned analyses. METHODS: Retrospective cohort study using electronic health records. Participants were aged ≥50 years registered in practices contributing to the Oxford Royal College of General Practitioners Research and Surveillance Centre between 2006 to 2017. Data include GP practice details, patient sociodemographic and clinical characteristics, twice-yearly electronic Frailty Index (eFI), deaths, medication use and primary and secondary care health service use. Participants in each cohort year by age group, GP and patient characteristics at cohort entry are described. RESULTS: The cohort includes 2,177,656 patients, contributing 15,552,946 person-years, registered at 419 primary care practices in England. The mean age was 61 years, 52.1% of the cohort was female, and 77.6% lived in urban environments. Frailty increased with age, affecting 10% of adults aged 50-64 and 43.7% of adults aged ≥65. The prevalence of long-term conditions and specific frailty deficits increased with age, as did the eFI and the severity of frailty categories. CONCLUSION: A comprehensive understanding of frailty dynamics will inform predictions of current and future care needs to facilitate timely planning of appropriate interventions, service configurations and workforce requirements. Analysis of this large, nationally representative cohort including participants aged ≥50 will capture earlier transitions to frailty and enable a detailed understanding of progression and impact. These results will inform novel simulation models which predict future health and service needs of older people living with frailty. STUDY REGISTRATION: Registered on www.clinicaltrials.gov October 25th 2019, NCT04139278 .

Relationships between non-communicable disease, social isolation and frailty in community dwelling adults in later life: findings from the Hertfordshire Cohort Study.

BACKGROUND: Social relationships play a fundamental role in individuals' lives and health, and social isolation is prevalent among older people. Chronic non-communicable diseases (NCDs) and frailty are also common in older adults. AIMS: To examine the association between number of NCDs and social isolation in a cohort of community-dwelling older adults in the UK, and to consider whether any potential association is mediated by frailty. METHODS: NCDs were self-reported by 176 older community-dwelling UK adults via questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale. Frailty was assessed by the Fried phenotype of physical frailty. RESULTS: The median (IQR) age of participants in this study was 83.1 (81.5-85.5) years for men and 83.8 (81.5-85.9) years for women. The proportion of socially isolated individuals was 19% in men and 20% in women. More women (18%) than men (13%) were identified as frail. The number of NCDs was associated with higher odds of being isolated in women (unadjusted odds ratio per additional NCD: 1.65, 95% CI 1.08, 2.52, p = 0.021), but not in men, and the association remained robust to adjustment, even when accounting for frailty (OR 1.85, 95% CI 1.06, 3.22, p = 0.031). DISCUSSION: Number of self-reported NCDs was associated with higher odds of social isolation in women but not in men, and the association remained after considering frailty status. CONCLUSIONS: Our observations may be considered by healthcare professionals caring for community-dwelling older adults with multiple NCDs, where enquiring about social isolation as part of a comprehensive assessment may be important.

Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people.

Osteoporosis, a common chronic metabolic bone disease is associated with considerable morbidity and mortality. As the prevalence of osteoporosis increases with age, a paralleled elevation in the rate of incident fragility fractures will be observed. This narrative review explores the origins of bone and considers physiological mechanisms involved in bone homeostasis relevant to management and treatment. Secondary causes of osteoporosis, as well as osteosarcopenia are discussed followed by an overview of the commonly used pharmacological treatments for osteoporosis in older people.

Associations Between Objectively Measured Physical Activity, Body Composition and Sarcopenia: Findings from the Hertfordshire Sarcopenia Study (HSS).

Regular physical activity (PA) is associated with reduced risk of the development and progression of musculoskeletal, metabolic and vascular disease. However, PA declines with age and this can contribute to multiple adverse outcomes. The aims of this study were to describe the relationship between accelerometer-determined PA, body composition and sarcopenia (the loss of muscle mass and function with age). Seven-day PA was measured using the GENEactiv accelerometer among 32 men and 99 women aged 74-84 years who participated in the Hertfordshire Sarcopenia Study. We measured mean daily acceleration and minutes/day spent in non-sedentary and moderate-to-vigorous physical activity (MVPA) levels. Body composition was measured by dual-energy X-ray absorptiometry, muscle strength by grip dynamometry and function by gait speed. Sarcopenia was defined according to the EWGSOP diagnostic algorithm. Men and women spent a median (inter-quartile range) of 138.8 (82, 217) and 186 (122, 240) minutes/day engaging in non-sedentary activity but only 14.3 (1.8, 30.2) and 9.5 (2.1, 18.6) min in MVPA, respectively. Higher levels of PA were associated with reduced adiposity, faster walking speed and decreased risk of sarcopenia. For example, a standard deviation (SD) increase in mean daily acceleration was associated with an increase in walking speed of 0.25 (95% CI 0.05, 0.45) SDs and a reduction in the risk of sarcopenia of 35% (95% CI 1, 57%) in fully adjusted analyses. PA was not associated with hand grip strength. Community-dwelling older adults in this study were largely sedentary but there was evidence that higher levels of activity were associated with reduced adiposity and improved function. PA at all intensity levels in later life may help maintain physical function and protect against sarcopenia.

Implementation of grip strength measurement in medicine for older people wards as part of routine admission assessment: identifying facilitators and barriers using a theory-led intervention.

BACKGROUND: Low grip strength in older inpatients is associated with poor healthcare outcomes including longer length of stay and mortality. Measuring grip strength is simple and inexpensive. However, it is not routinely used in clinical practice. We aimed to evaluate the implementation of grip strength measurement into routine clinical practice. METHODS: This implementation study was a mixed methods study based in five acute medical wards for older people in one UK hospital. Intervention design and implementation evaluation were based on Normalization Process Theory (NPT). A training program was developed and delivered to enable staff to measure grip strength and use a care plan for patients with low grip strength. Routine implementation and monitoring was assessed using the "implementation outcome variables" proposed by WHO: adoption, coverage, acceptability, fidelity, and costs analysis. Enablers and barriers of implementation were identified. RESULTS: One hundred fifty-five nursing staff were trained, 63% in just 3 weeks. Adoption and monthly coverage of grip strength measurement varied between 25 and 80% patients across wards. 81% of female patients and 75% of male patients assessed had low grip strength (< 27 kg for men and < 16 kg for women). Staff and patients found grip measurement easy, cheap and potentially beneficial in identifying high-risk patients. The total cost of implementation across five wards over 12 months was less than £2302. Using NPT, interviews identified enablers and barriers. Enablers included: highly motivated ward champions, managerial support, engagement strategies, shared commitment, and integration into staff and ward daily routines. Barriers included lack of managerial and staff support, and high turnover of staff, managers and champions. CONCLUSIONS: Training a large number of nurses to routinely implement grip strength measurement of older patients was feasible, acceptable and inexpensive. Champions' motivation, managerial support, and shared staff commitment were important for the uptake and normalisation of grip strength measurement. A high percentage of older patients were identified to be at risk of poor healthcare outcomes and would benefit from nutritional and exercise interventions. Measuring grip strength in these patients could provide an opportunity to identify those with normal grip strength for fast tracking through admission to discharge thereby reducing length of stay. TRIAL REGISTRATION: Clinicaltrials.gov NCTO2447445 . Registered May 18, 2015.

Learning from older peoples' reasons for participating in demanding, intensive epidemiological studies: a qualitative study.

BACKGROUND: Recruitment rates of older people in epidemiological studies, although relatively higher than in clinical trials, have declined in recent years. This study aimed to explore motivating factors and concerns among older participants in an intensive epidemiological study (Hertfordshire Sarcopenia Study - HSS) and identify those that could aid future recruitment to epidemiological studies and clinical trials. METHODS: Participants of the HSS fasted overnight and travelled several hours each way to the research facility at an English hospital for extensive diet/lifestyle questionnaires and investigations to assess muscle including blood tests and a muscle biopsy. We conducted semi-structured interviews with 13 participants (ten women) at the research facility in May-October 2015. The interviews were audio-taped, transcribed verbatim, coded and analysed thematically by three researchers. RESULTS: We identified personal motives for participation (potential health benefit for self and family; curiosity; comparing own fitness to others; socialising). Altruistic motives (benefit for other people; belief in importance of research) were also important. Participants voiced a number of external motives related to the study uniqueness, organisation and safety record; family support; and just 'being asked'. Anxiety about the biopsy and travel distance were the only concerns and were alleviated by smooth and efficient running of the study. CONCLUSIONS: Personal and altruistic reasons were important motivators for these older people to participate in demanding, intensive research. They valued belonging to a birth cohort with previous research experience, but personal contact with the research team before and after consent provided reassurance, aided recruitment to HSS and could be readily replicated by other researchers. Any fears or concerns related to certain aspects of a demanding, intensive study should ideally be explored at an early visit to establish a good relationship with the research team.

Lean mass, muscle strength and gene expression in community dwelling older men: findings from the Hertfordshire Sarcopenia Study (HSS).

Sarcopenia is associated with adverse health outcomes. This study investigated whether skeletal muscle gene expression was associated with lean mass and grip strength in community-dwelling older men. Utilising a cross-sectional study design, lean muscle mass and grip strength were measured in 88 men aged 68-76 years. Expression profiles of 44 genes implicated in the cellular regulation of skeletal muscle were determined. Serum was analysed for circulating cytokines TNF (tumour necrosis factor), IL-6 (interleukin 6, IFNG (interferon gamma), IL1R1 (interleukin-1 receptor-1). Relationships between skeletal muscle gene expression, circulating cytokines, lean mass and grip strength were examined. Participant groups with higher and lower values of lean muscle mass (n = 18) and strength (n = 20) were used in the analysis of gene expression fold change. Expression of VDR (vitamin D receptor) [fold change (FC) 0.52, standard error for fold change (SE) ± 0.08, p = 0.01] and IFNG mRNA (FC 0.31; SE ± 0.19, p = 0.01) were lower in those with higher lean mass. Expression of IL-6 (FC 0.43; SE ± 0.13, p = 0.02), TNF (FC 0.52; SE ± 0.10, p = 0.02), IL1R1 (FC 0.63; SE ± 0.09, p = 0.04) and MSTN (myostatin) (FC 0.64; SE ± 0.11, p = 0.04) were lower in those with higher grip strength. No other significant changes were observed. Significant negative correlations between serum IL-6 (R = -0.29, p = 0.005), TNF (R = -0.24, p = 0.017) and grip strength were demonstrated. This novel skeletal muscle gene expression study carried out within a well-characterized epidemiological birth cohort has demonstrated that lower expression of VDR and IFNG is associated with higher lean mass, and lower expression of IL-6, TNF, IL1R1 and myostatin is associated with higher grip strength. These findings are consistent with a role of proinflammatory factors in mediating lower muscle strength in community-dwelling older men.

Mortality, bone density and grip strength: lessons from the past and hope for the future?

Objectives: Therapeutic advances in the management of osteoporosis and sarcopenia have occurred at different rates over the last 2 decades. Here we examine associations between grip strength and BMD with subsequent all-cause and cause-specific mortality in a UK community-dwelling cohort. Methods: Data from 495 men and 414 women from the Hertfordshire Cohort Study were analysed. Grip strength was assessed by grip dynamometry, femoral neck BMD was ascertained using DXA and deaths were recorded from baseline (1998-2004) until 31 December 2018. Grip strength and BMD in relation to mortality outcomes (all-cause, cardiovascular-related, cancer-related and mortality due to other causes) were examined using Cox regression with adjustment for age and sex. Results: The mean baseline age of participants was 64.3 years (s.d. 2.5) and 65.9 years (s.d. 2.6) in men and women, respectively. Lower grip strength was associated with increased risk of all-cause mortality [hazard ratio (HR) 1.30 (95% CI 1.06, 1.58), P = 0.010] and cardiovascular-related mortality [HR 1.75 (95% CI 1.20, 2.55), P = 0.004]. In contrast, BMD was not associated with any of the mortality outcomes (P > 0.1 for all associations). Conclusion: We report strong relationships between grip strength and mortality compared with BMD. We hypothesize that this may reflect better recognition and treatment of low BMD in this cohort.

New horizons in the pathogenesis, diagnosis and management of sarcopenia.

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.

Prevalence of sarcopenia in community-dwelling older people in the UK using the European Working Group on Sarcopenia in Older People (EWGSOP) definition: findings from the Hertfordshire Cohort Study (HCS).

INTRODUCTION: sarcopenia is associated with adverse health outcomes. The aim of this study was to describe the prevalence of sarcopenia in community-dwelling older people in the UK using the European Working Group on Sarcopenia in Older People (EWGSOP) consensus definition. METHODS: we applied the EWGSOP definition to 103 community-dwelling men participating in the Hertfordshire Sarcopenia Study (HSS) using both the lowest third of dual-energy X-ray absorptiometry (DXA) lean mass (LM) and the lowest third of skin-fold-based fat-free mass (FFM) as markers of low muscle mass. We also used the FFM approach among 765 male and 1,022 female participants in the Hertfordshire Cohort Study (HCS). Body size, physical performance and self-reported health were compared in participants with and without sarcopenia. RESULTS: the prevalence of sarcopenia in HSS men (mean age 73 years) was 6.8% and 7.8% when using the lowest third of DXA LM and FFM, respectively. DXA LM and FFM were highly correlated (0.91, P < 0.001). The prevalence of sarcopenia among the HCS men and women (mean age 67 years) was 4.6% and 7.9%, respectively. HSS and HCS participants with sarcopenia were shorter, weighed less and had worse physical performance. HCS men and women with sarcopenia had poorer self-reported general health and physical functioning scores. CONCLUSIONS: this is one of the first studies to describe the prevalence of sarcopenia in UK community-dwelling older people. The EWGSOP consensus definition was of practical use for sarcopenia case finding. The next step is to use this consensus definition in other ageing cohorts and among older people in a range of health-care settings.

Adiposity is associated with widespread transcriptional changes and downregulation of longevity pathways in aged skeletal muscle.

BACKGROUND: Amongst healthy older people, a number of correlates of impaired skeletal muscle mass and function have been defined. Although the prevalence of obesity is increasing markedly in this age group, information is sparse about the particular impacts of obesity on ageing skeletal muscle or the molecular mechanisms that underlie this and associated disease risk. METHODS: Here, we examined genome-wide transcriptional changes using RNA sequencing in muscle biopsies from 40 older community-dwelling men from the Hertfordshire Sarcopenia Study with regard to obesity (body mass index [BMI] >30 kg/m2 , n = 7), overweight (BMI 25-30, n = 19), normal weight (BMI < 25, n = 14), and per cent and total fat mass. In addition, we used EPIC DNA methylation array data to investigate correlations between DNA methylation and gene expression in aged skeletal muscle tissue and investigated the relationship between genes within altered regulatory pathways and muscle histological parameters. RESULTS: Individuals with obesity demonstrated a prominent modified transcriptional signature in muscle tissue, with a total of 542 differentially expressed genes associated with obesity (false discovery rate ≤0.05), of which 425 genes were upregulated when compared with normal weight. Upregulated genes were enriched in immune response (P = 3.18 × 10-41 ) and inflammation (leucocyte activation, P = 1.47 × 10-41 ; tumour necrosis factor, P = 2.75 × 10-15 ) signalling pathways and downregulated genes enriched in longevity (P = 1.5 × 10-3 ) and AMP-activated protein kinase (AMPK) (P = 4.5 × 10-3 ) signalling pathways. Furthermore, differentially expressed genes in both longevity and AMPK signalling pathways were associated with a change in DNA methylation, with a total of 256 and 360 significant cytosine-phosphate-guanine-gene correlations identified, respectively. Similar changes in the muscle transcriptome were observed with respect to per cent fat mass and total fat mass. Obesity was further associated with a significant increase in type II fast-fibre area (P = 0.026), of which key regulatory genes within both longevity and AMPK pathways were significantly associated. CONCLUSIONS: We provide for the first time a global transcriptomic profile of skeletal muscle in older people with and without obesity, demonstrating modulation of key genes and pathways implicated in the regulation of muscle function, changes in DNA methylation associated with such pathways and associations between genes within the modified pathways implicated in muscle regulation and changes in muscle fibre type.

DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults.

BACKGROUND: While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in the muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to the development of ageing-associated diseases, we investigated whether differential DNA methylation was associated with IR in human primary muscle stem cells (myoblasts) from community-dwelling older individuals. METHODS: We measured DNA methylation (Infinium HumanMethylationEPIC BeadChip) in myoblast cultures from vastus lateralis biopsies (119 males/females, mean age 78.24 years) from the Hertfordshire Sarcopenia Study extension (HSSe) and examined differentially methylated cytosine phosphate guanine (CpG) sites (dmCpG), regions (DMRs) and gene pathways associated with HOMA2-IR, an index for the assessment of insulin resistance, and levels of glycated hemoglobin HbA1c. RESULTS: Thirty-eight dmCpGs (false discovery rate (FDR) < 0.05) were associated with HOMA2-IR, with dmCpGs enriched in genes linked with JNK, AMPK and insulin signaling. The methylation signal associated with HOMA2-IR was attenuated after the addition of either BMI (6 dmCpGs), appendicular lean mass index (ALMi) (7 dmCpGs), grip strength (15 dmCpGs) or gait speed (23 dmCpGs) as covariates in the model. There were 8 DMRs (Stouffer < 0.05) associated with HOMA2-IR, including DMRs within T-box transcription factor (TBX1) and nuclear receptor subfamily-2 group F member-2 (NR2F2); the DMRs within TBX1 and NR2F2 remained associated with HOMA2-IR after adjustment for BMI, ALMi, grip strength or gait speed. Forty-nine dmCpGs and 21 DMRs were associated with HbA1c, with cg13451048, located within exoribonuclease family member 3 (ERI3) associated with both HOMA2-IR and HbA1c. HOMA2-IR and HbA1c were not associated with accelerated epigenetic ageing. CONCLUSIONS: These findings suggest that insulin resistance is associated with differential DNA methylation in human primary myoblasts with both muscle mass and body composition making a significant contribution to the methylation changes associated with IR.

Associations of osteoporosis and sarcopenia with frailty and multimorbidity among participants of the Hertfordshire Cohort Study.

BACKGROUND: Ageing is commonly associated with sarcopenia (SP) and osteoporosis (OP), both of which are associated with disability, impaired quality of life, and mortality. The aims of this study were to explore the relationships between SP, OP, frailty, and multimorbidity in community-dwelling older adults participating in the Hertfordshire Cohort Study (HCS) and to determine whether coexistence of OP and SP was associated with a significantly heavier health burden. METHODS: At baseline, 405 participants self-reported their comorbidities. Cut-offs for low grip strength and appendicular lean mass index were used according to the EWSGOP2 criteria to define SP. OP was diagnosed when T-scores of < -2.5 were present at the femoral neck or the participant reported use of the anti-OP medications including hormone replacement therapy (HRT), raloxifene, or bisphosphonates. Frailty was defined using the standard Fried definition. RESULTS: One hundred ninety-nine men and 206 women were included in the study. Baseline median (interquartile range) age of participants was 75.5 (73.4-77.9) years. Twenty-six (8%) and 66 (21.4%) of the participants had SP and OP, respectively. Eighty-three (20.5%) reported three or more comorbidities. The prevalence of pre-frailty and frailty in the study sample was 57.5% and 8.1%, respectively. Having SP only was strongly associated with frailty [odds ratio (OR) 8.28, 95% confidence interval (CI) 1.27, 54.03; P = 0.027] while the association between having OP alone and frailty was weaker (OR 2.57, 95% CI 0.61, 10.78; P = 0.196). The likelihood of being frail was substantially higher in the presence of coexisting SP and OP (OR 26.15, 95% CI 3.13, 218.76; P = 0.003). SP alone and OP alone were both associated with having three or more comorbidities (OR 4.71, 95% CI 1.50, 14.76; P = 0.008 and OR 2.86, 95% CI 1.32, 6.22; P = 0.008, respectively) although the coexistence of SP and OP was not significantly associated with multimorbidity (OR 3.45, 95% CI 0.59, 20.26; P = 0.171). CONCLUSIONS: Individuals living with frailty were often osteosarcopenic. Multimorbidity was common in individuals with either SP or OP. Early identification of SP and OP not only allows implementation of treatment strategies but also presents an opportunity to mitigate frailty risk.

A study of diet in older community-dwelling adults in the UK during the COVID-19 pandemic: Findings from the Southampton Longitudinal Study of Ageing (SaLSA).

Introduction: Adequate nutrition is important for health in later life. Older adults are especially vulnerable to adverse outcomes following infection by COVID-19 and have commonly spent a disproportionate time within their own homes to reduce risk of infection. There are concerns that advice to shield may have led to malnutrition as older adults may modify daily routines including usual shopping habits. The aims of this study were to report self-reported pandemic-related changes in diet and examine lifestyle and medical correlates of these changes in older UK community-dwelling adults. Methods: We recruited 491 participants from the city of Southampton, UK. Participants completed a postal questionnaire in summer/autumn 2021, over a year after the first UK national lockdown was announced. The questionnaire ascertained demographic and lifestyle factors, in addition to number of comorbidities, nutrition risk scores, and presence of frailty. Associations between these participant characteristics in relation to self-reported changes in diet quality (lower, similar or higher when compared to before the first lockdown) were examined using ordinal logistic regression. Results: Median (lower quartile, upper quartile) age was 79.8 (77.0, 83.7) years. Overall, 11 (4.9%) men and 25 (9.4%) women had poorer diet quality compared to before the first UK lockdown. The following participant characteristics were associated with increased risk of being in a worse category for change in diet quality after adjustment for sex: lower educational attainment (p = 0.009); higher BMI (p < 0.001); higher DETERMINE (a malnutrition assessment) score (p = 0.004); higher SARC-F score (p = 0.013); and self-reported exhaustion in the previous week on at least 3 days (p = 0.002). Conclusions: Individuals at higher nutritional risk were identified as reporting increased risk of deterioration in diet quality during the pandemic. Further investigation of the factors leading to these changes, and an understanding of whether they are reversible will be important, especially for future pandemic management.

What impact does osteoarthritis have on ability to self-care and receipt of care in older adults? Findings from the Hertfordshire Cohort Study.

Objectives: Living independently remains the aim of older adults, but musculoskeletal conditions and frailty may hamper this. We examined relationships between osteoarthritis with ability to self-care and access to formal/informal care among community-dwelling older adults, comparing results to relationships between other musculoskeletal conditions of ageing (frailty, sarcopenia, osteoporosis) and these outcomes. Design: Data from the Hertfordshire Cohort Study were used. Osteoarthritis (hand, hip or knee) was defined by clinical examination. Osteoporosis was assessed using dual-energy X-ray absorptiometry and medication use. Sarcopenia was assessed using EWSGOP2 criteria, frailty using Fried criteria. Ability to self-care and access to formal/informal care were self-reported. Results: 443 men and women aged approximately 75 years participated. Osteoarthritis was reported by 26.8% participants; 11.8% had low grip strength; 21.4% had osteoporosis; 8.6% had sarcopenia; 7.6% were identified as frail. Most participants (90.7%) reported no problems with self-care, but more than one-fifth (21.4%) reported having received formal or informal care at home in the previous year. Odds of reporting difficulties with self-care were significantly greater (p â€‹< â€‹0.05) for participants with osteoarthritis and for those with frailty, but not for those with osteoporosis or sarcopenia. Odds of receiving care at home in the past year were significantly greater among participants with osteoarthritis and among those with frailty, but not among those with osteoporosis or sarcopenia. Conclusions: Frailty and osteoarthritis were associated with both difficulties with self-care and receipt of care; osteoporosis and sarcopenia were not. These results highlight the contribution of clinical osteoarthritis to ability to live independently in later life, and the need to actively manage the condition in older adults.

Determinants of muscle density and clinical outcomes: Findings from the Hertfordshire Cohort Study.

PURPOSE: The age-related loss of skeletal muscle mass and strength is associated with adverse health outcomes. However, to date, peripheral quantitative computed tomography (pQCT)-derived muscle density has been little studied. We used a well characterised cohort of older adults to identify lifestyle and anthropometric determinants of pQCT-derived muscle density measured 11 years later, and to report relationships between pQCT-derived muscle density with history of falls and prevalent fractures. METHODS: A lifestyle questionnaire was administered to 197 men and 178 women, aged 59-70 at baseline. After a median of 11.5 (IQR 10.9, 12.3) years, pQCT (Stratec XCT2000) of the radius and tibia was performed to measure forearm muscle density (FMD) and calf muscle density (CMD). Presence of falls and fractures since the age of 45 were determined through participant recall; vertebral fractures were also ascertained through vertebral fracture assessment using iDXA. Total hip BMD (TH aBMD) was assessed using DXA. Baseline characteristics in relation to muscle density at follow-up were examined using linear regression; associations between muscle density and prior falls and fractures were investigated using logistic regression. All analyses were adjusted for sex and age. RESULTS: Mean (SD) age at muscle density measurement was 76.3 (2.6) years. Mean (SD) FMD was 79.9 (3.1) and 77.2 (3.2) among males and females, respectively; CMD was 80.7 (2.6) and 78.5 (2.6) among males and females, respectively. Significant sex-differences in muscle density were observed at each site (p < 0.001). Female sex, lower weight, and lower body mass index were associated (p < 0.05) with both lower FMD and CMD. Additional correlates of lower CMD included older age and shorter stature. Lifestyle measures were not associated with muscle density in this cohort. Lower FMD was related to increased risk of previous fracture (odds ratio (95 % CI) per SD lower FMD: 1.42 (1.07, 1.89), p = 0.015) but not after adjustment for TH aBMD (p > 0.08). No significant relationships were seen between muscle density and falls. CONCLUSION: Female sex, older age, and lower BMI were associated with subsequent lower muscle density in older community-dwelling adults. Lower FMD was related to increased risk of previous fracture. Changes in muscle density over time might precede adverse outcomes such as falls and fractures and may be a long-term predictor of frailty. It could be also suggested that muscle density could be a more clinically meaningful surrogate of functional decline and disability than muscle size or mass, but more studies are needed to support this notion.

Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS).

BACKGROUND: Sarcopenia is the age-related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed. METHODS: Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia-associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96. RESULTS: Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia-associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E-03), oxidative phosphorylation (P = 2.78E-02), and voltage-gated calcium channels (P = 1.59E-04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E-35), sarcopenia and gait speed (P = 4.78E-03), and sarcopenia and grip strength (P = 7.55E-06). There was also an over-representation of the sarcopenia, ALMi, grip strength, and gait speed-associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis. CONCLUSIONS: These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.

A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach.

BACKGROUND: the European Working Group on Sarcopenia in Older People has developed a clinical definition of sarcopenia based on low muscle mass and reduced muscle function (strength or performance). Grip strength is recommended as a good simple measure of muscle strength when 'measured in standard conditions'. However, standard conditions remain to be defined. METHODS: a literature search was conducted to review articles describing the measurement of grip strength listed in Medline, Web of Science and Cochrane Library databases up to 31 December 2009. RESULTS: there is wide variability in the choice of equipment and protocol for measuring grip strength. The Jamar hand dynamometer is the most widely used instrument with established test-retest, inter-rater and intra-rater reliability. However, there is considerable variation in how it is used and studies often provide insufficient information on the protocol followed making comparisons difficult. There is evidence that variation in approach can affect the values recorded. Furthermore, reported summary measures of grip strength vary widely including maximum or mean value, from one, two or three attempts, with either hand or the dominant hand alone. CONCLUSIONS: there is considerable variation in current methods of assessing grip strength which makes comparison between studies difficult. A standardised method would enable more consistent measurement of grip strength and better assessment of sarcopenia. Our approach is described.