Ageing is accompanied by reduced muscle mass and strength, defined as sarcopenia . Catabolic inflammatory processes will enhance this process, especially at advanced age . Even healthy ageing results in slight elevations of circulating proinflammatory mediators, corresponding to a chronic low-grade inflammatory profile (CLIP) . Elderly persons presenting pronounced CLIP show lower muscle mass and muscle strength . Causes of ageing-related CLIP include alterations in T-cell function, immune cell senescence, alteration of the extracellular matrix, increased fat mass and foci of chronic infection .
Elderly people possess an important residual, but latent, physical potential, which can be mobilized by training. Physical exercise has also strong regulating and favourable effects on CLIP , for example, by lowering expression of TLR4 leading to lower lipopolysaccharide (LPS)-induced cytokine release . Physical exercise would thus reduce both the basal inflammatory status and the acute inflammatory response upon aggression in the aged. CLIP is part of the concept of ‘inflammaging’  that describes a benefit at young age from a highly responsive immune system showing good resistance against infections, but a disadvantage when ageing by higher CLIP and sarcopenia. ‘Anti-inflammaging’ refers to low inflammatory responses rendering more susceptible to infectious diseases at young age, but resulting in lower CLIP and survival advantage in old age . In this context, physical exercise would shift patients from an ‘inflammaging’ towards an ‘anti-inflammaging’ profile.
The aim of this review is to report the recent evidence concerning the links between CLIP and sarcopenia.
PubMed [search key: (‘Sarcopenia’ [Mesh] OR ‘Muscle, Skeletal’ [Mesh] OR ‘Muscular Atrophy’ [Mesh] OR ‘Muscle Weakness’ [Mesh] OR dynapenia) AND (‘Inflammation’ [Mesh] OR ‘Chemokines’ [Mesh] OR ‘Cytokines’ [Mesh] OR ‘Receptors, Cytokine’ [Mesh] OR ‘Acute-Phase Proteins’ [Mesh] OR ‘Acute-Phase Reaction’ [Mesh])] and Web-of-Science (search key: TS = (sarcopenia OR skeletal muscle OR muscle atrophy OR muscle weakness OR dynapenia) AND TS = (inflammation OR cytokine* OR acute phase*) AND TS = (aged OR elderly OR ageing OR aging OR old)) were screened for articles published since 2010 (last search on 15 July 2011), resulting in 285 and 140 hits, respectively. Studies were included if they were written in English and if they reported interactions between CLIP and sarcopenia. Studies were excluded when dealing with specific chronic diseases (e.g. rheumatoid arthritis and diabetes), acutely ill patients (e.g. sepsis) or dementia. This procedure resulted in 18 relevant articles. Finally, the reference lists of the included studies were screened, resulting in three additional studies.
Randomized controlled trials (RCTs) were assessed using the NICE checklist . All assessments were performed independently by two reviewers (I.B. and I.B.); if assessment outcomes were conflicting, a consensus-based final score was attributed.
The main participants’ characteristics (sex, community-dwelling or institutionalized, country, population type, age) were identified. Data regarding parameters reflecting CLIP, muscle performance and muscle mass, and their interaction were identified and appraised.
RESULTS AND DISCUSSION
Twenty-one articles were included, among which 12 with observational and nine with interventional design (four RCT and five non-RCT).
Systemic inflammatory markers
Twelve cross-sectional observational studies were identified, among which seven report on circulating interleukin (IL)-6, and/or C-reactive protein (CRP) and/or tumour necrosis factor (TNF)-α, and one study on soluble TNF-α and IL-6 receptors (Table 1). These inflammatory markers consistently showed negative associations with muscle mass [10▪▪,12▪], strength [11▪,16▪], performance [11▪,14▪▪] and aerobic fitness [18▪], as well as physical function [11▪,12▪,16▪] and frailty [13▪]. One recent longitudinal study was identified [10▪▪] linking CLIP to sarcopenia in community-dwelling elderly followed up for 5 years. These results further strengthen former observations linking sarcopenia to CLIP in cross-sectional and longitudinal studies.
Table 1-a Recent evi...Image Tools
It must be mentioned, however, that two studies [14▪▪,19▪▪] have included persons with knee osteoarthritis, but who were otherwise healthy, a condition that has been associated with increased inflammation  and might not be simply a model of physical inactivity as suggested in these publications. Furthermore, the outcome parameters reflecting sarcopenia throughout the selected studies have different applicability in the clinical context. Muscle mass is only one of the parameters and functional evaluations are currently considered as a necessary component for the diagnosis and evaluation of sarcopenia. Muscle strength and endurance can be easily evaluated (even in bedside conditions). Our group has elaborated and validated a fatigue resistance test based on grip strength as well as a simple equation to calculate grip work that can easily be integrated in comprehensive geriatric assessment [11▪]. These measures can be used in older persons even when gait speed, a measure put forward in recent consensus studies [2,23], cannot be obtained .
Inflammatory markers at the tissue level
Four biopsy studies (Table 1) explored intramuscular inflammation-related pathways [15▪,17▪▪,18▪,19▪▪]. In one biopsy study, IL-6 and TNF-α correlated negatively with Akt and its substrate AS160, downstream molecules of the insulin-signalling pathway that regulates GLUT-4 translocation and glucose metabolism. Inversely, the activated, phosphorylated form of AS160 (P-AS160) correlated positively with aerobic fitness [18▪]. However, these results do not allow the identification of the full pathway by which Akt and its substrates interfere with CLIP-induced sarcopenia (for review see ).
In one study, mitochondrial oxidative capacity, lean mass and muscle strength were decreased, whereas intramuscular CRP was increased in older inactive patients compared to the recreationally active young and old controls [19▪▪]. In another study [17▪▪], older sedentary patients showed a lower lean mass compared to young sedentary patients, and lower muscle strength than older active and young sedentary patients. Interestingly, higher intramuscular phosphorylated inhibitor of NFκB (pIKBα) and nuclear p65 subunit of NFκB were observed in older compared to young sedentary patients [17▪▪]. In this context, Thalacker-Mercer et al.[15▪] reported differentially modulated intramuscular gene expression following unaccustomed high-intensity resistance loading in old and young patients, comprising an upregulation of NFκB, as well as signal transducer and activator of transcription-3 (STAT3) and heat shock protein 70 (Hsp70) in older compared to young patients. It has previously been shown that TNF-α upregulates NFκB and muscle ring finger-1 (an ubiquitin ligase, MURF-1), resulting in increased ubiquitination of muscle proteins with subsequent dissociation of actin and myosin myofilaments and their degradation by the ubiquitin–proteasome pathway. Oxidative stress and increased NFκB signalling thus constitute important pathways linking CLIP to sarcopenia (for review see ).
STAT3 has previously been shown to induce expression of Hsp70 (for review see ). Hsp70 is one of the most stress-inducible Hsp. It acts as a chaperone to preserve muscle proteins or target them for degradation  and has been associated with sarcopenia . A better muscle protection has been demonstrated in mice overexpressing Hsp70 . Although levels of Hsp70 in peripheral blood mononuclear cells in older patients are correlated with circulating IL-6 and TNF-α, the production of Hsp in response to stress is blunted with age . Therefore, the upregulated expression of Hsp70 in muscle cells reported by Thalacker-Mercer et al.[15▪] and others  most probably reflects the increased inflammatory milieu in the older patients, whereas the cytoprotective response remains disproportionately low.
Subcutaneous fat biopsies were analysed in two studies [20,21]: obese black and white postmenopausal women showed a higher expression of TNF-α and IL-6, which was related to lower grip strength. IL-6 was also positively related to total body fat mass . In, otherwise healthy, overweight or obese elective vertebral surgery patients, subcutaneous fat IL-6 expression correlated positively with the amount of intermuscular adipose tissue (IMAT), reflecting decreased muscle quality . The exact origin of IMAT in vertebral muscles of chronic back pain patients remains unclear, and might be disease-related, rather than only age-related, and less representative for sarcopenia. Nevertheless, IMAT increases with age, possibly resulting from satellite cell differentiation into adipocytes, and is a known source of proinflammatory cytokines . Notably, most studies retrieved for the present review included a high proportion of overweight and obese individuals.
Long-term effects of exercise
Four relatively small-scale RCTs were identified and their quality appraised (Tables 2 and 3). Three RCTs compared different exercise interventions [33▪▪,34▪,35▪]. Circulating IL-6 (but not CRP) decreased after 12 weeks of moderate resistance training in healthy middle-aged men compared to sedentary controls. This effect, however, was related to higher baseline levels and was lost after 2 weeks of detraining [35▪]. In another study, low-intensity resistance training was compared to high-intensity resistance training in community-dwelling elderly. High-intensity resistance training showed better improvement of muscle performance and muscle mass; circulating IL-6 was not significantly influenced and TNF-α decreased only in the low-intensity resistance training group [34▪]. In nursing home residents, both aerobic and resistance training increased muscle performance compared to controls after 16 weeks. CRP, however, was reduced only after 16 weeks of detraining [33▪▪]. Notably, although not dealing with specific diseases, the participants of this study presented significant comorbidity.
Five non-RCT trials, including almost exclusively women (Table 2), reported effects of exercise on CLIP [37▪,38▪,39▪▪,40▪,41▪]. Four studies globally demonstrate significant decreases in circulating inflammatory cytokines and Hsp70, increases in muscle strength and mass, and inverse correlations between changes in inflammatory and muscular parameters. Only one study, including 14 healthy women with a mean age of only 40 years, reported no decrease in basal levels of any of the inflammatory cytokines after the intervention [38▪]. In these patients, basal and exercise-induced levels of five out of the six cytokines analysed were below the detection limit. Regarding circulating levels of IL-6, the studies from Ferreira et al.[38▪] and Ogawa et al.[40▪], not dealing with obese patients, are the only interventional studies not reporting significant changes following physical exercise. Similarly, in the previously published Quebec Family Study , cardiorespiratory fitness was no longer associated with CLIP when corrected for visceral adipose tissue, whereas fat mass and visceral adipose tissue remained correlated with CRP and IL-6. These results suggest adipose tissue as being a major source of CLIP, what might explain why sarcopenic obesity is associated with worse function than sarcopenia in lean individuals . On the other hand, no associations between changes in IL-6 and changes in fat mass have been reported in the studies under review here.
Table 2-b Recent evi...Image Tools
Although reporting significant within and between group differences, in none of the RCTs’ relationships between changes in inflammatory markers and muscle performance were reported. Only Ogawa et al.[40▪] described a correlation between the relative change in CRP (significant decrease) and TNF-α (nonsignificant decrease) and the relative change in subscapular muscle thickness, suggesting (but not demonstrating) a causal relationship.
A recent review  concluded that increasing aerobic physical activity could be effective, especially in individuals with pronounced CLIP, and suggested further studies to determine the amount of exercise required to reduce inflammation. In this regard, the study by Onambélé-Pearson et al.[34▪] proposes that low-intensity resistance training leads to lower increases in muscle strength, but may be more efficient to reduce inflammation. Sample size, however, was small and study quality moderate. Intriguingly, although not significant, circulating IL-6 increased by 19.2% in the high-intensity resistance training group. In this context, acute exercise-induced elevations of IL-6 are a well known phenomenon, which is positively related to the intensity and duration of the exercise (see later section in this review). It remains, however, unclear whether this might have interfered with the results reported by this group. The observational studies by Buford et al.[17▪▪] and Safdar et al. [19▪▪] suggest that regular recreational physical activity may be sufficient to maintain oxidative capacity and avoid upregulation of catabolic pathways implicating NFκB at old age. An interesting exercise modality leading to decreases in inflammatory markers is hybrid training, using electrically stimulated and voluntary contractions, in that it reduces the required individual effort and the time requested for each session by roughly 50% as described by Kawaguchi et al.[39▪▪]. In addition, the hybrid training device is portable and can be placed at the bedside making its use promising in older patients with functional limitations or acute disease-induced immobility.
Acute exercise-induced effects
The use of an acute bout of exercise to induce an increase in circulating inflammatory cytokines in Beavers et al.[36▪] points to an interesting paradigm: an acute inflammatory response has beneficial effects, contributing to protection and repair, whereas chronic, long-standing inflammation is detrimental . In addition, the acute inflammatory response to unaccustomed exercise-induced muscle damage does not preclude a beneficial effect of repeated long-term exercise on the basal inflammatory profile. Therefore, outcomes may vary with respect to the time point after the last exercise session at which inflammation is measured and the intensity of exercise used.
Furthermore, one study showed comparable postexercise increases in IL-6 in old and young patients [15▪]. In the light of known benefits of short-term inflammation in tissue repair, decreases in exercise-induced serum levels and in LPS-induced monocytic expression of IL-6 [41▪] may not necessarily represent a beneficial effect on CLIP, but rather reflect a decreased immunity following heavy exertion  or a lower level of exercise-induced muscle damage in well trained muscles. However, exercise-induced IL-6 release acts in a hormone-like fashion, increasing glucose uptake and fatty acid oxidation locally and inducing hepatic glucose production and adipose tissue lipolysis . Lesser increases after exercise may, therefore, also reflect muscular adaptations in energy metabolism.
One RCT compared nutritional supplements using soy (rich in isoflavones and leucin) or milk supplements during 4 weeks and could not identify a beneficial effect on eccentric exercise-induced systemic inflammation [36▪]. It is supposed that a high-quality protein diet, consisting of repeated small amounts of total protein (<30 g/intake) rich in essential amino acids, as well as vitamin D supplementation, alone or in association with resistance training, may have beneficial effects on CLIP and sarcopenia (for review see ).
No recent studies have been identified with respect to drug treatment of CLIP and sarcopenia. Potential pharmaceutical interventions include IL-6 and CRP lowering statins, angiotensin-converting enzyme inhibitors (reducing proteolytic effects of angiotensin II that inhibits phosphorylation of Forkhead box O3 (transcription factor, FOXO-3) and stimulates caspase-3), TNF-α inhibitors, nitric oxide donors (acting as calpain inhibitor), and PPAR-α agonists (downregulating NFκB) (for review see [2,48–50]). However, unless the drug can specifically be targeted to muscle tissue, major side-effects are to be expected. Targeting muscle-specific transcription factors such as MyoD, myogenin, MRF4 and myf-5 that decrease during the ageing process and are negatively influenced by TNF-α  might be promising. NSAIDs that may be useful in muscle weakness associated with acute inflammatory conditions  (I. Beyer et al., unpublished observation) have not yet shown clear benefits on CLIP .
Recent research strengthens CLIP's relationship with sarcopenia, with TNF-α and IL-6 as most reported inflammatory parameters. Adiposity contributes to CLIP and new studies should take fat mass into account. Underlying mechanisms are progressively unravelled, including oxidative and proteolytic pathways. Physical exercise seems the best intervention to reduce CLIP and counter sarcopenia. However, IL-6 is also released during exercise as an energy-signalling molecule, in a hormone-like fashion unrelated to inflammation, and exercise-induced changes in IL-6 require careful interpretation. To date, an optimal amount of exercise remains elusive, and more research is warranted to unravel the exact dose–response relationship.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 93).
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