Sarcopenia: Current Clinical and Research Issues

Sarcopenia is the age-related progressive decline of muscle mass, strength and function. It is not due to diseases, but a normal part of the aging process, and multiple physiological and psychological factors seem to contribute to it. Sarcopenia has been associated with a higher risk of falls, incident disability and all-cause mortality in the elderly. Despite this phenomenon has major clinical, social and economic consequences in older persons, its study is still limited and/or partial. The major issues making difficult the design of clinical trials on sarcopenia are: the multidimensional physiological mechanisms determining it, the lack of standardized definitions, the difficulties in operatively defining this dynamic mechanism, and the different methodologies able to estimate the muscle mass and function. The present review will 1) overview the current clinical and research issues related to the study of sarcopenia in the elderly, and 2) discuss the possible solutions on the basis of evidence on the topic. DEFINITION OF SARCOPENIA The term “sarcopenia” (from Greek sarx for flesh, and penia for loss) is commonly used to describe one of the most noticeable age-related modifications, that is the progressive decline of muscle mass, strength and function [1, 2]. Skeletal muscle declines in both men and women with aging. Muscle strength and mass reach their peaks in the teens and twenties, and begin to fall in the thirties. A 10-15% rate of decline in muscle strength has been estimated per decade of life after the age of 50 years. This decline becomes even faster after 75 years of age [3]. The sarcopenia phenomenon has been reported in a wide range of species in animals as well as in humans. After all, if this loss of muscle mass is an age-related phenomenon, it ought to be universal because every living being is aging. For example, progressive loss of muscle mass and function has been reported in Caernorhabditis elegans, a short-lived nematode, extensively studied to explore the aging process, and whose genome was completely sequenced [4]. In fact, a gradual disorganization and decrease in myosin thick filaments in the sarcomeres of older Caernorhabditis elegans have been observed. Similarly to what occurring in humans, nematodes with earlier motor dysfunction show lower life expectancies. Sarcopenia is a bidimensional phenomenon (Fig. 1) [5], because simulatenously considering (by definition) declines in both quantity (i.e., muscle mass) and quality (i.e. muscle function/strength). Nevertheless, large part of the current evidence on the topic is mainly focused on muscle function/strength modifications rather than also considering the parallel body composition changes. Although this choice (primarily due to the availabity of better assessment methods) might be legitimate because considering the skeletal *Address correspondence to this author at the Department of Aging and Geriatric Research, University of Florida – Institute on Aging, P.O. Box 112610, Gainesville, FL 32611, USA; Tel: +1 (352) 273-5917; Fax: +1 (352) 273-5920; E-mail: [email protected] muscle decline through a component of it (i.e. strength and function loss), it is still limiting the evaluation to a monodimensional approach. Fig. (1). The bi-dimensional nature of sarcopenia. Sarcopenia might be considered as the “muscular component” of the frailty syndrome, sharing with it the multicausal nature and the dynamic process [6]. In fact, sarcopenia is not only characterized by common features with this geriatric syndrome, such as poor endurance, physical inactivity, slow gait speed, muscle fatigability, and decreased mobility [7, 8]. It is also associated with an increased risk of several major health-related events in older persons, including physical disability and mortality [9, 10]. Besides the major clinical consequences, sarcopenia is also extremely burdensome on the health care system from an economic point of view. In fact, it has been estimated that the health care costs due to sarcopenia in the United States in 2000 were about $18.5 billion [11]. It is likely this figure will significantly increase in the next future due to the progressive aging of the population. Sarcopenia: Current Clinical and Research Issues The Open Geriatric Medicine Journal, 2008, Volume 1 15 Unfortunately, several conceptual and methodological issues limit the study of this phenomenon, so that sarcopenia is often considered as a mere “matter for researchers” with low clinical relevance. Moreover, the lack of standardized (operative) definitions, standardized methodologies to measure the muscle decline, and the inability to properly capture the dynamicity of the sarcopenia process are responsible for controversies and inconsistencies in literature. These difficulties are likely to explain the extreme scarcity of clinical trials considering sarcopenia as primary outcome. In the present review, we discuss the current issues limiting the study of sarcopenia, and provide some recommendations for methods, techniques, and measurements to consider in the evaluation of the age-related muscle decline. Moreover, we suggest which biological and clinical features should be considered in the recruitment of potential participants to clinical trials on sarcopenia. Finally, we discuss the role that physical exercise/activity as preventive/treatment strategy against the age-related skeletal muscle loss. CONCEPTUAL ISSUES ABOUT SARCOPENIA IN THE NEED OF CLARIFICATION As stated above, sarcopenia represents one most the most evident effects of the aging process on our organism. Therefore, its study may be able to clarify many mechanisms related to aging, and potentially open new scenarios for preventive medicine. Nevertheless, its definition implies several conceptual issues that are not easy to overcome when translating the hypotheses into the research field. One of the major problems found by researchers when designing clinical trials on sarcopenia resides in the longterm nature of this process over time. In fact, the age-related decline of skeletal muscle starts in the thirties to develop throughout the life. Moreover, by definition, it is a continuous process strongly connected with age, so that everyone experiences this skeletal muscle decline. Considering these two facts together, a clinical trial on sarcopenia should consider an extremely long follow-up (with consequent high costs) to evaluate whether, for example, a specific intervention is capable to reduce the already slow body composition changes occurring with age (and even experienced by any possible control group) [5]. Translational studies on animal models may partly solve these issues by providing preliminary data to be later verified in humans. However, the evaluation of the long sarcopenia process still remains difficult to exhaustively evaluate in humans. Several studies have solved this issue by comparing results obtained from a sample of healthy older individuals to a sample of healthy young controls. This approach implicitly accepts that the simple absence of clinical conditions makes similar and comparable a young person in his/her twenties to an older subject in his/her sixties (or even more). The exclusion of clinical conditions may appear able to isolate the “normal” aging process from all the potential confounders influencing it. Unfortunately, although this approach may be legitimate (and possibly the best way to study the long-term phenomenon of aging), it has several limitations, such as not considering the role played by cultural, lifestyle and subclinical factors/conditions. When approaching the sarcopenia topic, it is evident the large controversy existing behind the clinical meaning of this condition. If sarcopenia is not a disease, why do we want to “treat” it? Some reasons might be found in several papers presenting the loss of muscle mass as an age-related phenomenon potentially leading to severe health consequences [9, 10]. However, a growing part of evidence is refusing the hypothesis that sarcopenia is a risk factor for health-related events. In fact, several Authors have increasingly observed that fat tissue (and intramuscular fat infiltration) is the real responsible for the onset of health-related events rather the lean tissue [12-14]. Consequently, preventing or delaying sarcopenia may not be particularly important because of the uncertain role that skeletal muscle per se may have on health. Further studies are needed to clarify this issue because of crucial importance for the definition of the clinical importance of sarcopenia. In fact, if sarcopenia is just considered as the manifestation of the aging process on the skeletal muscle, the study of this phenomenon may imply the shifting from a geriatric to a gerontological field. It is noteworthy that most Authors tend to give a larger importance to the functional component of sarcopenia (i.e. loss of muscle strength) rather than to its apparent one (i.e. loss of muscle mass). If this may represent a way to explore a still largely uncovered field, it is important to take into account how the functional surrogates of sarcopenia (e.g. physical function measures) may go beyond mere measures of muscle strength, but represent markers of well-being. Therefore, an intervention improving muscle strength (and, consequently, increasing muscle mass) may not necessarily be beneficial because intervening on the skeletal muscle. Its benefits may find a broader explanation in an overall improvement and in the inhibition of the physical decline vicious cycle. Fig. (2). Muscle decline is influenced by positive and negative factors modifying the “normal aging” trajectory. Another major limitation influencing the design and development of clinical trials on sarcopenia is the wide spectrum of potential confounders able to (negatively or positively) affect the skeletal muscle decline (Fig. 2) [15-17]. In fact, multiple sociodemographic (e.g. gender, race/ethnicity), behavioral (e.g., physical inactivity, malnutrition, smoking...), biological (e.g. inflammation...), and clinical (e.g. 16 The Open Geriatric Medicine Journal, 2008, Volume 1 Cesari et al. clinical conditions...) factors are able to accelerate the normal age-related muscle decline trajectory. On the other hand, positive confounders also exist capable to reduce the skeletal muscle decline rate (e.g. physical activity, hormone replacement therapy, immunomodulatory medications...). If sarcopenia is a pure age-related phenomenon, the study of it should carefully exclude all these positive and negative confounders able to modify the aging process of the muscle. Only in this way we will be able to capture the real and only aging effect. Otherwise, these confounders may potentially be responsible for biased results. The translation of this concept is extremely hard into practice, especially because sarcopenia is a phenomenon of older age, when subjects tend to present a higher number of (sub)clinical conditions. CURRENT METHODOLOGIES TO MEASURE SKELETAL MUSCLE MASS One of the major restrains to the design and development of clinical trials on sarcopenia resides in the multiple imaging methodologies that can be adopted to estimate the skeletal muscle parameters. If sarcopenia has to be considered as a condition worth to be investigated in clinical trials, a unique and standardized method of assessment of the skeletal muscle is needed. Moreover, the standardization of the skeletal muscle assessment may facilitate the identification of a possible critical threshold distinguishing the age-related phenomenon from the clinically relevant risk factor for negative events. Currently, the most used techniques to evaluate the skeletal muscle mass include anthropometry, creatinine excretion, bioelectrical impedance analysis (BIA), peripheral quantitative computerized tomography (pQCT), dual energy X-ray absoptiometry (DEXA), neutron activation, computerized tomography (CT), and magnetic resonance imaging (MRI). A list of the major strengths and weaknesses of all these techniques is presented in Table 1. MRI and CT represent by far the most accurate imaging methods to determine muscle mass. They are also able to provide parameters of muscle quality (e.g. muscle density, intramuscular infiltrates of fat). Nevertheless, the high costs and the technical difficulties of these procedures make them difficult to be implemented in large and/or not sufficiently funded clinical trials. The pQCT can be considered as a legitimate alternative to these “gold standards”, even if a loss of accuracy is implied. This methodology is based on a portable CT scanner able to measure cross-sectional areas of bone (including its subcompartments), muscle, and adipose tissue at upper and lower limbs. Moreover, muscle and bone density can be measured as well. A limitation common to all these three methodologies is related to the lack of adjustment for body size (consequently requiring a second measure). In fact, for example, a higher muscle area might just reflect a larger body size rather than a healthier status of the assessed skeletal muscle. Moreover, it should not be underestimated that these techniques provide results estimating muscle mass in a specific part (slice) of the body, so that the generalization of results to the whole organism (or even to other parts of the same district) might be arguable. An alternative method to estimate the entire body muscle mass is based on the in vivo neutron activation analysis combined with the 40K whole body counting [18, 19]. The rationale of this method is based on the existence of a difference in the potassium-to-nitrogen ratio between the skeletal muscle and the non-skeletal muscle tissues. If total body potassium (from the 40K whole body counting) and total body nitrogen (from promptneutron activation analysis) are known, these ratios can be mathematically derived and applied to predict the subject’s skeletal muscle mass. However, besides of the still unclear validity, this method is even more expensive than CT [20]. The application of DEXA for the muscle mass estimation has created an attractive alternative to more expensive methods. However, it needs to be taken into account when considering this technique that the accuracy of DEXA for predicting muscle mass in people of different age groups and in some pathological conditions may vary. For example, there is a tendency for DEXA to overestimate muscle mass [20], possibly because this method does not differentiate between water and bone-free lean tissue. This might lead to significant bias in older persons due to extracellular fluid accumulation [21]. Theoretically, the measurement of urinary creatinine excretion is one of the most specific indexes of total body skeletal muscle mass because creatine, the precursor of creatinine, originates almost exclusively from skeletal muscle. Unfortunately, creatinine excretion shows a daily variation, consequently providing an inaccurate estimate. Moreover, to assess urinary creatinine excretion, the subject is required to be on a meat-free diet for few days and a prolonged urine collection is needed [21]. Even if inexpensive, anthropometric measurements are very limited in their accuracy [22]. Rolland and colleagues [23] showed that calf circumference is only moderately correlated with appendicular lean mass as determined by DEXA scan. Moreover, anthropometric measures are based on certain uncertain assumptions about the adipose tissue distribution (along the length and circumference of the limbs), and the mean cross-sectional area of muscles and bones [24, 25]. Moreover, malnutrition, comorbidities, and/or poor health status (as frequently occurring in older persons) may furtherly bias the estimate of muscle mass with anthropometric measures (mainly due to the reduced amount of subcutaneous adipose tissue). THE LACK OF A WELL-ESTABLISHED DEFINING CUT-POINT FOR SARCOPENIA A standard and widely-accepted quantitative definition of sarcopenia is not currently available in literature. All the biological measures to be clinically meaningful require to be categorized, so to identify a critical threshold distinguishing a “normal” vs an “at risk” value. Moreover, the identification of a cut-point also provides a target to theoretically establish whether a specific intervention is successful or not. Sarcopenia is not an exception. Unfortunately, several issues limit the identification of such cut-point. First of all, it is important to keep in mind that the initial amount of muscle mass (and strength) plays a major role in the muscle decline process [6]. In fact, as Marcell noted [26], the level of initial muscle mass (as well as the muscle quality) are crucial in reaching the clinically-meaningful threshold of sarcopenia. For example, a relevant reduction of muscle mass in a bodybuilder may still spare an amount of lean Sarcopenia: Current Clinical and Research Issues The Open Geriatric Medicine Journal, 2008, Volume 1 17 mass greater than the one commonly presented by a healthy normal individual. Therefore, the greater the starting reserve capacity, the longer it will be before the critical threshold of sarcopenia is crossed. Sarcopenia is a difficult condition to be identified in the real world. This difficulty resides in 1) the progressive and “longitudinal” nature of this phenomenon, 2) the different available methodologies to assess body composition, 3) the bi-dimensional nature of the phenomenon, and 4) the lack of Table 1. Methodologies to Estimate the Muscle Mass Method Strengths Weaknesses