United Kingdom

Methods: This report included Biobank participants recruited between 2006-2010 with COVID-19 test data. Cindex was used to examine predictive discrimination of individual Fried’s frailty components (slowness, weakness, low physical activity, exhaustion, weight loss) and overall status for two COVID-19 outcomes: 1) Mild disease: a positive COVID-19 test from a community setting without evidence of severe disease 2) Severe disease: a positive in-hospital COVID-19 test or COVID-19 as a primary cause of death defined as severe COVID-19. Results: • Out of 358,433 included in the main analysis, 9,679 patients were classified as having mild COVID-19 and 2,964 were classified as having severe COVID-19. • The prevalence of physical frailty was highest in the severe COVID-19 group (8.1%) compared to mild COVID-19 group (3.2%) and with no COVID-19 diagnosis (2.9%). • For severe COVID-19 outcomes, selfreported walking pace provided the greatest risk discrimination compared to other individual frailty indicators, or overall frailty status. Results for mild COVID-19 were similar, however C-index improvement were lower. Summary: A simple self-reported measure of walking pace provides the greatest predictive discrimination for severe COVID-19 outcomes compared to other frailty indicators or overall frailty status.

ISTRC 2021 - International Sarcopenia Translational Research Conference

Physical frailty components and risk prediction of COVID-19 outcomes: UK Biobank analysis


walking pace

frailty

covid-19

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Background: •The increasing longevity of the world’s population together with prolonged survival in many chronic diseases means that more people have loss of mobility. •To target mobility loss effectively and thus be able to prevent it, we need valid tools that can detect and measure it in daily life (1). •It is also of vital importance that mobility outcomes are assessed in relation to other ageing syndromes, including sarcopenia and frailty. Digital technology has the potential for measuring and monitoring digital mobility outcomes in the real world, but as yet there are no robust, validated technology solutions. Methods: • The overarching objectives of Mobilise-D (“Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement”) are to: • Deliver a valid solution for real-world digital mobility assessment; • Validate digital mobility outcomes in predicting clinical outcome in a variety of disease states including Parkinson’s disease, chronic obstructive pulmonary disease, multiple sclerosis, and proximal femoral fracture; and • Obtain regulatory and health stakeholder approval for digital mobility assessment. Results: •Mobilise-D is funded by the European Innovative Medicines Initiative 2 Joint Undertaking, & includes 34 international research partners based at leading international universities and some of the world’s largest pharmaceutical and technical companies. •Mobilise-D started on 1 April 2019 and will run for five years. •Real-world walking speed and related outcomes assessed in 5 chronic disease populations to derive a device-agnostic algorithm that can be used to predict medically relevant clinical outcomes (e.g., falls, hospitalizations, disability, death) from mobility assessment •A sub-study on sarcopenia and frailty will be conducted within each cohort. Conclusion: Mobilise-D's results will directly facilitate drug development and establish the roadmap for clinical implementation of new, complementary tools to identify, stratify and monitor disability, thereby enabling widespread, cost-effective access to optimal clinical mobility management through personalised healthcare.

Connecting digital mobility assessment to sarcopenia and frailty: the Mobilise-D study

Introduction: • CT-based body composition can distinguish between lean and fat tissue, in contrast to BMI • Low skeletal muscle index (SMI) and low skeletal muscle radiodensity (SMD) are associated with survival in several cancer types • In renal cell cancer (RCC) evidence is limited and inconsistent. Methods: • Patients diagnosed with RCC from 2008-2012 were included • CT-scans at L3 level were collected to assess skeletal muscle index (SMI), skeletal muscle density (SMD), visceral adipose tissue index (VATI) and subcutaneous adipose tissue (SATI) • Clinical data were retrieved from medical records • Multivariable Cox regression with restricted cubic splines were used for examining body composition and overall survival (OS) and recurrence-free survival (RFS) • Analyses were adjusted for age at diagnosis, smoking, tumor stage, Fuhrman grade (and MSKCC and mGPS for stage IV) and mutually adjusted for other body composition parameters. • Stage I-III and stage IV were analyzed separately and gender-specific results are presented. Results: • 719 stage I-III and 320 stage IV patients were included  • Median follow up was 6.35 years (interquartile range 1.41-8.23). Conclusion: • Higher SMD and higher VATI were marginally associated with better survival in RCC patients and might be useful for better prognostication. • However, the added value to current prognostic scores needs to be investigated. 

Skeletal muscle radiodensity and visceral fat are associated with overall survival in renal cell cancer

Introduction: The relationship between body composition and survival in locally advanced rectal cancer patients is under investigation. Methods: A retrospective study of all patients with clinical stage 2-3 rectal cancer who completed neoadjuvant chemoradiotherapy (nCRT) and surgery between 2010 and 2015 at Western Health was performed. Body composition was measured at the third lumbar vertebrae on pre-neoadjuvant treatment imaging. Skeletal muscle index (SMI), adipose tissue and mean muscle attenuation (Hounsfield units, HU) were measured. Primary outcomes were overall (OS) and diseasefree survival (DFS). Results: There were 139 patients treated for stage 2-3 low rectal cancer over 5 years. There were 32 disease recurrences and 30 deaths. Sarcopenia did not result in worse survival. Visceral obesity was predictive of OS (HR 6.43; 95% CI 1.06- 39.1). Skeletal muscle index (cm2/m2) and mean muscle attenuation (HU) were independently associated with improved OS (HR 0.83; 95% CI 0.71-0.96 and HR 0.88; 95%CI 0.78-0.99 respectively) in a multivariate model. The surface area (cm2) of subcutaneous and visceral adipose tissue was independently predictive of OS (HR 1.18; 95%CI 1.03-1.33 and HR 1.16; 95% CI 1.03-1.31 respectively) and DFS (HR 1.13; 95% CI 1.01-1.28 and HR 1.13; 95% 1.00-1.26 respectively) in a multivariate model. Conclusion: CT derived measures of adiposity, muscle mass and density can predict survival in patients with locally advanced rectal cancer undergoing multimodal curative treatment. International cut points for defining body composition phenotypes need revision and may not be suitable for this population.

The association between body composition and survival in locally advanced rectal cancer: An Australian study

Background: Sarcopenia, or a gradual decrease in muscle mass and function, is an inevitable part of the ageing process. Due to reduced muscle strength and power, sarcopenia is a major cause of physical frailty in the elderly, resulting in mobility problems and a loss of physical function and independence. Despite extensive research, sarcopenia is still not well understood at the molecular level. This work aims to determine the effect of dietary restriction (DR) on sarcopenia, as dietary restriction is known to increase average lifespan in a wide variety of organisms. The nematode Caenorhabditis elegans is often used as an invertebrate model system for sarcopenia. In this study, we used a transgenic strain of C. elegans with one of its main muscle proteins, myosin heavy chain B (unc54), fluorescently labelled with GFP to quantify the rate of muscle loss in C. elegans. Average lifespan and age-dependent motility was also determined at various severity of DR. Collectively, our findings show that DR affects sarcopenia; worms under mild and medium DR display a delayed onset of sarcopenia compared to control and severe DR. Methodology: C. elegans isolates: C. elegans N2 (Bristol) expressing GFP-tagged muscle protein (unc54::GFP) was a generous gift from Dr András Málnási-Csizmadi (Eötvös Loránd University, Budapest, Hungary). DR: Worms were cultured on NGM plates (control) or DR plates and transferred to new plates every other day. All lifespan assays were performed at 20°C. Diets were restricted by diluting the concentration of the E.coli food source and included FUdR to supress reproduction. Peptone was removed from the DR media to prevent bacterial growth on the plates. The number of dead and live worms were counted daily, and worms were considered dead when they no longer responded to a gentle touch with a sterilized wormpick. Motility was assessed by subjecting the worms to gentle stroking with a wormpick and their response to the stimulus was grouped into one of three motility classes. Results: Mild and Medium DR increases the lifespan of C. elegans - Worms under mild and medium DR showed the most significant increase in mean lifespan compared to control (P < 0.001 and P = 0.011, respectively). Severe DR resulted in starvation, causing a reduction in mean lifespan (P = 0.026). These results are in line with previous research, which found that worms subjected to mild DR had a longer lifespan, while worms under severe DR had a shorter lifespan. Age-related decline in motility is slower under mild and medium DR - Age-dependent motility data suggests DR alters the motility of C.elegans. Exit from class I occurs later for mild and medium DR conditions compared to control and severe DR. Similarly, the timing of both entry and exit from class II occurs later for mild and medium DR, compared to control and severe DR. Age-related muscle loss is delayed under mild and medium DR - Age-related decrease in GFP-myosin fluorescence was observed, suggesting pronounced sarcopenia for control and various DR conditions. The onset of sarcopenia, however, was dependent on the growth conditions used. Worms under mild and medium DR displayed a delayed onset of sarcopenia compared to the control and Severe DR group. For example, on day 14 of adulthood, the level of GFP-myosin fluorescence is significantly lower in control and severe DR relative to mild and medium DR. Mild and medium DR improves healthspan in C. elegans - Under mild and medium DR, both lifespan and healthspan was extended with a proportional reduction in gerospan. In contrast, worms under control and severe DR showed decreased healthspan and increased gerospan, consistent with the reduced days spent in motility class I and II. Conclusions: • Mild and medium DR increases lifespan and healthspan in C. elegans compared to control. • DR alters motility properties of C.elegans - mild and medium DR conditions delay transition from fitness class I (highest motility) to class II (reduced motility), compared to control, suggesting a delayed onset of sarcopenia. • Fluorescence data confirm increased muscle density and delayed onset of sarcopenia under mild and medium DR conditions compared to control. • Moderate DR improves healthspan and delays the onset of sarcopenia whereas severe DR reduces healthspan and accelerates sarcopenia.

Effect of Dietary Restriction on Muscle Aging in Caenorhabditis elegans

Background: 6 months Exposure to Cigarette smoke 6 months Exposure to Sham-cigarette smoke 2. CS Group 1. Control Group Sarcopenia is a major comorbidity in patients with chronic obstructive pulmonary disease (COPD)1, which has been associated to decreased physical activity. Cigarette smoke (CS) is the leading cause of COPD promoting peripheral muscle wasting and dysfunction. Anabolic and catabolic processes have been associated to sarcopenia in these patients, however the role of intramuscular extracellular matrix (ECM) has not been investigated2. Fibronectin is a glycoprotein ECM, essential for the adhesion of myoblasts on their ECM niche. Ageing of the skeletal muscle has been linked to decreased expression of intramuscular fibronectin and to reduced sensitivity of its receptor (β1-integrin), impacting on FGF2 essential growth factor for satellite cells3,4,5. COL1A1 is an intramuscular ECM involved in muscle regeneration and upregulated upon anabolic stimuli such as exercise training6. This study aims to investigate alterations in the expression of fibronectin and COL1A1 in response to CS. It is hypothesised CS alters the expression of ECMs in perypheral skeletal muscle. The role of ECM in sarcopenia still needs to be demonstrated. Materials and methods: Guinea pig model of COPD. Guinea pigs (n7-10) were exposed to cigarette smoke (24 h, 5 d/wk) for 6 months. Control animals were exposed to sham-cigarette smoke. Gastrocnemius were collected 24 hs after last treatment. (n=7-10). All experiments were approved by institutional Animal Research Committee at Hospital Clinic (Barcelona, Spain). Total RNA was isolated from skeletal muscle from all groups from the COPD guinea pig model as shown above. Intramuscular ECMs were quantified by real-time PCR in reversed transcribed cDNA. Primers were designed and sequences are shown in Table 1. The mRNA expression was calculated using the 2−△△Ct method and is presented as fold changes relative to GAPDH normalisation. Results: Effect of cigarette smoking in gene expression of fibronectin in skeletal muscle - CS significantly reduced the expression of fibronectin (*p=0.022) in a guinea pig model of COPD compared to the controls exposed to sham CS. Values are presented as mean fold change ± SEM; n=6-10. Effect of cigarette smoking in gene expression of COL1A1 in skeletal muscle - CS significantly reduced the expression of COL1A2 (***p=0.0001) in a guinea pig model of COPD compared to the controls exposed to sham CS. Values are presented as mean fold change ± SEM; n=7-10. Conclusions: • Cigarette smoke treatment decreased the expression of the ECMs fibronectin and collagen A1 in peripheral skeletal muscle of a guinea pig model of COPD. • As fibronectin and COL1A1 are integral components of intramuscular ECM and are involved in muscle structure and myogenesis2, their transcriptional downregulation may impact on the capacity of the skeletal muscle regeneration and maintenance of muscle mass.

Cigarette smoke decreases the expression of fibronectin and COL1A1 in the locomotor muscle of a guinea pig model of COPD

Background: Sarcopenia (loss of muscle mass, strength and function with age) is associated with disability, mortality and significant healthcare costs • Previous studies have examined measures of muscle mass, strength and function in relation to adverse health outcomes • No studies have explored both levels and changes in these measures in relation to multiple health outcomes in a single cohort • We examined this among participants of the Health, Aging and Body Composition (Health ABC) Study. Methods: • Analyses were based on 1412 men and 1490 women (aged 70-79 years at baseline) from the Health ABC Study (USA) • Characteristics ascertained from baseline (Year 1) to Year 6 • Muscle function by gait speed • Muscle strength by grip dynamometry • Appendicular lean mass (ALM) from DXA • Exposures for gait speed, grip strength and ALM • Mean levels over Years 1 to 6 • Change in z-scores (age and sex-specific) from Years 1 to 6 using linear mixed models • Time-to-first-event Cox regression was used to examine exposures in relation to adverse health outcomes. All models accounted for age, sex and ethnicity; fully-adjusted models also accounted for socio-demographic, lifestyle and clinical characteristics. • 10-year follow-up of outcomes after Year 6 • Deaths (adjudicated) • Hospital admissions (self-reported and adjudicated) • Low trauma fractures (self-reported and adjudicated) • Falls (self-reported). Results: • Participant characteristics are presented in Table 1 • Sarcopenia components were greater among men • Deaths and hospital admissions were more common among men • Low trauma fractures and falls were more common among women • Predictors of adverse health outcomes (Figure 1) • Mortality: lower levels and greater declines in each component • Hospital admission: lower levels and greater declines in each component; p=0.06 for ALM level • Low trauma fracture: lower levels of each component and greater declines in gait speed • Falls: lower gait speed and grip strength and greater declines in gait speed and ALM. Conclusion: • Lower levels and greater declines in muscle mass, strength and function predicted adverse outcomes • Lower gait speed and grip strength were more strongly associated with outcomes than lower ALM • Lifecourse interventions to maximise peak levels in earlier life and to reduce declines in later life may reduce disease burden in this age group. 

Level and change in sarcopenia components predict adverse health outcomes: findings from the Health, Aging and Body Composition Study

Background: • Identifying low muscle strength is a key step in many operational definitions of sarcopenia including the one proposed by the European Working Group on Sarcopenia in Older People-2 (EWGSOP2). • Assessment of grip strength is commonly used to identify people with low muscle strength. • There are a number of sources of variation in the protocols commonly used to assess grip strength including the type of hand-held dynamometer used. • Studies have shown marked variation in the grip strength achieved by individuals when tested using different makes and models of dynamometer. • The implications of these measurement differences for the case-finding of low muscle strength are not fully understood. • We aimed to assess the impact of measurement differences between 4 different types of commonly-used hand-held dynamometers on the case-finding of low muscle strength. Methods: STUDY DESIGN Randomised, repeated measurements cross-over study. STUDY PARTICIPANTS 118 men and women aged 45-74y who had previously taken part in a market research study, resided in London or the South East of England and met eligibility criteria, attended an assessment at a research office in central London between October 2015 and January 2016. MEASUREMENTS Maximum grip strength (kg) (of 2 trials in each hand) was assessed using four different handheld dynamometers (shown in figure A) in a randomly allocated order. ANALYSIS EWGSOP2 recommended cut-points (<27kg for men; <16kg for women) were applied to estimate prevalence of low muscle strength for each device. Agreement between devices was assessed using kappa statistics. Results: • Mean differences in maximum grip strength of between 4 and 5kg were found when comparing the hydraulic/spring-gauge devices with the electronic devices (Lessof et al, Under review). • These differences were reflected in marked variations in prevalence estimates of low muscle strength by dynamometer type (see figure B) with a range of 3% to 22% for men and 3% to 15% for women. • Of the 13 men classified as having low muscle strength by at least 1 dynamometer, only 1 man (8%) was identified by all 4 dynamometers and 7 men (54%) were identified by just 1 dynamometer (see figure C). • Of the 15 women classified as having low muscle strength by at least 1 dynamometer, only 1 woman (7%) was identified by all 4 dynamometers and 10 women (67%) were identified by just 1 dynamometer (see figure C). • This poor agreement between devices was reflected in kappa statistics comparing pairs of devices which ranged from 0.13 to 0.55. Conclusions: • Case-finding of low muscle strength is influenced by the type of hand-held dynamometer used. • It is important to identify the sources of variation in the measurement of grip strength (which include dynamometer type, body position during testing etc.) and consider the implications of these for sarcopenia. • We need to fully standardise the assessment of each of the different components of commonly used operational definitions of sarcopenia. • Where standardisation cannot be achieved, methods to take account of sources of variation in measurement need to be identified. • Options for this may include the development of correction factors and the use of different reference values and cut-points for different measurement devices.

Impact of variation in device used to measure grip strength on the identification of low muscle strength: Findings from a randomised cross-over study

Background: • Identifying individuals with low grip strength is an initial step in many operational definitions of sarcopenia. • Evidence indicates that contemporaneous Russian populations may have lower mean levels of grip strength than other populations in northern Europe with important implications for sarcopenia. Methods: Study participants - Men and women aged 40-69y from the Russian Know Your Heart study (KYH) (n=3,833) and the seventh survey of the Norwegian Tromsø Study (n=5,598) with valid grip strength measures KYH – a cross-sectional survey of men and women residing in 2 Russian cities - Novosibirsk & Arkhangelsk – recruited from the general population using random sampling of addresses from regional health insurance databases conducted in 2015-2018 Tromsø Study – a longitudinal study of men and women residing in the municipality of Tromsø, Norway, seventh survey conducted in 2015-2016. Measurements - The same standardised protocols were used to assess grip strength in both studies. Grip strength was assessed by trained health professionals using Jamar+ Digital dynamometers following the Southampton protocol. Maximum grip strength (kg) (of 3 trials in each hand) was used in analyses. Analysis - Grip strength by age, sex and study was modeled using linear regression and between-study differences were predicted from these models. Results: • Mean grip strength was higher among Tromsø than KYH study participants and this difference did not vary markedly by age or sex (figure 1). • Adjustment for covariates, most notably height, attenuated between-study differences but these differences were still evident at younger ages (figure 2). • For example, estimated between-study differences in mean grip strength in fullyadjusted models were 2.2kg (95% CI 1.4, 3.1) at 40 years and 1.0kg (95% CI 0.5, 1.5) at 65 years in men (age x study interaction p=0.09) and 1.1kg (95% CI 0.4, 1.9) at age 40 years and -0.2kg (95% CI -0.7, 0.3) at 65 years in women (age x study interaction p<0.01). Conclusions: • We found between-study differences in mean grip strength at ages 40-69 years that are likely to translate into greater future risk of sarcopenia and poorer prospects of healthy ageing for Russian than Norwegian study participants. • For example, the average Russian participant had a similar level of grip strength to a Norwegian participant 7 years older. • Height has its origins in childhood. As this covariate had the most marked impact on between-study differences in grip strength this suggests that these differences may have their origins in early life. • This supports the need for life course approaches to the prevention of sarcopenia and promotion of healthy ageing.

Between-study differences in grip strength: a comparison of Norwegian and Russian adults aged 40-69 years

Introduction: One in three older adults fall yearly with 30-50% of falls resulting in injury. Falls are estimated to cost £2.3bn yearly in the UK. With an ageing population there is a growing need to be able to identify fallers in order to target fall prevention strategies. Methods: This was an observational cohort study of 4,239 participants (60-90 years) from Wave 6 and 7 of the English Longitudinal Study of Ageing. Low muscle strength (dynapenia) and obesity were defined using criteria below at Wave 6. Selfreported data on falls and fall-related injuries (2-year followup) were collected (Wave 7). Multiple logistic regression analyses were performed adjusting for age, sex and previous fall history. AUC was calculated from logistic models. Conclusion: Abdominal obesity and dynapenia appear to confer a greater risk of falls than either component alone. However, individual discrimination was low. The current challenge remains to find a way to operationalise a functionally relevant definition of dynapenic obesity at an individual level.

Dynapenic Abdominal Obesity as a risk factor for falls and fall-related injuries

Background: Weak grip strength is associated with a range of adverse health outcomes such as disability and mortality1 and an accelerated decline in grip strength confers an even greater health risk2 . Two important areas to consider are long-term conditions (LTCs), which can be used to identify individuals at increased risk of sarcopenia using routine health records, and lifestyle factors, which are potentially modifiable and targets for intervention. Methods: Participants We used data from UK Biobank participants who had grip strength measured at baseline (2006-10) and a subsequent study visit around nine years later. Ethical approval for UK Biobank was obtained from the North West Multi-Centre Research Ethics Committee. At baseline, participants’ LTCs were self-reported and categorised against a hierarchy. The number of LTC categories present was categorised as 0, 1, 2 and 3+ (with 2+ categories classed as multimorbidity). Lifestyle factors (body mass index (BMI), smoking, diet and physical activity) were assessed. Change in grip strength was grouped into four patterns: decline, stable low, stable high or reference (no change or increase)3 . Statistical analysis The sample was restricted to participants with complete data on LTCs, lifestyle factors and patterns of grip strength change. We used multinomial logistic regression to assess associations between exposures (categories of LTCs, multimorbidity and lifestyle factors) and outcome (pattern of grip strength change). Results: A total of 44,315 (51.1% female) participants at ages 40-70 were included in the final sample. The median time between visits was 9.2 (7.6, 10.3) years. In terms of patterns of grip strength change, 6.2% had stable low strength, 6.9% had stable high strength, 15.5% experienced a decline in strength and the remainder (71.4%) were in the reference pattern. Most categories of LTCs had significant independent associations with grip strength change (results not shown). There were graded associations between the degree of multimorbidity and pattern of grip strength change, independent of lifestyle factors. For example, those with three or more categories of LTCs were at increased risk of decline in grip strength, a marked increase in stable low grip strength and were less likely to experience stable high grip strength. All lifestyle factors had significant associations except frequent consumption of processed meat. Low physical activity was associated with adverse patterns of grip strength, while raised BMI had divergent associations (both the decline and stable high patterns of grip strength change). Conclusion: Individuals living with multimorbidity and those with lifestyle risk factors are at increased risk of low muscle strength and loss of strength over time. Our findings suggest potential target groups in mid-life for assessment of grip strength, leading to established interventions such as resistance exercise training and the identification of participants for future research studies.

Long-term conditions, multimorbidity, lifestyle factors and change in grip strength over 9 years of follow-up: findings from 44,315 UK Biobank participants

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