184 Table 2 Possible biomarkers to be used in trials on sarcopenia Inclusion– exclusion criteria Baseline evaluation End-point assessment Muscle function Physical performance +++ measures Muscle strength measures +++ Disability +++ Muscle mass Anthropometry + Bioelectrical impedance + analysis Dual energy X-ray absorp- +++ tiometry Computerized tomography ++ Magnetic resonance ++ imaging Echography ++ Electrical impedance + myography Mechanisms, biological confoundersa Inflammation ++ Oxidative damage ++ Antioxidants ++ Apoptosis + Nutritional parameters +++ (albumin, hemoglobin, urinary creatinine, etc.) Hormones ++ (dehydroepiandrosterone, testosterone, insulin-like growth factor-1, etc.) +++ +++ +++ - + ++ +++ +++ ++ ++ ++ ++ ++ ++ ++ ++ +++ +++ +++ - + ++ +++ +++ ++ ++ ++ ++ ++ ++ ++ ++ - not recommended for this use; + may be of use, but severely limited; ++ suitable for this use; +++ recommended for this use a The importance of all of these biomarkers in the evaluation of sarco- penia will largely depend on the study hypotheses, the specific aims, and/or the target population in muscle strength [21]. It is also noteworthy that pharmaco- logic interventions that increase muscle mass/size do not necessarily improve voluntary strength. Similarly, physical activity interventions that increase muscle strength do not necessarily augment muscle size [22, 23]. Noticeably, gains in muscle strength secondary to increased physical activity generally precede measurable changes in skeletal muscle mass/size. The progressive muscle atrophy with aging is associated with a loss of overall muscle force and changes in force and power generation of the remaining muscle fibers [24]. Howev- er, several additional physiological mechanisms that accompa- ny the phenomenon of sarcopenia may directly influence muscle function and force production with advancing age. Recent evidence has shown that adipose tissue accumulation around and between muscle fibers concomitant with reductions J Cachexia Sarcopenia Muscle (2012) 3:181–190 in muscle cross-sectional area occurs with aging, and that this skeletal muscle attenuation is inversely associated with muscle performance [18, 25]. Age-related changes in the nervous system may also play a substantial role in the decline in muscle power generation [26]. These include loss of motor neurons and concomitant remodeling of motor units through collateral reinnervation [27], impairment of neuromuscular activation observed as decreased maximal motor unit firing rates [28–30], and uncoordinated patterns of intermuscular neural activation [31]. Finally, changes in individual muscle fiber composition and intrinsic contractile properties may influence the decline in muscle force among older adults. For instance, cross-sectional observations suggest that reductions in muscle torque may be related to changes in fiber composition and, in particular, to the preferential atrophy of type II (fast-twitch) fibers with aging [32]. Specific changes in the intrinsic ability of aged muscle to generate force have also been observed [33]. Decreases in specific force (force normalized per cross section- al area) and unloaded shortening velocity in type I and IIA fibers have been reported in older males compared with young controls [32, 34]. Conversely, recent longitudinal data have demonstrated that, despite reductions in whole muscle cross- sectional area, single muscle fiber contractile function is pre- served with advancing age as existing fibers may compensate and partially correct these deficits, therefore maintaining opti- mal force-generating capacity [14]. Although precise and valid measures of muscle mass are important components of sarcopenia assessment, these gross measures of muscle size do not adequately account for the dynamic components (force, power, activation) of muscle func- tion that are responsible for performing activities of daily living. Future trials on sarcopenia adopting clinically meaning- ful endpoints should evaluate these key biomarkers of muscle function through the use of state-of-the-art methodologies. 5 Quantitative assessment of sarcopenia The bidimensional definition of sarcopenia simultaneously includes a functional parameter (i.e., muscle performance) and a quantitative index (i.e., muscle mass). Therefore, techniques aimed at capturing the objective amount of skel- etal muscle mass are required. Multiple methodologies are currently available to accomplish this task [35]. DXA is the most commonly used imaging technique for several reasons: first of all, because it is commonly available in clinical and research settings, being relatively inexpensive, sufficiently precise, and well-accepted by older persons. Second, the initial operative definition of sarcopenia proposed by Baumgartner and colleagues [3] was based on appendicular lean mass measured by DXA. Later on, DXA was used to provide alternative definitions of sarcopenia based on the fat-adjusted residual method