CHAPTER THREE
Sarcopenia and Nutrition Alessandro Laviano1, Chiara Gori, Serena Rianda Department of Clinical Medicine, Sapienza University, Rome, Italy 1 Corresponding author: e-mail address: [email protected]
Contents 1. 2. 3. 4.
Introduction Definition of Sarcopenia Mechanisms of Sarcopenia Diagnosing Sarcopenia 4.1 EWGSOP criteria 4.2 IWGS criteria 4.3 Defining cutoff values 4.4 Comparison of sarcopenia defined by EWGSOP and IWGS 4.5 Stages of sarcopenia 4.6 Consensus statement by the Society of Sarcopenia, Cachexia and Wasting Disorders 5. Sarcopenia and Dynapenia 6. Clinical Consequences of Sarcopenia 7. Sarcopenia: A Specific Geriatric Syndrome? 8. Nutrition Therapy for Sarcopenia 8.1 Supplementation with essential amino acids 8.2 Other nutrients 9. Conclusions References
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Abstract Preserving or restoring adequate nutritional status is a key factor to delay the onset of chronic diseases and to accelerate recovery from acute illnesses. In particular, consistent and robust data show the loss of muscle mass, that is, sarcopenia, is clinically relevant since it is closely related to increased morbidity and mortality in healthy individuals and patients. Sarcopenia is defined as the age-related loss of muscle mass and function. International study groups have recently proposed separate definitions and diagnostic criteria for sarcopenia. Unfortunately, the rate of agreement in assessing the prevalence of sarcopenia is just fair, which highlights the need for a common effort to harmonize definitions and diagnostic criteria. Sarcopenia should be distinct from myopenia, which is the disease-associated loss of muscle mass, although in clinical practice it may be impossible to separate them (i.e., in old cancer patients). The pathogenesis of sarcopenia
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is complex and multifactorial. Consequently, its treatment should target the different factors involved, including quantitatively and qualitatively inappropriate food intake and reduced physical activity.
1. INTRODUCTION Optimal nutritional status is a key factor in preserving healthy conditions, in facilitating recovery from acute diseases, and in extending survival of patients suffering from chronic diseases. For decades, body weight and its relationship with height (i.e., body mass index, BMI) have been considered robust markers of nutritional status. Consequently, involuntary and significant weight loss (i.e., >5% of usual body weight in 1–3 months) is generally regarded as a marker of nutritional risk and malnutrition. Although it is acknowledged that simple and easily available tools are needed and indispensable to assess the nutritional status of entire populations, concerns are raised when such tools are used to evaluate single patients. In fact, it is now clearly established that body composition analysis provides more solid information regarding not only nutritional status but also on the clinical consequences of nutritional risk and malnutrition on clinical outcome. Considering that in daily practice, the assessment of patients’ clinical risk is of the utmost importance, it is self-evident that enhancing the relevance of preserving/restoring nutritional status may increase the daily implementation of nutritional assessment and therapy. Indeed, doctors will be then convinced that malnutrition is a relevant clinical risk factor similar to blood pressure, heart rate, cholesterol levels, etc. Human body can be divided into different compartments, which range from the molecular compartment (i.e., enzymes, structural proteins, lipid aggregates, etc.) to the organ level (i.e., gastrointestinal tract, nervous system, etc.). In daily clinical practice, subtle differences between compartments are not relevant, although it is acknowledged that diseases starts from the derangement of molecular events, yielding to cellular, tissue, and then organ dysfunctions. The increasing prevalence of obesity and the increased sensitivity/specificity of body composition analysis tools contributed to focus the interest of clinicians and researchers on two body compartments, muscle mass and adipose tissue. It is now becoming clearer and widely accepted that significant and clinically relevant nutritional changes are hidden when measuring body weight only. In particular, muscle mass
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and its progressive loss (i.e., sarcopenia) have been repeatedly demonstrated to predict clinically relevant events in aging people and in different clinical conditions as well.
2. DEFINITION OF SARCOPENIA Aging is associated with profound changes in nutritional status. In “As You Like it,” Act II, Scene VII, lines 157–161, William Shakespeare describes the phenotype of sarcopenia, highlighting the progressive decline of nutritional status, clearly evident from the sixth decade of life: “The sixth age shifts/Into the lean and slipper’d pantaloon/With spectacles on nose and pouch on side,/His youthful hose well sav’d, a world to wide/For his shrunk shank.” Although this early acknowledgment demonstrates that this syndrome, at those times not yet termed sarcopenia, was commonly observed since the sixteenth century, only in the 1930s the causal relationship between sarcopenia and aging was recognized, when Critchley reported that muscle loss was related to and occurs with aging (Critchley, 1931). In particular, a decline of lean body mass is observed, whose main components are muscle mass and bone mass. In the 1970s, due to the better definition of the cellular changes occurring with aging, it was proposed that age-related muscle loss results from atrophy and loss of type II muscle fibers (Larsson, 1978, 1983). The term sarcopenia derives from the Greek words “sarx” (¼flesh) and “penia” (¼deficiency). It was originally described by Evans and Campbell (1993) and further refined by Evans in 1995 (Evans, 1995). However, it was Rosenberg who used it for the first time in 1997 to define a geriatric syndrome (Rosenberg, 1997). Since the first attempts to elaborate the concept, the term sarcopenia was confined to the age-related loss of muscle mass and therefore relates to a specific subset of individuals, that is, older adults. The definition of sarcopenia has been the focus of different study groups. In 2009, the European Union Geriatric Medicine Society initiated a study group to create operational definitions of sarcopenia, that is, the European Working Group on Sarcopenia in Older People (EWGSOP). Experts representing different scientific societies, including the European Society for Clinical Nutrition and Metabolism, the International Academy of Nutrition and Aging, and the International Association of Gerontology and Geriatrics—European Region, were also invited to join the project (Cruz-Jentoft et al., 2010). The outcome of the consensus was the following definition: “Sarcopenia is a syndrome characterized by progressive and
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generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death” (Cruz-Jentoft et al., 2010). In the same year, a different group of experts (International Working Group on Sarcopenia, IWGS) convened to reach a new definition of sarcopenia and the result of their work was that “sarcopenia is the ageassociated loss of skeletal muscle mass and function. Sarcopenia is a complex syndrome that is associated with muscle mass loss alone or in conjunction with increased fat mass. The causes of sarcopenia are multifactorial and can include disuse, changing endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. While cachexia may be a component of sarcopenia, the two conditions are not the same” (International Working Group on Sarcopenia, 2011). Both definitions are very similar and focus on the specificity of the target population (i.e., older adults) and on the simultaneous deficit of muscle mass and function.
3. MECHANISMS OF SARCOPENIA Sarcopenia is a universal syndrome, which develops early in the course of human life, most likely during early adulthood. In fact, between the age of 30 and 80, a 30% reduction of muscle mass is generally observed (Frontera et al., 2000), which is the result of a quantitative and qualitative decline of muscle fibers (Lexell, Henriksson–Larsen, Wimblod, & Sjostrom, 1983). Human muscles are heterogeneous entities, which differ in terms of anatomical position, speed of shortening, specific shape, etc. Considering the clinical relevance of sarcopenia and the potential benefits associated with its prevention/treatment, it would be extremely important to assess whether it involves all muscle fibers or has a specific target, in order to develop effective therapeutic strategies. Skeletal muscles are characterized by types of their constituting muscle units and fibers. In particular, slow, fast fatigable, and fast fatigue-resistant motor units have been identified, composed by type I, IIA, and IIB fibers, respectively (Ciciliot, Rossi, Dyar, Blaauw, & Schiaffino, 2013). The morphological changes of sarcopenia are still matter of debate. Early studies showed a shift in muscle fiber composition with a higher type I/type II fiber ratio during aging (Larsson, 1978), due to selective atrophy of type II fibers (Lexell, Taylor, & Sjostrom, 1988; Porter, Vandervoort, & Lexell, 1995). Therefore, it was proposed that sarcopenia resulted from a
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preferential loss of type II fibers (Larsson, 1983), due to a reduction in highintensity activities that recruit these fibers, while type I fibers are used for most activities of daily living and during submaximal exercise (e.g., walking). At the molecular level, a number of characteristic changes occur in muscles during aging. Among others, an increase in hybrid type I and II fibers (Doherty, 2003; Reeves, Narici, & Maganaris, 2006) with advancing age has been described. Also, within the muscle, there is a decrease in noncontractile area along with a decrease in cross-bridging between the fibers. Single-fiber intrinsic force is decreased. Of specific interest are the results of studies investigating changes in the activity of receptors located on muscle fibers. In this light, there is a decline in the number of T-tubule dihydropyridine receptors and an increase in uncoupled ryanodine receptors. In particular, ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium-release channel required for muscle contraction. In a recent and elegant experimental study, RyR1 from aged (24 months) rodents was compared to RyR1 from younger (3–6 months) adults (Andersson et al., 2011). This RyR1 channel complex remodeling resulted in “leaky” channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice (Andersson et al., 2011). Treating aged mice with S107 stabilized binding of calstabin1, which is a channel stabilizing subunit, to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species, and enhanced tetanic Ca release, musclespecific force, and exercise capacity (Andersson et al., 2011). This observation provides molecular explanations to the well-established age-related reduction of twitch contraction time and of maximum shortening speed. It has been postulated that sarcopenia results from a preceding age-related denervation of myofibers. To assess this hypothesis, Deschenes et al. investigated in an experimental model whether signs of denervation were apparent at the neuromuscular junction before fiber atrophy, or fiber-type conversion could be documented (Deschenes, Roby, Eason, & Harris, 2010). Plantaris and soleus muscles were obtained from young adult (10 months) and early aged (21 months) rats. Pre- and postsynaptic neuromuscular joint morphology was quantified and myofiber profiles (fiber size and fiber-type composition) assessed. Results show that in the lightly recruited plantaris, significant signs of denervation were noted in aged rats, while the same muscles displayed no change in myofiber profile. In the heavily recruited soleus, however, there was little evidence of denervation
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and again no alterations in myofiber profile. These results suggest that age-related denervation occurs before myofiber atrophy and that high amounts of neuromuscular activity may delay the onset of age-related denervation and sarcopenia. Beyond the muscle-specific morphological and functional changes, the aging muscle suffers from important tendon changes which impact on muscular force (Narici & Maganaris, 2006; Onambele, Narici, & Maganaris, 2006; Reeves et al., 2006; Sipila & Suominen, 1996). Aging promotes a decrease in tendon stiffness which, coupled with the shortening of muscle fascicles, results in smaller pennation angles (Kubo et al., 2003; Mian, Thorn, Ardigo, Minetti, & Narici, 2007) and a decrease in specific force (i.e., fascicle force/physiological cross-sectional area). Of specific clinical relevance is the observation that aging is generally associated with a greater decline in lower body than upper body and extensor compared to flexor strength (Newman et al., 2005). Overall, there is a much greater decline in strength than muscle mass, with the decline in isometric knee extensor strength being between 55% and 76% (Doherty, 2003; Rolland, Perry, Patrick, Banks, & Morley, 2007). These changes may contribute to the decline in gait velocity that occurs with aging. As previously mentioned, sarcopenia is a universal, early and progressive phenomenon with a complex, multifactorial etiology. It is important to note that the impact on sarcopenia of many causes vary by the age of the individual (Table 3.1). The reasons for the changes outlined in Table 3.1 are manifold and include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living (von Haehling, Morley, & Anker, 2012). Genetic background has a major impact on the development and severity of sarcopenia (Carey, Farnfield, Tarquinio, & Cameron-Smith, 2007; Schrager et al., 2004; Welle, Brooks, Delehanty, Needler, & Thornton, 2003). In their recent report, Ibebunjo et al. determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months (Ibebunjo et al., 2013). These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular
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Table 3.1 Sarcopenia etiology by age Age Potential causes
Effects
20–40 Decreased physical activity, decreased type II muscle fiber size and amount, maintenance of type I fibers
Decreased physical activity, decreased type II muscle fiber size and amount, maintenance of type I fibers
Decreased aerobic and sprinting 40–60 Loss of motor units accelerates, decreased physical activity, increased capacity even with rigorous exercise, increased body fatness, insulin body fatness, decreased androgens resistance, decreased muscle protein synthesis 60–70 Decreased physical activity, reduced androgen and growth factor levels, menopause, increased total body and visceral fat, chronic disease, impaired appetite regulation
Inflammation (increased cytokine levels), insulin resistance and type 2 diabetes, nutritional deficiencies (protein, vitamin D, and other micronutrients), reduced muscle protein synthesis
70 þ
Fear of falling, low functional capacity, mild cognitive impairment, inflammation and increased muscle protein breakdown
Further reduction in physical activity, bouts of enforced inactivity due to illness, hospitalization depression, increased body fatness
Adapted from International Working Group on Sarcopenia (2011).
evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation (Ibebunjo et al., 2013). Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins (Ibebunjo et al., 2013). Nutritional status and, in particular, protein intake, energy intake, and vitamin D status are key factors modulating the phenotypical expression of sarcopenia (Campbell, Crim, Dallal, Young, & Evans, 1994; Campbell, Trappe, Wolfe, & Evans, 2001; Chapman, Macintosh, Morley, & Horowitz, 2002; Katsanos, Kobayashi, Sheffield-Moore, Aarsland, & Wolfe, 2005; Visser, Deeg, & Lips, 2003; Volpi, Sheffield-Moore, Rasmussen, & Wolfe, 2001). In the Tasmanian Older Adult Cohort Study, 740 noninstitutionalized older adults (50% female; mean age 62 7 years) were sampled from electoral rolls (Scott, Blizzard, Fell, Giles, & Jones, 2010). Dietary nutrient intake, appendicular lean mass, and muscle strength of the knee extensors were examined at baseline and follow-up (2.6 0.4 years later). Results obtained show that failing to meet the recommended dietary intake for protein was associated with
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significantly lower appendicular lean mass at baseline (0.81 kg) and followup (0.79 kg). Energy-adjusted protein intake was a positive predictor of change in appendicular lean mass over 2.6 years (Scott et al., 2010). However, no significant associations were observed between nutrient intake and muscle strength (Scott et al., 2010). Also vitamin D status appears to influence sarcopenia (Lee, Lee, et al., 2013), although recent data seem to question the relevance of vitamin D intake. In a cross-sectional analysis of 1989 community-dwelling women (mean age 80.5 3.8 years) from the EPIDe´miologie de l’OSte´oporose study, low intakes of vitamin D (50% of the total body potassium (TBK) pool. Therefore, TBK estimates the volume of muscle mass. More recently, partial body potassium of the arm has been proposed as a simpler alternative (Wielopolski et al., 2006). Anthropometric measures (mid-upper arm circumference and skin-fold thickness) can be easily used in ambulatory settings to estimate muscle mass. Calf circumference correlates positively with muscle mass, and calf circumference 65 years) of gait speed. If gait speed is 0.8 m/s, then muscle mass should be assessed and if it is low, then sarcopenia can be diagnosed (Cruz-Jentoft et al., 2010). In older adults with gait speed >0.8 m/s and low muscle strength, muscle mass should be assessed. If it is low, then diagnosis of sarcopenia can be made (Cruz-Jentoft et al., 2010).
4.2. IWGS criteria According to the IWGS, diagnosis of sarcopenia is based on gait speed 5% usual body weight); recent hospitalization; other chronic conditions (i.e., type 2 diabetes mellitus, chronic heart failure, chronic obstructive pulmonary disease, chronic kidney disease, rheumatoid arthritis, and cancer) (International Working Group on Sarcopenia, 2011).
4.3. Defining cutoff values Cut-off points depend upon the measurement technique chosen and on the availability of reference studies. EWGSOP recommends use of normative (healthy young adult) rather than other predictive reference populations, with cutoff points at two standard deviations below the mean reference value (Cruz-Jentoft et al., 2010). A list of cutoff value suggested by EWGSOP is available in Cruz-Jentoft et al. (2010), publication which is freely downloadable from Internet. However, more research is urgently needed in order to obtain good reference values for populations around the world.
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4.4. Comparison of sarcopenia defined by EWGSOP and IWGS As previously mentioned, EWGSOP and IWGS definitions of sarcopenia are very similar, but the diagnostic criteria differ. Consequently, it could be hypothesized that by applying either one or the other, the prevalence of sarcopenia largely varies. Large studies have tried to assess the discrepancies which result from using EWGSOP or IWGS definitions and diagnostic criteria. Patil et al. applied sarcopenia definitions to 409 community-dwelling, independently living women (mean age: 74.2 3.0 years) in Tampere, Finland (Patil et al., 2013). Skeletal muscle mass index (SMI), gait speed, and handgrip strength were used for sarcopenia diagnosis. Prevalence of sarcopenia was 0.9% and 2.7% according to the EWGSOP and IWGS, respectively. Women with higher gait speed had significantly lower body weight and fat mass percentage, higher lean mass percentage, and better functional ability. Women with a low SMI weighed significantly less, with no significant differences in other outcome measures. SMI, gait speed, and grip strength were significantly correlated (Patil et al., 2013). Lee et al. studied 100 young healthy volunteers and 408 elderly people from the I-Lan county of Taiwan (Lee, Liu, et al., 2013). Parameters studied included anthropometry, skeletal muscle mass measured by DXA, relative appendicular skeletal muscle index (RASM), percentage SMI, 6-m walking speed as a marker of physical performance, and handgrip strength. The prevalence of sarcopenia was 5.8–14.9% in men and 4.1–16.6% in women according to IWGS and EWGSOP criteria by using RASM or SMI as the muscle mass indices. The agreement of sarcopenia diagnosed by IWGS and EWGSOP criteria was only fair by using either RASM or SMI. The prevalence of sarcopenia was lower by the IWGS definition than the EWGSOP definition, but it was remarkably lower by using RASM than SMI in both criteria. Overall, sarcopenic individuals defined by SMI were older, had a higher BMI but similar total skeletal muscle mass, and had poorer muscle strength and physical performance than nonsarcopenic individuals. However, by using RASM, sarcopenic individuals had less total skeletal muscle mass but similar BMI than nonsarcopenic individuals. Multivariable logistic regression showed that age was the strongest associative factor for sarcopenia in both IWGS and EWGSOP criteria (Lee, Liu, et al., 2013). Large epidemiological studies consistently showed that the agreement of sarcopenia defined by IWGS and EWGSOP is only fair, and the prevalence
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may vary largely by using different markers of skeletal muscle mass. It is therefore imperative that proper selections of cutoff values of handgrip strength, walking speed, and skeletal muscle indices are made, which also consider gender and ethnic differences. This effort is of key importance to reach universal diagnostic criteria for sarcopenia.
4.5. Stages of sarcopenia Sarcopenia is a universal and progressive syndrome. Consequently, this clinical condition progresses from an early stage into more severe phenotypical expressions. From a therapeutical point of view, it would be clinically relevant if sarcopenia could be categorized into stages, in order to help clinical management by identifying windows of opportunity during which appropriate therapies are more likely to yield significant results. The EWGSOP proposed a conceptual staging as “presarcopenia,” “sarcopenia,” and “severe sarcopenia” (Cruz-Jentoft et al., 2010). The “presarcopenia” stage is characterized by low muscle mass with no impact on muscle strength or physical performance. This stage can only be identified by techniques that measure muscle mass accurately and in reference to standard populations (Cruz-Jentoft et al., 2010). The “sarcopenia” stage is characterized by low muscle mass, plus low muscle strength or low physical performance (Cruz-Jentoft et al., 2010). “Severe sarcopenia” is the stage identified when all three criteria of the definition are met (low muscle mass, low muscle strength, and low physical performance) (Cruz-Jentoft et al., 2010). Recognizing stages of sarcopenia may help in selecting treatments and setting appropriate recovery goals. Staging may also support design of research studies that focus on a particular stage or on stage changes over time. It should be highlighted that EWGSOP sarcopenia staging is still a conceptual framework, which needs to be supported by clinical investigations.
4.6. Consensus statement by the Society of Sarcopenia, Cachexia and Wasting Disorders Recently, a consensus conference convened by the Society of Sarcopenia, Cachexia and Wasting Disorders has concluded that “sarcopenia, i.e., reduced muscle mass, with limited mobility” should be considered an important clinical entity and that most older persons should be screened for this condition (Morley et al., 2011). In particular, “sarcopenia with limited mobility” can be diagnosed in a person with muscle loss whose walking speed is equal to or less than 1 m/s or who walks less than 400 m during a
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6-min walk, and who has a lean appendicular mass corrected for height squared of 2 SD or more below the mean of healthy persons between 20 and 30 years of age of the same ethnic group (Morley et al., 2011). However, these criteria remain cumbersome in daily clinical practice and easily applicable tests such as handgrip strength testing or one of the biomarkers mentioned above may help to identify patients in need of a more thorough examination (Morley et al., 2011). As further discussed in a subsequent section of this chapter, no consensus has been reached by the experts convened by the Society of Sarcopenia, Cachexia and Wasting Disorders as to whether the term sarcopenia should be limited to older persons above 60 years of age or whether it should be used in adults of any age, particularly also in patients with chronic disease (Morley et al., 2011).
5. SARCOPENIA AND DYNAPENIA Age-related muscle loss does not necessarily result in an equivalent reduction of muscle strength. Therefore, sarcopenia and dynapenia (i.e., reduced muscle strength) are related but not correlated conditions. Recent longitudinal data from the Health ABC Study indicate that the decline in muscle strength is much more rapid than the concomitant loss of muscle mass and that the change in quadriceps muscle area only explains about 6–8% of the between-subject variability in the change in knee extensor muscle strength (Delmonico et al., 2009). Data from the InChianti Study showed that muscle cross-sectional area of the calf was not associated with an increased risk of mortality when covariates were considered (Cesari, Pahor, et al., 2009). Also, Newman et al. (2006) demonstrated that muscle mass and cross-sectional area were not associated with risk of mortality. However, both grip and knee extensor muscle strength was highly associated with mortality, despite accounting for muscle mass, suggesting that sarcopenia may be secondary to the effects of dynapenia (Cesari, Pahor, et al., 2009). Collectively, these findings indicate that muscle strength— and not simply muscle mass—is a critical factor for determining both physical disability and mortality in older adults. However, it should be also noted that reduction of muscle strength with age is not the only cause of the loss of physical function, since there are many other conditions that can dramatically impair physical function (i.e., poor cardiopulmonary function, cognitive deficits, etc.).
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The mechanisms responsible for declining muscle strength can be attributed to a combination of “neural” and “muscular” factors. For example, deficits in neural (central) activation, such as that due to a reduction in descending excitatory drive from supraspinal centers and/or suboptimal motor unit recruitment and rate coding, could result in dynapenia (Marini & Clark, 2012). Additionally, a reduction in the intrinsic forcegenerating capacity of muscle, changes in actomyosin structure and function, and infiltration of adipocytes into muscle fibers could result in dynapenia (Marini & Clark, 2012). In recent years, the aging-specific cortical changes have begun to be explored. Results show that aging is associated with widespread qualitative and quantitative changes in the motor cortex and spinal cord. Among other neural deficits, morphometric changes occur in the motor cortex, including volumetric reduction of the premotor cortex neuron cell body size (Haug & Eggers, 1991), cortical atrophy of areas near the primary motor cortex (Salat et al., 2004), and reduction in the total length of myelinated fibers (Marner, Nyengaard, Tang, & Pakkenberg, 2003). Aging is also associated with changes of the serotonergic (Morgan, May, & Finch, 1987), cholinergic (Bartus, Dean, Beer, & Lippa, 1982), adrenergic (Bigham & Lidow, 1995), and dopaminergic (Segovia, Porras, Del Arco, & Mora, 2001) systems. Finally, aging results in cortical hypoexcitability (Kossev, Schrader, Dauper, Dengler, & Rollnik, 2002), impaired modulation of the activity of inappropriate motor networks when required (Heuninckx, Wenderoth, Debaere, Peeters, & Swinnen, 2005), and reduced cortical plasticity (Fathi et al., 2009). When considered together, these evidence suggest that age-related neural changes contribute to age-related reductions in motor performance although the exact relationship to strength loss is yet to be determined.
6. CLINICAL CONSEQUENCES OF SARCOPENIA The relevance of any clinical syndrome is based on its impact on patient’s outcome. In this light, sarcopenia is a clinical condition which significantly impacts on health, economic, and social outcome measures. Sarcopenia is correlated with functional decline and disability (Baumgartner et al., 1998). Data are often stronger in men than in women, most likely as the results of the indexing method used. Sarcopenia has been demonstrated to predict falls. Among the most recent studies supporting the relationship between sarcopenia and falls risk, Scott et al. investigated 681
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volunteers (48% female; mean age: 61.4 7.0 years) over a 5-year period (Scott et al., 2013). Appendicular lean mass, handgrip strength, and lower limb strength were assessed. Falls risk was determined using the physiological profile assessment. Anthropometric definitions and performance-based definitions of sarcopenia were examined. The lowest 20% of the sex-specific distribution for each definition at baseline was classified as sarcopenia. After 5 years, sarcopenia prevalence increased for all operational definitions. Men classified with sarcopenia according to anthropometric definitions and women classified with sarcopenia according to performance-based definitions had significant increases in falls risk over 5 years compared to individuals without sarcopenia (Scott et al., 2013). Therefore, sarcopenia prevalence generally increases at a higher rate when assessed using performance-based definitions. Sarcopenia is associated with increases in falls risk over 5 years in community-dwelling middle-aged and older adults, but sex-specific differences may exist according to different anthropometric or performance-based definitions (Scott et al., 2013). In the longitudinal Rancho Bernardo study, sarcopenia was shown to be predictive of falls (Castillo et al., 2003). Janssen (2006) examined 5036 men and women over 65 enrolled in the Cardiovascular Health Study. He reported that the likelihood of disability was 79% greater for those with “severe” sarcopenia but not significantly different for those with “moderate” sarcopenia compared with those with normal muscle mass. During 8-year follow-up, only those with severe sarcopenia were more likely to develop physical disability. Finally, sarcopenia predicts nosocomial infection during hospitalization (Cosqueric et al., 2006) and mortality (Roubenoff, 2000), although muscle strength and physical performance are more robust predictors, as previously mentioned. In recent years, a close relationship between increased fat mass, low muscle mass, and poor health outcome has been identified. The term sarcopenic obesity was first used by Heber et al. (1996) and describes persons with reduced body mass out of proportion to their adipose mass. Sarcopenic obesity is associated with disability, gait problems, and falls to a greater extent than persons with “proportionate” sarcopenia (Baumgartner et al., 2004). Supporting evidence were reported by the Framingham and National Health and Nutrition Examination Survey studies, which confirmed that older adults with large adipose tissue and low muscle mass had the highest rate of disabilities (Davison, Ford, Cogswell, & Dietz, 2002). These consistent data point to the fact that the development of disability and impaired mobility in older people has a complex etiology. Muscle mass is an important, but not the only predictor of muscle strength or physical
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function, since fat has several adverse effects on muscle function. As an example, the presence of a large adipose tissue is associated with greater intramuscular lipid and reduced muscle quality, defined as reduced strength/cross-sectional area (Goodpaster, 1999). Also, it cannot be excluded that body fatness decreases the capacity to generate power, and muscle power is more closely related to functional capacity than muscle strength (Bassey et al., 1992). It is therefore likely that to further refine the operational definition of sarcopenia, fat mass should be taken into account.
7. SARCOPENIA: A SPECIFIC GERIATRIC SYNDROME? Muscle wasting is a common feature of many chronic diseases, including cancer, chronic kidney disease, and chronic pulmonary disease (Ruegg & Glass, 2011). Since the molecular mechanisms of diseaseassociated muscle wasting and age-related muscle loss are similar (Ruegg & Glass, 2011), the term sarcopenia could be used to encompass muscle and strength loss, independently of the underlying causative factors (i.e., aging, disease, therapies, etc.). This approach would also help in minimizing confounding factors when assessing muscle mass in older adults with chronic diseases. In fact, it would be difficult to define and characterize in this growing population of patients how much muscle loss is secondary to aging and how much results from disease-associated metabolic changes. Muscle wasting is the key feature of the cachexia syndrome, which is associated with chronic and acute diseases (Fearon, Strasser, et al., 2011). Cachexia has recently been defined as a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle (Fearon, Strasser, et al., 2011). Similar to what has been described for age-related muscle loss, cachexia is frequently associated with inflammation, insulin resistance, anorexia, and increased breakdown of muscle proteins (Durham, Dillon, & Sheffield-Moore, 2009; Morley, Anker, & Evans, 2009). Thus, cachectic individuals are also sarcopenic, but most sarcopenic individuals are not considered cachectic. Therefore, debate has started on whether the muscular component of the definition of cachexia (i.e., disease-associated muscle loss) could be defined as sarcopenia, and thus categorized according to criteria set for sarcopenia. The EWGSOP proposed a practical approach based on the clinical knowledge that in some individuals, a clear and single cause of sarcopenia can be identified, whereas in other cases, no evident cause can be isolated
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Table 3.3 Categories of sarcopenia
Primary sarcopenia Age-related sarcopenia
No other cause evident except aging
Secondary sarcopenia Activity-related sarcopenia Can result from bed rest, sedentary lifestyle, deconditioning, or zero-gravity conditions Disease-related sarcopenia
Associated with advanced organ failure (heart, lung, liver, kidney, brain), inflammatory disease, malignancy, or endocrine disease
Nutrition-related sarcopenia
Results from inadequate dietary intake of energy and/or protein, as with malabsorption, gastrointestinal disorders, or use of medications that cause anorexia
(Cruz-Jentoft et al., 2010). Thus, EWGSOP proposed to stratify individuals into the categories of primary sarcopenia and secondary sarcopenia (CruzJentoft et al., 2010). Sarcopenia is defined as “primary” (or age-related) when no other cause is evident but aging itself. In contrast, Sarcopenia can be considered “secondary” when one or more other causes are evident (Table 3.3). In the majority of older adults, the etiology of sarcopenia is multifactorial so that it is not possible to characterize each individual as having a primary or secondary condition. This frequent undetermined situation is consistent with the general knowledge that sarcopenia is a multifaceted geriatric syndrome. Recently, a group of experts in the field of cachexia proposed that disease-associated muscle loss should be defined with a specific term to differentiate it from the age-related muscle loss (Fearon, Evans, & Anker, 2011). Indeed, concern may arise when using the diagnostic criteria of sarcopenia, which were developed for older people, to younger patients. By applying diagnostic criteria developed for those over 65 to patients who are aged 40, underestimation of the magnitude of their deficit will inevitably occur. To address this concern, the authors rejected the use of the term sarcopenia as a blanket term for muscle wasting at any age and from any cause, but accepted that sarcopenia should be reserved for (clinically significant) muscle wasting of the elderly (Fearon, Evans, et al., 2011). Consequently, a new term had to be found, different from “muscle wasting” since it is already used to describe a pathophysiologic process and not used or accepted
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to describe a medical entity requiring intervention. Also, “muscle wasting” translates poorly into other languages, which has hindered widespread acceptance outside groups communicating in English. Therefore, the group of experts proposed the new term “myopenia,” which results from the Greek words “myo” (¼muscle) and “penia” (¼deficit, loss). Therefore, myopenia is defined as a clinically relevant degree of muscle wasting that is associated either with impaired functional capacity and/or with increased risk of morbidity or mortality (Fearon, Evans, et al., 2011). The precise cutpoints to diagnose myopenia may be disease- or condition-specific. Myopenia can be diagnosed when a certain degree of muscle loss over time has occurred (for instance, at least 5% in 6–12 months) or when muscle mass is below a certain threshold level (Fearon, Evans, et al., 2011). For the latter, for instance, this could be a muscle mass below the 5th centile of healthy 30-year olds or a fat-free mass index
Sarcopenia and Nutrition Alessandro Laviano1, Chiara Gori, Serena Rianda Department of Clinical Medicine, Sapienza University, Rome, Italy 1 Corresponding author: e-mail address: [email protected]
Contents 1. 2. 3. 4.
Introduction Definition of Sarcopenia Mechanisms of Sarcopenia Diagnosing Sarcopenia 4.1 EWGSOP criteria 4.2 IWGS criteria 4.3 Defining cutoff values 4.4 Comparison of sarcopenia defined by EWGSOP and IWGS 4.5 Stages of sarcopenia 4.6 Consensus statement by the Society of Sarcopenia, Cachexia and Wasting Disorders 5. Sarcopenia and Dynapenia 6. Clinical Consequences of Sarcopenia 7. Sarcopenia: A Specific Geriatric Syndrome? 8. Nutrition Therapy for Sarcopenia 8.1 Supplementation with essential amino acids 8.2 Other nutrients 9. Conclusions References
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Abstract Preserving or restoring adequate nutritional status is a key factor to delay the onset of chronic diseases and to accelerate recovery from acute illnesses. In particular, consistent and robust data show the loss of muscle mass, that is, sarcopenia, is clinically relevant since it is closely related to increased morbidity and mortality in healthy individuals and patients. Sarcopenia is defined as the age-related loss of muscle mass and function. International study groups have recently proposed separate definitions and diagnostic criteria for sarcopenia. Unfortunately, the rate of agreement in assessing the prevalence of sarcopenia is just fair, which highlights the need for a common effort to harmonize definitions and diagnostic criteria. Sarcopenia should be distinct from myopenia, which is the disease-associated loss of muscle mass, although in clinical practice it may be impossible to separate them (i.e., in old cancer patients). The pathogenesis of sarcopenia
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is complex and multifactorial. Consequently, its treatment should target the different factors involved, including quantitatively and qualitatively inappropriate food intake and reduced physical activity.
1. INTRODUCTION Optimal nutritional status is a key factor in preserving healthy conditions, in facilitating recovery from acute diseases, and in extending survival of patients suffering from chronic diseases. For decades, body weight and its relationship with height (i.e., body mass index, BMI) have been considered robust markers of nutritional status. Consequently, involuntary and significant weight loss (i.e., >5% of usual body weight in 1–3 months) is generally regarded as a marker of nutritional risk and malnutrition. Although it is acknowledged that simple and easily available tools are needed and indispensable to assess the nutritional status of entire populations, concerns are raised when such tools are used to evaluate single patients. In fact, it is now clearly established that body composition analysis provides more solid information regarding not only nutritional status but also on the clinical consequences of nutritional risk and malnutrition on clinical outcome. Considering that in daily practice, the assessment of patients’ clinical risk is of the utmost importance, it is self-evident that enhancing the relevance of preserving/restoring nutritional status may increase the daily implementation of nutritional assessment and therapy. Indeed, doctors will be then convinced that malnutrition is a relevant clinical risk factor similar to blood pressure, heart rate, cholesterol levels, etc. Human body can be divided into different compartments, which range from the molecular compartment (i.e., enzymes, structural proteins, lipid aggregates, etc.) to the organ level (i.e., gastrointestinal tract, nervous system, etc.). In daily clinical practice, subtle differences between compartments are not relevant, although it is acknowledged that diseases starts from the derangement of molecular events, yielding to cellular, tissue, and then organ dysfunctions. The increasing prevalence of obesity and the increased sensitivity/specificity of body composition analysis tools contributed to focus the interest of clinicians and researchers on two body compartments, muscle mass and adipose tissue. It is now becoming clearer and widely accepted that significant and clinically relevant nutritional changes are hidden when measuring body weight only. In particular, muscle mass
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and its progressive loss (i.e., sarcopenia) have been repeatedly demonstrated to predict clinically relevant events in aging people and in different clinical conditions as well.
2. DEFINITION OF SARCOPENIA Aging is associated with profound changes in nutritional status. In “As You Like it,” Act II, Scene VII, lines 157–161, William Shakespeare describes the phenotype of sarcopenia, highlighting the progressive decline of nutritional status, clearly evident from the sixth decade of life: “The sixth age shifts/Into the lean and slipper’d pantaloon/With spectacles on nose and pouch on side,/His youthful hose well sav’d, a world to wide/For his shrunk shank.” Although this early acknowledgment demonstrates that this syndrome, at those times not yet termed sarcopenia, was commonly observed since the sixteenth century, only in the 1930s the causal relationship between sarcopenia and aging was recognized, when Critchley reported that muscle loss was related to and occurs with aging (Critchley, 1931). In particular, a decline of lean body mass is observed, whose main components are muscle mass and bone mass. In the 1970s, due to the better definition of the cellular changes occurring with aging, it was proposed that age-related muscle loss results from atrophy and loss of type II muscle fibers (Larsson, 1978, 1983). The term sarcopenia derives from the Greek words “sarx” (¼flesh) and “penia” (¼deficiency). It was originally described by Evans and Campbell (1993) and further refined by Evans in 1995 (Evans, 1995). However, it was Rosenberg who used it for the first time in 1997 to define a geriatric syndrome (Rosenberg, 1997). Since the first attempts to elaborate the concept, the term sarcopenia was confined to the age-related loss of muscle mass and therefore relates to a specific subset of individuals, that is, older adults. The definition of sarcopenia has been the focus of different study groups. In 2009, the European Union Geriatric Medicine Society initiated a study group to create operational definitions of sarcopenia, that is, the European Working Group on Sarcopenia in Older People (EWGSOP). Experts representing different scientific societies, including the European Society for Clinical Nutrition and Metabolism, the International Academy of Nutrition and Aging, and the International Association of Gerontology and Geriatrics—European Region, were also invited to join the project (Cruz-Jentoft et al., 2010). The outcome of the consensus was the following definition: “Sarcopenia is a syndrome characterized by progressive and
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generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death” (Cruz-Jentoft et al., 2010). In the same year, a different group of experts (International Working Group on Sarcopenia, IWGS) convened to reach a new definition of sarcopenia and the result of their work was that “sarcopenia is the ageassociated loss of skeletal muscle mass and function. Sarcopenia is a complex syndrome that is associated with muscle mass loss alone or in conjunction with increased fat mass. The causes of sarcopenia are multifactorial and can include disuse, changing endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. While cachexia may be a component of sarcopenia, the two conditions are not the same” (International Working Group on Sarcopenia, 2011). Both definitions are very similar and focus on the specificity of the target population (i.e., older adults) and on the simultaneous deficit of muscle mass and function.
3. MECHANISMS OF SARCOPENIA Sarcopenia is a universal syndrome, which develops early in the course of human life, most likely during early adulthood. In fact, between the age of 30 and 80, a 30% reduction of muscle mass is generally observed (Frontera et al., 2000), which is the result of a quantitative and qualitative decline of muscle fibers (Lexell, Henriksson–Larsen, Wimblod, & Sjostrom, 1983). Human muscles are heterogeneous entities, which differ in terms of anatomical position, speed of shortening, specific shape, etc. Considering the clinical relevance of sarcopenia and the potential benefits associated with its prevention/treatment, it would be extremely important to assess whether it involves all muscle fibers or has a specific target, in order to develop effective therapeutic strategies. Skeletal muscles are characterized by types of their constituting muscle units and fibers. In particular, slow, fast fatigable, and fast fatigue-resistant motor units have been identified, composed by type I, IIA, and IIB fibers, respectively (Ciciliot, Rossi, Dyar, Blaauw, & Schiaffino, 2013). The morphological changes of sarcopenia are still matter of debate. Early studies showed a shift in muscle fiber composition with a higher type I/type II fiber ratio during aging (Larsson, 1978), due to selective atrophy of type II fibers (Lexell, Taylor, & Sjostrom, 1988; Porter, Vandervoort, & Lexell, 1995). Therefore, it was proposed that sarcopenia resulted from a
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preferential loss of type II fibers (Larsson, 1983), due to a reduction in highintensity activities that recruit these fibers, while type I fibers are used for most activities of daily living and during submaximal exercise (e.g., walking). At the molecular level, a number of characteristic changes occur in muscles during aging. Among others, an increase in hybrid type I and II fibers (Doherty, 2003; Reeves, Narici, & Maganaris, 2006) with advancing age has been described. Also, within the muscle, there is a decrease in noncontractile area along with a decrease in cross-bridging between the fibers. Single-fiber intrinsic force is decreased. Of specific interest are the results of studies investigating changes in the activity of receptors located on muscle fibers. In this light, there is a decline in the number of T-tubule dihydropyridine receptors and an increase in uncoupled ryanodine receptors. In particular, ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium-release channel required for muscle contraction. In a recent and elegant experimental study, RyR1 from aged (24 months) rodents was compared to RyR1 from younger (3–6 months) adults (Andersson et al., 2011). This RyR1 channel complex remodeling resulted in “leaky” channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice (Andersson et al., 2011). Treating aged mice with S107 stabilized binding of calstabin1, which is a channel stabilizing subunit, to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species, and enhanced tetanic Ca release, musclespecific force, and exercise capacity (Andersson et al., 2011). This observation provides molecular explanations to the well-established age-related reduction of twitch contraction time and of maximum shortening speed. It has been postulated that sarcopenia results from a preceding age-related denervation of myofibers. To assess this hypothesis, Deschenes et al. investigated in an experimental model whether signs of denervation were apparent at the neuromuscular junction before fiber atrophy, or fiber-type conversion could be documented (Deschenes, Roby, Eason, & Harris, 2010). Plantaris and soleus muscles were obtained from young adult (10 months) and early aged (21 months) rats. Pre- and postsynaptic neuromuscular joint morphology was quantified and myofiber profiles (fiber size and fiber-type composition) assessed. Results show that in the lightly recruited plantaris, significant signs of denervation were noted in aged rats, while the same muscles displayed no change in myofiber profile. In the heavily recruited soleus, however, there was little evidence of denervation
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and again no alterations in myofiber profile. These results suggest that age-related denervation occurs before myofiber atrophy and that high amounts of neuromuscular activity may delay the onset of age-related denervation and sarcopenia. Beyond the muscle-specific morphological and functional changes, the aging muscle suffers from important tendon changes which impact on muscular force (Narici & Maganaris, 2006; Onambele, Narici, & Maganaris, 2006; Reeves et al., 2006; Sipila & Suominen, 1996). Aging promotes a decrease in tendon stiffness which, coupled with the shortening of muscle fascicles, results in smaller pennation angles (Kubo et al., 2003; Mian, Thorn, Ardigo, Minetti, & Narici, 2007) and a decrease in specific force (i.e., fascicle force/physiological cross-sectional area). Of specific clinical relevance is the observation that aging is generally associated with a greater decline in lower body than upper body and extensor compared to flexor strength (Newman et al., 2005). Overall, there is a much greater decline in strength than muscle mass, with the decline in isometric knee extensor strength being between 55% and 76% (Doherty, 2003; Rolland, Perry, Patrick, Banks, & Morley, 2007). These changes may contribute to the decline in gait velocity that occurs with aging. As previously mentioned, sarcopenia is a universal, early and progressive phenomenon with a complex, multifactorial etiology. It is important to note that the impact on sarcopenia of many causes vary by the age of the individual (Table 3.1). The reasons for the changes outlined in Table 3.1 are manifold and include denervation of motor units and a net conversion of fast type II muscle fibers into slow type I fibers with resulting loss in muscle power necessary for activities of daily living (von Haehling, Morley, & Anker, 2012). Genetic background has a major impact on the development and severity of sarcopenia (Carey, Farnfield, Tarquinio, & Cameron-Smith, 2007; Schrager et al., 2004; Welle, Brooks, Delehanty, Needler, & Thornton, 2003). In their recent report, Ibebunjo et al. determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months (Ibebunjo et al., 2013). These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular
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Table 3.1 Sarcopenia etiology by age Age Potential causes
Effects
20–40 Decreased physical activity, decreased type II muscle fiber size and amount, maintenance of type I fibers
Decreased physical activity, decreased type II muscle fiber size and amount, maintenance of type I fibers
Decreased aerobic and sprinting 40–60 Loss of motor units accelerates, decreased physical activity, increased capacity even with rigorous exercise, increased body fatness, insulin body fatness, decreased androgens resistance, decreased muscle protein synthesis 60–70 Decreased physical activity, reduced androgen and growth factor levels, menopause, increased total body and visceral fat, chronic disease, impaired appetite regulation
Inflammation (increased cytokine levels), insulin resistance and type 2 diabetes, nutritional deficiencies (protein, vitamin D, and other micronutrients), reduced muscle protein synthesis
70 þ
Fear of falling, low functional capacity, mild cognitive impairment, inflammation and increased muscle protein breakdown
Further reduction in physical activity, bouts of enforced inactivity due to illness, hospitalization depression, increased body fatness
Adapted from International Working Group on Sarcopenia (2011).
evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation (Ibebunjo et al., 2013). Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins (Ibebunjo et al., 2013). Nutritional status and, in particular, protein intake, energy intake, and vitamin D status are key factors modulating the phenotypical expression of sarcopenia (Campbell, Crim, Dallal, Young, & Evans, 1994; Campbell, Trappe, Wolfe, & Evans, 2001; Chapman, Macintosh, Morley, & Horowitz, 2002; Katsanos, Kobayashi, Sheffield-Moore, Aarsland, & Wolfe, 2005; Visser, Deeg, & Lips, 2003; Volpi, Sheffield-Moore, Rasmussen, & Wolfe, 2001). In the Tasmanian Older Adult Cohort Study, 740 noninstitutionalized older adults (50% female; mean age 62 7 years) were sampled from electoral rolls (Scott, Blizzard, Fell, Giles, & Jones, 2010). Dietary nutrient intake, appendicular lean mass, and muscle strength of the knee extensors were examined at baseline and follow-up (2.6 0.4 years later). Results obtained show that failing to meet the recommended dietary intake for protein was associated with
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significantly lower appendicular lean mass at baseline (0.81 kg) and followup (0.79 kg). Energy-adjusted protein intake was a positive predictor of change in appendicular lean mass over 2.6 years (Scott et al., 2010). However, no significant associations were observed between nutrient intake and muscle strength (Scott et al., 2010). Also vitamin D status appears to influence sarcopenia (Lee, Lee, et al., 2013), although recent data seem to question the relevance of vitamin D intake. In a cross-sectional analysis of 1989 community-dwelling women (mean age 80.5 3.8 years) from the EPIDe´miologie de l’OSte´oporose study, low intakes of vitamin D (50% of the total body potassium (TBK) pool. Therefore, TBK estimates the volume of muscle mass. More recently, partial body potassium of the arm has been proposed as a simpler alternative (Wielopolski et al., 2006). Anthropometric measures (mid-upper arm circumference and skin-fold thickness) can be easily used in ambulatory settings to estimate muscle mass. Calf circumference correlates positively with muscle mass, and calf circumference 65 years) of gait speed. If gait speed is 0.8 m/s, then muscle mass should be assessed and if it is low, then sarcopenia can be diagnosed (Cruz-Jentoft et al., 2010). In older adults with gait speed >0.8 m/s and low muscle strength, muscle mass should be assessed. If it is low, then diagnosis of sarcopenia can be made (Cruz-Jentoft et al., 2010).
4.2. IWGS criteria According to the IWGS, diagnosis of sarcopenia is based on gait speed 5% usual body weight); recent hospitalization; other chronic conditions (i.e., type 2 diabetes mellitus, chronic heart failure, chronic obstructive pulmonary disease, chronic kidney disease, rheumatoid arthritis, and cancer) (International Working Group on Sarcopenia, 2011).
4.3. Defining cutoff values Cut-off points depend upon the measurement technique chosen and on the availability of reference studies. EWGSOP recommends use of normative (healthy young adult) rather than other predictive reference populations, with cutoff points at two standard deviations below the mean reference value (Cruz-Jentoft et al., 2010). A list of cutoff value suggested by EWGSOP is available in Cruz-Jentoft et al. (2010), publication which is freely downloadable from Internet. However, more research is urgently needed in order to obtain good reference values for populations around the world.
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4.4. Comparison of sarcopenia defined by EWGSOP and IWGS As previously mentioned, EWGSOP and IWGS definitions of sarcopenia are very similar, but the diagnostic criteria differ. Consequently, it could be hypothesized that by applying either one or the other, the prevalence of sarcopenia largely varies. Large studies have tried to assess the discrepancies which result from using EWGSOP or IWGS definitions and diagnostic criteria. Patil et al. applied sarcopenia definitions to 409 community-dwelling, independently living women (mean age: 74.2 3.0 years) in Tampere, Finland (Patil et al., 2013). Skeletal muscle mass index (SMI), gait speed, and handgrip strength were used for sarcopenia diagnosis. Prevalence of sarcopenia was 0.9% and 2.7% according to the EWGSOP and IWGS, respectively. Women with higher gait speed had significantly lower body weight and fat mass percentage, higher lean mass percentage, and better functional ability. Women with a low SMI weighed significantly less, with no significant differences in other outcome measures. SMI, gait speed, and grip strength were significantly correlated (Patil et al., 2013). Lee et al. studied 100 young healthy volunteers and 408 elderly people from the I-Lan county of Taiwan (Lee, Liu, et al., 2013). Parameters studied included anthropometry, skeletal muscle mass measured by DXA, relative appendicular skeletal muscle index (RASM), percentage SMI, 6-m walking speed as a marker of physical performance, and handgrip strength. The prevalence of sarcopenia was 5.8–14.9% in men and 4.1–16.6% in women according to IWGS and EWGSOP criteria by using RASM or SMI as the muscle mass indices. The agreement of sarcopenia diagnosed by IWGS and EWGSOP criteria was only fair by using either RASM or SMI. The prevalence of sarcopenia was lower by the IWGS definition than the EWGSOP definition, but it was remarkably lower by using RASM than SMI in both criteria. Overall, sarcopenic individuals defined by SMI were older, had a higher BMI but similar total skeletal muscle mass, and had poorer muscle strength and physical performance than nonsarcopenic individuals. However, by using RASM, sarcopenic individuals had less total skeletal muscle mass but similar BMI than nonsarcopenic individuals. Multivariable logistic regression showed that age was the strongest associative factor for sarcopenia in both IWGS and EWGSOP criteria (Lee, Liu, et al., 2013). Large epidemiological studies consistently showed that the agreement of sarcopenia defined by IWGS and EWGSOP is only fair, and the prevalence
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may vary largely by using different markers of skeletal muscle mass. It is therefore imperative that proper selections of cutoff values of handgrip strength, walking speed, and skeletal muscle indices are made, which also consider gender and ethnic differences. This effort is of key importance to reach universal diagnostic criteria for sarcopenia.
4.5. Stages of sarcopenia Sarcopenia is a universal and progressive syndrome. Consequently, this clinical condition progresses from an early stage into more severe phenotypical expressions. From a therapeutical point of view, it would be clinically relevant if sarcopenia could be categorized into stages, in order to help clinical management by identifying windows of opportunity during which appropriate therapies are more likely to yield significant results. The EWGSOP proposed a conceptual staging as “presarcopenia,” “sarcopenia,” and “severe sarcopenia” (Cruz-Jentoft et al., 2010). The “presarcopenia” stage is characterized by low muscle mass with no impact on muscle strength or physical performance. This stage can only be identified by techniques that measure muscle mass accurately and in reference to standard populations (Cruz-Jentoft et al., 2010). The “sarcopenia” stage is characterized by low muscle mass, plus low muscle strength or low physical performance (Cruz-Jentoft et al., 2010). “Severe sarcopenia” is the stage identified when all three criteria of the definition are met (low muscle mass, low muscle strength, and low physical performance) (Cruz-Jentoft et al., 2010). Recognizing stages of sarcopenia may help in selecting treatments and setting appropriate recovery goals. Staging may also support design of research studies that focus on a particular stage or on stage changes over time. It should be highlighted that EWGSOP sarcopenia staging is still a conceptual framework, which needs to be supported by clinical investigations.
4.6. Consensus statement by the Society of Sarcopenia, Cachexia and Wasting Disorders Recently, a consensus conference convened by the Society of Sarcopenia, Cachexia and Wasting Disorders has concluded that “sarcopenia, i.e., reduced muscle mass, with limited mobility” should be considered an important clinical entity and that most older persons should be screened for this condition (Morley et al., 2011). In particular, “sarcopenia with limited mobility” can be diagnosed in a person with muscle loss whose walking speed is equal to or less than 1 m/s or who walks less than 400 m during a
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6-min walk, and who has a lean appendicular mass corrected for height squared of 2 SD or more below the mean of healthy persons between 20 and 30 years of age of the same ethnic group (Morley et al., 2011). However, these criteria remain cumbersome in daily clinical practice and easily applicable tests such as handgrip strength testing or one of the biomarkers mentioned above may help to identify patients in need of a more thorough examination (Morley et al., 2011). As further discussed in a subsequent section of this chapter, no consensus has been reached by the experts convened by the Society of Sarcopenia, Cachexia and Wasting Disorders as to whether the term sarcopenia should be limited to older persons above 60 years of age or whether it should be used in adults of any age, particularly also in patients with chronic disease (Morley et al., 2011).
5. SARCOPENIA AND DYNAPENIA Age-related muscle loss does not necessarily result in an equivalent reduction of muscle strength. Therefore, sarcopenia and dynapenia (i.e., reduced muscle strength) are related but not correlated conditions. Recent longitudinal data from the Health ABC Study indicate that the decline in muscle strength is much more rapid than the concomitant loss of muscle mass and that the change in quadriceps muscle area only explains about 6–8% of the between-subject variability in the change in knee extensor muscle strength (Delmonico et al., 2009). Data from the InChianti Study showed that muscle cross-sectional area of the calf was not associated with an increased risk of mortality when covariates were considered (Cesari, Pahor, et al., 2009). Also, Newman et al. (2006) demonstrated that muscle mass and cross-sectional area were not associated with risk of mortality. However, both grip and knee extensor muscle strength was highly associated with mortality, despite accounting for muscle mass, suggesting that sarcopenia may be secondary to the effects of dynapenia (Cesari, Pahor, et al., 2009). Collectively, these findings indicate that muscle strength— and not simply muscle mass—is a critical factor for determining both physical disability and mortality in older adults. However, it should be also noted that reduction of muscle strength with age is not the only cause of the loss of physical function, since there are many other conditions that can dramatically impair physical function (i.e., poor cardiopulmonary function, cognitive deficits, etc.).
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The mechanisms responsible for declining muscle strength can be attributed to a combination of “neural” and “muscular” factors. For example, deficits in neural (central) activation, such as that due to a reduction in descending excitatory drive from supraspinal centers and/or suboptimal motor unit recruitment and rate coding, could result in dynapenia (Marini & Clark, 2012). Additionally, a reduction in the intrinsic forcegenerating capacity of muscle, changes in actomyosin structure and function, and infiltration of adipocytes into muscle fibers could result in dynapenia (Marini & Clark, 2012). In recent years, the aging-specific cortical changes have begun to be explored. Results show that aging is associated with widespread qualitative and quantitative changes in the motor cortex and spinal cord. Among other neural deficits, morphometric changes occur in the motor cortex, including volumetric reduction of the premotor cortex neuron cell body size (Haug & Eggers, 1991), cortical atrophy of areas near the primary motor cortex (Salat et al., 2004), and reduction in the total length of myelinated fibers (Marner, Nyengaard, Tang, & Pakkenberg, 2003). Aging is also associated with changes of the serotonergic (Morgan, May, & Finch, 1987), cholinergic (Bartus, Dean, Beer, & Lippa, 1982), adrenergic (Bigham & Lidow, 1995), and dopaminergic (Segovia, Porras, Del Arco, & Mora, 2001) systems. Finally, aging results in cortical hypoexcitability (Kossev, Schrader, Dauper, Dengler, & Rollnik, 2002), impaired modulation of the activity of inappropriate motor networks when required (Heuninckx, Wenderoth, Debaere, Peeters, & Swinnen, 2005), and reduced cortical plasticity (Fathi et al., 2009). When considered together, these evidence suggest that age-related neural changes contribute to age-related reductions in motor performance although the exact relationship to strength loss is yet to be determined.
6. CLINICAL CONSEQUENCES OF SARCOPENIA The relevance of any clinical syndrome is based on its impact on patient’s outcome. In this light, sarcopenia is a clinical condition which significantly impacts on health, economic, and social outcome measures. Sarcopenia is correlated with functional decline and disability (Baumgartner et al., 1998). Data are often stronger in men than in women, most likely as the results of the indexing method used. Sarcopenia has been demonstrated to predict falls. Among the most recent studies supporting the relationship between sarcopenia and falls risk, Scott et al. investigated 681
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volunteers (48% female; mean age: 61.4 7.0 years) over a 5-year period (Scott et al., 2013). Appendicular lean mass, handgrip strength, and lower limb strength were assessed. Falls risk was determined using the physiological profile assessment. Anthropometric definitions and performance-based definitions of sarcopenia were examined. The lowest 20% of the sex-specific distribution for each definition at baseline was classified as sarcopenia. After 5 years, sarcopenia prevalence increased for all operational definitions. Men classified with sarcopenia according to anthropometric definitions and women classified with sarcopenia according to performance-based definitions had significant increases in falls risk over 5 years compared to individuals without sarcopenia (Scott et al., 2013). Therefore, sarcopenia prevalence generally increases at a higher rate when assessed using performance-based definitions. Sarcopenia is associated with increases in falls risk over 5 years in community-dwelling middle-aged and older adults, but sex-specific differences may exist according to different anthropometric or performance-based definitions (Scott et al., 2013). In the longitudinal Rancho Bernardo study, sarcopenia was shown to be predictive of falls (Castillo et al., 2003). Janssen (2006) examined 5036 men and women over 65 enrolled in the Cardiovascular Health Study. He reported that the likelihood of disability was 79% greater for those with “severe” sarcopenia but not significantly different for those with “moderate” sarcopenia compared with those with normal muscle mass. During 8-year follow-up, only those with severe sarcopenia were more likely to develop physical disability. Finally, sarcopenia predicts nosocomial infection during hospitalization (Cosqueric et al., 2006) and mortality (Roubenoff, 2000), although muscle strength and physical performance are more robust predictors, as previously mentioned. In recent years, a close relationship between increased fat mass, low muscle mass, and poor health outcome has been identified. The term sarcopenic obesity was first used by Heber et al. (1996) and describes persons with reduced body mass out of proportion to their adipose mass. Sarcopenic obesity is associated with disability, gait problems, and falls to a greater extent than persons with “proportionate” sarcopenia (Baumgartner et al., 2004). Supporting evidence were reported by the Framingham and National Health and Nutrition Examination Survey studies, which confirmed that older adults with large adipose tissue and low muscle mass had the highest rate of disabilities (Davison, Ford, Cogswell, & Dietz, 2002). These consistent data point to the fact that the development of disability and impaired mobility in older people has a complex etiology. Muscle mass is an important, but not the only predictor of muscle strength or physical
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function, since fat has several adverse effects on muscle function. As an example, the presence of a large adipose tissue is associated with greater intramuscular lipid and reduced muscle quality, defined as reduced strength/cross-sectional area (Goodpaster, 1999). Also, it cannot be excluded that body fatness decreases the capacity to generate power, and muscle power is more closely related to functional capacity than muscle strength (Bassey et al., 1992). It is therefore likely that to further refine the operational definition of sarcopenia, fat mass should be taken into account.
7. SARCOPENIA: A SPECIFIC GERIATRIC SYNDROME? Muscle wasting is a common feature of many chronic diseases, including cancer, chronic kidney disease, and chronic pulmonary disease (Ruegg & Glass, 2011). Since the molecular mechanisms of diseaseassociated muscle wasting and age-related muscle loss are similar (Ruegg & Glass, 2011), the term sarcopenia could be used to encompass muscle and strength loss, independently of the underlying causative factors (i.e., aging, disease, therapies, etc.). This approach would also help in minimizing confounding factors when assessing muscle mass in older adults with chronic diseases. In fact, it would be difficult to define and characterize in this growing population of patients how much muscle loss is secondary to aging and how much results from disease-associated metabolic changes. Muscle wasting is the key feature of the cachexia syndrome, which is associated with chronic and acute diseases (Fearon, Strasser, et al., 2011). Cachexia has recently been defined as a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle (Fearon, Strasser, et al., 2011). Similar to what has been described for age-related muscle loss, cachexia is frequently associated with inflammation, insulin resistance, anorexia, and increased breakdown of muscle proteins (Durham, Dillon, & Sheffield-Moore, 2009; Morley, Anker, & Evans, 2009). Thus, cachectic individuals are also sarcopenic, but most sarcopenic individuals are not considered cachectic. Therefore, debate has started on whether the muscular component of the definition of cachexia (i.e., disease-associated muscle loss) could be defined as sarcopenia, and thus categorized according to criteria set for sarcopenia. The EWGSOP proposed a practical approach based on the clinical knowledge that in some individuals, a clear and single cause of sarcopenia can be identified, whereas in other cases, no evident cause can be isolated
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Table 3.3 Categories of sarcopenia
Primary sarcopenia Age-related sarcopenia
No other cause evident except aging
Secondary sarcopenia Activity-related sarcopenia Can result from bed rest, sedentary lifestyle, deconditioning, or zero-gravity conditions Disease-related sarcopenia
Associated with advanced organ failure (heart, lung, liver, kidney, brain), inflammatory disease, malignancy, or endocrine disease
Nutrition-related sarcopenia
Results from inadequate dietary intake of energy and/or protein, as with malabsorption, gastrointestinal disorders, or use of medications that cause anorexia
(Cruz-Jentoft et al., 2010). Thus, EWGSOP proposed to stratify individuals into the categories of primary sarcopenia and secondary sarcopenia (CruzJentoft et al., 2010). Sarcopenia is defined as “primary” (or age-related) when no other cause is evident but aging itself. In contrast, Sarcopenia can be considered “secondary” when one or more other causes are evident (Table 3.3). In the majority of older adults, the etiology of sarcopenia is multifactorial so that it is not possible to characterize each individual as having a primary or secondary condition. This frequent undetermined situation is consistent with the general knowledge that sarcopenia is a multifaceted geriatric syndrome. Recently, a group of experts in the field of cachexia proposed that disease-associated muscle loss should be defined with a specific term to differentiate it from the age-related muscle loss (Fearon, Evans, & Anker, 2011). Indeed, concern may arise when using the diagnostic criteria of sarcopenia, which were developed for older people, to younger patients. By applying diagnostic criteria developed for those over 65 to patients who are aged 40, underestimation of the magnitude of their deficit will inevitably occur. To address this concern, the authors rejected the use of the term sarcopenia as a blanket term for muscle wasting at any age and from any cause, but accepted that sarcopenia should be reserved for (clinically significant) muscle wasting of the elderly (Fearon, Evans, et al., 2011). Consequently, a new term had to be found, different from “muscle wasting” since it is already used to describe a pathophysiologic process and not used or accepted
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to describe a medical entity requiring intervention. Also, “muscle wasting” translates poorly into other languages, which has hindered widespread acceptance outside groups communicating in English. Therefore, the group of experts proposed the new term “myopenia,” which results from the Greek words “myo” (¼muscle) and “penia” (¼deficit, loss). Therefore, myopenia is defined as a clinically relevant degree of muscle wasting that is associated either with impaired functional capacity and/or with increased risk of morbidity or mortality (Fearon, Evans, et al., 2011). The precise cutpoints to diagnose myopenia may be disease- or condition-specific. Myopenia can be diagnosed when a certain degree of muscle loss over time has occurred (for instance, at least 5% in 6–12 months) or when muscle mass is below a certain threshold level (Fearon, Evans, et al., 2011). For the latter, for instance, this could be a muscle mass below the 5th centile of healthy 30-year olds or a fat-free mass index
