Background: Frailty is an aging syndrome caused by exceeding a threshold of decline across multiple organ systems leading to a decreased resistance to stressors. Treatment for frailty focuses on multi-domain interventions to target multiple affected functions in order to decrease the adverse outcomes of frailty. No systematic reviews on the effectiveness of multi-domain interventions exist in a well-defined frail population. Objectives: This systematic review aimed to determine the effect of multi-domain compared to mono-domain interventions on frailty status and score, cognition, muscle mass, strength and power, functional and social outcomes in (pre)frail elderly (≥65 years). It included interventions targeting two or more domains (physical exercise, nutritional, pharmacological, psychological, or social interventions) in participants defined as (pre)frail by an operationalized frailty definition.
Methods: The databases PubMed, EMBASE, CINAHL, PEDro, CENTRAL, and the Cochrane Central register of Controlled Trials were searched from inception until September 14, 2016. Additional articles were searched by citation search, author search, and reference lists of relevant articles. The protocol for this review was registered on PROSPERO (CRD42016032905). Results: Twelve studies were included, reporting a large diversity of interventions in terms of content, duration, and follow-up period. Overall, multi-domain interventions tended to be more effective than mono-domain interventions on frailty status or score, muscle mass and strength, and physical functioning. Results were inconclusive for cognitive, functional, and social outcomes. Physical exercise seems to play an essential role in the multi-domain intervention, whereby additional interventions can lead to further improvement (eg, nutritional intervention). Conclusion: Evidence of beneficial effects of multi-domain compared to mono-domain interventions is limited but increasing. Additional studies are needed, focusing on a well-defined frail population and with specific attention to the design and the individual contribution of mono-domain interventions. This will contribute to the development of more effective interventions for frail elderly.

Sarcopenia is a geriatric syndrome with increasing importance due to the aging of the population. It is known to impose a major burden in terms of morbidity, mortality and socio-economic costs. Therefore, adequate preventive and treatment strategies are required. Progressive resistance training and protein supplementation are currently recommended for the prevention and treatment of sarcopenia. Omega-3 polyunsaturated fatty acids (PUFAs) might be an alternative therapeutic agent for sarcopenia due to their anti-inflammatory properties, which target the ‘inflammaging’, the age-related chronic low-grade inflammation which is assumed to contribute to the development of sarcopenia. In addition, omega-3 PUFAs may also have an anabolic effect on muscle through activation of the mTOR signaling and reduction of insulin resistance. This narrative review provides an overview of the current knowledge about omega-3 PUFAs and their role in the prevention and treatment of sarcopenia. We conclude that there is growing evidence for a beneficial effect of omega-3 PUFAs supplementation in sarcopenic older persons, which may add to the effect of exercise and/or protein supplementation. However, the exact dosage, frequency and use (alone or combined) in the treatment and prevention of sarcopenia still need further exploration.

Background: Age‐related chronic low‐grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia‐defining parameters, quality of life (QoL), and physical activity in middle‐aged and older men.Methods: Men aged 40–79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003–2005) and again after a median follow‐up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high‐sensitive C‐reactive protein (hs‐CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF‐36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole‐body dual X‐ray absorptiometry) and strength. In this subgroup, cross‐sectional associations between baseline inflammatory markers and sarcopenia‐defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking.Results: At baseline, hs‐CRP and WBC were negatively associated with PASE score (hs‐CRP: β = −7.920, P < 0.001; and WBC: β = −4.552, P < 0.001) and the physical component score of SF‐36 (hs‐CRP: β = −1.025, P < 0.001; and WBC: β = −0.364, P < 0.001). Baseline WBC levels were negatively associated with gait speed (β = −0.013; P = 0.025), quadriceps isometric 90° (β = −5.983; P = 0.035) and isokinetic 60°/s peak torque/body weight (β = −5.532; P = 0.027). The prevalence of sarcopenia at baseline was 18.1% (n = 81). Of those without sarcopenia at baseline, 64 (18.6%) satisfied criteria for sarcopenia at follow‐up. There were no significant associations between baseline inflammatory markers and either prevalent or incident sarcopenia, or change in level of sarcopenia‐defining parameters between baseline and follow‐up.Conclusions: In middle‐aged and older men, hs‐CRP and WBC were negatively associated with QoL and PASE scores, while WBC was negatively associated with gait speed and knee strength. Associations with hs‐CRP remained significant in all ages, whereas WBC levels were only associated with PASE, gait speed and knee strength in older adults (60–79 years). Baseline inflammatory markers (hs‐CRP, WBC and albumin) did not predict functional decline, decline in physical activity, decreased QoL or incident sarcopenia.

To explore the relationship between inflammatory markers and sarcopenia-related traits in sarcopenic older adults. Baseline data of the ongoing Exercise and Nutrition for Healthy AgeiNg (ENHANce) study were used for a secondary, exploratory, cross-sectional analysis. ENHANce is a 5-armed triple blinded randomized controlled trial, in older adults (>65y) with sarcopenia defined according to the revised criteria of the European Working Group of Sarcopenia in Older People (EWGSOP2) aiming to assess the effect of combined anabolic interventions (protein supplement, omega-3 supplement and physical exercise) on physical performance, compared to single/placebo interventions. Inflammatory markers C-reactive protein (hs-CRP), albumin, interleukin-1β (IL-1β), IL-6, IL-8, and tumour necrosis factor-α (TNF-α) were assessed at baseline. Spearman's rho (ρ) correlation coefficients were calculated to associate these inflammatory markers with baseline sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass [aLM], gait speed, Short Physical Performance Battery), physical activity (step count) and quality of life (SF-36, SarQoL). We included 40 sarcopenic subjects (15 men/25 women, age 77.1 ± 6.8 years). Contrary to expectations, the pro-inflammatory IL-1β correlated positively with handgrip strength (ρ: 0.376; p = 0.024) and IL-6 with aLM (ρ: 0.334; p = 0.0433). IL-6 inversely correlated with step count (ρ:-0.358; p = 0.048). Subgroup analysis revealed important gender differences. IL-8 inversely correlated with handgrip strength in women (ρ: -0.425; p = 0.034) but not in men. In contrast, pro-inflammatory cytokines CRP (ρ: -0.615; p = 0.019), IL-6 (ρ: -0.604; p = 0.029) and TNF-α (ρ: -0.615; p = 0.025) inversely correlated with the SF-36 physical component score in men but not in women. Although Inflammageing might play a role in sarcopenia-related traits, this exploratory study highlights an important role of gender. Future research should take this into account when elucidating the Inflammageing-sarcopenia interplay.

Background: The Exercise and Nutrition for Healthy AgeiNg (ENHANce) project aims to assess the combined effects of exercise and nutritional interventions to prevent loss of skeletal muscle mass and function with ageing, and to determine the underlying mechanisms of action.Methods: One hundred eightycommunity-dwelling sarcopenic individuals (≥ 65 years) are allocated in a randomized controlled trial (RCT) in a 1:1 ratio into five groups for a 12-week intervention period, followed by a 12-week follow-up period: 1) exercise intervention +protein placebo +omega-3 fatty acids placebo; 2) protein +omega-3 fatty acids placebo; 3) exercise intervention +protein +omega-3 fatty acids placebo; 4) exercise intervention +protein +omega-3 fatty acids; 5) protein placebo +omega-3 fatty acids placebo. All interventions are in line with recommendations of expert groups such as the American College of Sports Medicine and the PROT-AGE study group and individualized to the physical capabilities and nutritional intake of each participant. Sarcopenia is diagnosed by the assessment of gait speed, handgrip strength (Jamar handheld dynamometer), chair stand test and muscle mass (DXA) according to the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. Participants, researchers and statisticians are blinded to omega-3 fatty acids and protein treatment. Compliance to the exercise program, protein and omega-3 fatty acids interventions is objectively measured, by monitoring movement by an activity monitor, determining nitrogen content in urine and analyzing the fatty acid composition of the red blood cell membrane. The primary outcome of the RCT is the change in Short Physical Performance Battery (SPPB) score. Secondary endpoints are, among others, changes in muscle mass, strength and function, objective compliance to interventions, changes in muscle and blood biomarkers related to sarcopenia, cognition, quality of life and falls.Discussion: This RCT in well-defined sarcopenic older adults assesses the effects of combined anabolic interventions, including the additive effects of omega-3 fatty acids supplements, compared to single or placebo interventions. Compliance with the exercise intervention and with the intake of nutritional supplements is measured objectively. Also, blood and muscle samples will be used to explore the underlying determinants that contribute to the mechanism of action of anabolic interventions.Trial registration: Clinicaltrials.gov:NCT03649698, retrospectively registered at 28 August 2018, first participant was randomized 16 February 2018.