GDF-15 is associated with sarcopenia and frailty in acutely admitted older medical patients.

BACKGROUND: Growth differentiation factor-15 (GDF-15) has been associated with senescence, lower muscle strength, and physical performance in healthy older people. Still, it is not clear whether GDF-15 can be utilized as a biomarker of sarcopenia and frailty in the early stages of hospitalization. We investigated the association of plasma GDF-15 with sarcopenia and frailty in older, acutely admitted medical patients. METHODS: The present study is based on secondary analyses of cross-sectional data from the Copenhagen PROTECT study, a prospective cohort study including 1071 patients ≥65 years of age admitted to the acute medical ward at Copenhagen University Hospital, Bispebjerg, Denmark. Muscle strength was assessed using handgrip strength, and lean mass was assessed using direct segmental multifrequency bioelectrical impedance analyses and used to clarify the potential presence of sarcopenia defined according to guidelines from the European Working Group on Sarcopenia in Older People. Frailty was evaluated using the Clinical Frailty Scale. Plasma GDF-15 was measured using electrochemiluminescence assays from Meso Scale Discovery (MSD, Rockville, MD, USA). RESULTS: We included 1036 patients with completed blood samples (mean age 78.9 ± 7.8 years, 53% female). The median concentration of GDF-15 was 2669.3 pg/mL. Systemic GDF-15 was significantly higher in patients with either sarcopenia (P < 0.01) or frailty (P < 0.001) compared with patients without the conditions. Optimum cut-off points of GDF-15 relating to sarcopenia and frailty were 1541 and 2166 pg/mL, respectively. CONCLUSIONS: Systemic GDF-15 was higher in acutely admitted older medical patients with sarcopenia and frailty compared with patients without. The present study defined the optimum cut-off for GDF-15, related to the presence of sarcopenia and frailty, respectively. When elevated above the derived cutoffs, GDF-15 was strongly associated with frailty and sarcopenia in both crude and fully adjusted models.

Feasibility of Assessing Older Patients in the Acute Setting: Findings From the Copenhagen PROTECT Study.

OBJECTIVES: Older patients are typically underrepresented in clinical trials despite representing a major proportion of the patient population. We aim to describe the feasibility of performing body composition measures, physical function measures, and patient-reported questionnaires within the first 24 hours of admission in a large sample of older acutely admitted medical patients. In addition, we aim to characterize patients with missing measurements. DESIGN: Secondary analyses of cross-sectional data from a cohort study. SETTING AND PARTICIPANTS: A total of 1071 acutely admitted patients aged ≥65 years from the acute medical ward at Bispebjerg Hospital, were enrolled within the first 24 hours of hospitalization. METHODS: Body composition was investigated using direct segmental multifrequency bioelectrical impedance analyses (DSM-BIA) and physical function was assessed using hand grip strength (HGS) and the 30-second sit-to-stand test (STS). The orientation-memory-concentration test (OMC) was used to evaluate the prevalence of cognitive impairments within 24 hours of hospitalization, and the OMC in conjunction with the Strength, Assistance walking, Rise from a chair, Climb stairs, and Falls questionnaire (SARC-F) was used to assess the feasibility of patient-reported outcomes (PROs). RESULTS: Mean age was 78.8 ± 7.8 years (53.0% female). HGS was performed in 96.2% of the enrolled patients, whereas the PRO, 30-second STS, and DSM-BIA were performed in 91.2%, 69.2%, and 59.8% of patients, respectively. The main barrier for performing the 30-second STS and body composition measurements was an inability to mobilize the patient from the hospital bed. CONCLUSIONS AND IMPLICATIONS: The assessment of HGS and PROs show excellent feasibility in clinical research including older patients, even when the patients are enrolled and tested within 24 hours of an acute admission. Assessments of DSM-BIA and the 30-second STS show good feasibility but are less feasible in immobile patients often presenting as more frail, weaker, and cognitively impaired.

Changes in systemic GDF15 across the adult lifespan and their impact on maximal muscle power: the Copenhagen Sarcopenia Study.

BACKGROUND: Although growth differentiation factor 15 (GDF15) is known to increase with disease and is associated with low physical performance, the role of GDF15 in normal ageing is still not fully understood. Specifically, the influence of circulating GDF15 on impairments in maximal muscle power (a major contributor to functional limitations) and the underlying components has not been investigated. METHODS: Data from 1305 healthy women and men aged 20 to 93 years from The Copenhagen Sarcopenia Study were analysed. Circulating levels of GDF15 and markers of inflammation (tumor necrosis factor-alpha, interleukin-6, and high-sensitivity C-reactive protein) were measured by ELISA (R&D Systems) and multiplex bead-based immunoassays (Bio-Rad). Relative (normalized to body mass), allometric (normalized to height squared), and specific (normalized to leg muscle mass) muscle power were assessed by the Nottingham power rig [leg extension power (LEP)] and the 30 s sit-to-stand (STS) muscle power test. Total body fat, visceral fat, and leg lean mass were assessed by dual energy X-ray absorptiometry. Leg skeletal muscle index was measured as leg lean mass normalized to body height squared. RESULTS: Systemic levels of GDF15 increased progressively as a function of age in women (1.1 ± 0.4 pg·mL-1 ·year-1 ) and men (3.3 ± 0.6 pg·mL-1 ·year-1 ) (both P < 0.05). Notably, GDF15 increased at a faster rate from the age of 65 years in women (11.5 ± 1.2 pg·mL-1 ·year-1 , P < 0.05) and 70 years in men (19.3 ± 2.3 pg·mL-1 ·year-1 , P < 0.05), resulting in higher GDF15 levels in men compared with women above the age of 65 years (P < 0.05). Independently of age and circulatory markers of inflammation, GDF15 was negatively correlated to relative STS power (P < 0.05) but not LEP, in both women and men. These findings were mainly explained by negative associations of GDF15 with specific STS power in women and men (both P < 0.05). CONCLUSIONS: A J-shaped relationship between age and systemic GDF15 was observed, with men at older age showing steeper increases and elevated GDF15 levels compared with women. Importantly, circulating GDF15 was independently and negatively associated with relative STS power, supporting the potential role of GDF15 as a sensitive biomarker of frailty in older people.

Associations between inflammatory markers, body composition, and physical function: the Copenhagen Sarcopenia Study.

BACKGROUND: Chronic low-grade inflammation has been suggested as one of the key elements in the development of sarcopenia, but in contrast to disease-related loss of muscle mass, the role of chronic low-grade inflammation in age-related (primary) sarcopenia is still not clear. The aim of this study was to investigate low-grade inflammation in relation to age and the potential association between inflammatory biomarkers and body composition, muscle strength and physical performance in a healthy Danish cohort. METHODS: There were 1160 generally healthy men and women (range: 22-93 years) included. Appendicular lean mass (ALM) and visceral fat normalized to height (kg/m2 ) was assessed by dual-energy X-ray absorptiometry (iDXA, GE Lunar). Muscle strength and physical performance were evaluated by handgrip strength (HGS), 30 s sit-to-stand performance, and maximal gait speed (GS). Systemic levels of TNF-α, IL-6, IL-1ß, IL-4, IL-13, and IFN-γ were measured using multiplex bead-based immunoassays (Bio-Rad). hsCRP was assessed using latex particle-enhanced immunoturbidimetric assays (Roche Diagnostics). RESULTS: With age, ALM/h2 , HGS, sit-to-stand performance and GS decreased, whereas visceral fat/h2 increased in both men and women (P < 0.05). Systemic levels of hsCRP, TNF-α, IL-4, and IFN-γ increased with age in men and women (P < 0.05), while IL-1ß increased in women only (P < 0.01). Higher levels of hsCRP were associated with lower ALM/h2 in elderly (≥65 years) men and women (P < 0.001). Higher levels of hsCRP were associated with lower handgrip strength in elderly women (P < 0.05) whereas higher levels of hsCRP was not associated with lower HGS in elderly men (P = 0.056). Higher levels of hsCRP were associated with lower GS (P < 0.05), whereas IFN-γ was positively associated with GS in elderly women (P < 0.05), but not elderly men. Visceral fat index was positively associated with hsCRP in elderly men and women (P < 0.001). Compared with elderly with normal HGS, elderly men and women with low HGS displayed higher levels of TNF-α and hsCRP (P < 0.05). CONCLUSIONS: With age, systemic levels of hsCRP, TNF-α, IL-4, and IFN-γ increased, with hsCRP and TNF-α being especially elevated in more physically frail elderly supporting the association between low-grade systemic inflammation and poor physical function. In contrast, only high levels of hsCRP were weakly associated with low muscle mass and positively associated with visceral fat and low physical function, suggesting that chronic low-grade inflammation is not the main driver of age-related loss of muscle mass as previously suggested.

Assessment of functional sit-to-stand muscle power: Cross-sectional trajectories across the lifespan.

BACKGROUND: The 30-s sit-to-stand (STS) muscle power test is a valid test to assess muscle power in older people; however, whether it may be used to assess trajectories of lower-limb muscle power through the adult lifespan is not known. This study evaluated the pattern and time course of variations in relative, allometric and specific STS muscle power throughout the lifespan. METHODS: Subjects participating in the Copenhagen Sarcopenia Study (729 women and 576 men; aged 20 to 93 years) were included. Lower-limb muscle power was assessed with the 30-s version of the STS muscle power test. Allometric, relative and specific STS power were calculated as absolute STS power normalized to height squared, body mass and leg lean mass as assessed by DXA, respectively. RESULTS: Relative STS muscle power tended to increase in women (0.08 ±â€¯0.05 W·kg-1·yr-1; p = 0.082) and increased in men (0.14 ±â€¯0.07 W·kg-1·yr-1; p = 0.046) between 20 and 30 years, followed by a slow decline (-0.05 ±â€¯0.05 W·kg-1·yr-1 and -0.06 ±â€¯0.08 W·kg-1·yr-1, respectively; both p > 0.05) between 30 and 50 years. Then, relative STS power declined at an accelerated rate up to oldest age in men (-0.09 ±â€¯0.02 W·kg-1·yr-1) and in women until the age of 75 (-0.09 ±â€¯0.01 W·kg-1·yr-1) (both p < 0.001). A lower rate of decline was observed in women aged 75 and older (-0.04 ±â€¯0.02 W·kg-1·yr-1; p = 0.039). Similar age-related patterns were noted for allometric and specific STS power. CONCLUSIONS: The STS muscle power test appears to provide a feasible and inexpensive tool to monitor cross-sectional trajectories of muscle power throughout the lifespan.

Biomarkers for length of hospital stay, changes in muscle mass, strength and physical function in older medical patients: protocol for the Copenhagen PROTECT study-a prospective cohort study.

INTRODUCTION: Sarcopenia is generally used to describe the age-related loss of muscle mass and strength believed to play a major role in the pathogenesis of physical frailty and functional impairment that may occur with old age. The knowledge surrounding the prevalence and determinants of sarcopenia in older medical patients is scarce, and it is unknown whether specific biomarkers can predict physical deconditioning during hospitalisation. We hypothesise that a combination of clinical, functional and circulating biomarkers can serve as a risk stratification tool and can (i) identify older acutely ill medical patients at risk of prolonged hospital stays and (ii) predict changes in muscle mass, muscle strength and function during hospitalisation. METHOD AND ANALYSIS: The Copenhagen PROTECT study is a prospective cohort study consisting of acutely ill older medical patients admitted to the acute medical ward at Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark. Assessments are performed within 24 hours of admission and include blood samples, body composition, muscle strength, physical function and questionnaires. A subgroup of patients transferred to the Geriatric Department are included in a smaller geriatric cohort and have additional assessments at discharge to evaluate the relative change in circulating biomarker concentrations, body composition, muscle strength and physical function during hospitalisation. Enrolment commenced 4 November 2019, and proceeds until August 2021. ETHICS AND DISSEMINATION: The study protocol has been approved by the local ethics committee of Copenhagen and Frederiksberg (H-19039214) and the Danish Data Protection Agency (P-2019-239) and all experimental procedures were performed in accordance with the Declaration of Helsinki. Findings from the project, regardless of the outcome, will be published in relevant peer-reviewed scientific journals in online (www.clinicaltrials.gov). TRIAL REGISTRATION NUMBER: NCT04151108.

Relation between leg extension power and 30-s sit-to-stand muscle power in older adults: validation and translation to functional performance.

This study aimed to assess the validity and functional relevance of a standardized procedure to assess lower limb muscle power by means of the 30-s sit-to-stand (STS) test when compared to leg extension power (LEP), traditional STS performance and handgrip strength. A total of 628 community-dwelling older subjects (60-93 years) from the Copenhagen Sarcopenia Study were included. Physical performance was assessed by the 30-s STS and 10-m maximal gait speed tests. Handgrip strength and LEP were recorded by a hand-held dynamometer and the Nottingham power rig, respectively. STS muscle power was calculated using the subjects' body mass and height, chair height and the number of repetitions completed in the 30-s STS test. We found a small albeit significant difference between LEP and unilateral STS power in older men (245.5 ± 88.8 vs. 223.4 ± 81.4 W; ES = 0.26; p < 0.05), but not in older women (135.9 ± 51.9 vs. 138.5 ± 49.6 W; ES = 0.05; p > 0.05). Notably, a large positive correlation was observed between both measures (r = 0.75; p < 0.001). Relative STS power was more strongly related with maximal gait speed than handgrip strength, repetition-based STS performance and relative LEP after adjusting for age (r = 0.53 vs 0.35-0.45; p < 0.05). In conclusion, STS power obtained from the 30-s STS test appeared to provide a valid measure of bilateral lower limb power and was more strongly related with physical performance than maximal handgrip strength, repetition-based STS performance and LEP.

Age- and Sex-Specific Changes in Lower-Limb Muscle Power Throughout the Lifespan.

BACKGROUND: Our main goal was to evaluate the pattern and time course of changes in relative muscle power and its constituting components throughout the life span. METHODS: A total of 1,305 subjects (729 women and 576 men; aged 20-93 years) participating in the Copenhagen Sarcopenia Study took part. Body mass index (BMI), leg lean mass assessed by dual-energy X-ray absorptiometry (DXA), and leg extension muscle power (LEP) assessed by the Nottingham power rig were recorded. Relative muscle power (normalized to body mass) and specific muscle power (normalized to leg lean mass) were calculated. Segmented regression analyses were used to identify the onset and pattern of age-related changes in the recorded variables. RESULTS: Relative muscle power began to decline above the age of 40 in both women and men, with women showing an attenuation of the decline above 75 years. Relative muscle power decreased with age due to (i) the loss of absolute LEP after the fourth decade of life and (ii) the increase in BMI up to the age of 75 years in women and 65 years in men. The decline in absolute LEP was caused by a decline in specific LEP up to the age of 75 in women and 65 in men, above which the loss in relative leg lean mass also contributed. CONCLUSIONS: Relative power decreased (i) above 40 years by the loss in absolute power (specific power only) and the increase in body mass, and (ii) above ~70 years by the loss in absolute power (both specific power and leg lean mass).