JAMDA xxx (2014) 1e2
JAMDA journal homepage: www.jamda.com
Editorial
Sarcopenia: There Is a Need for Some Steps Forward Jean-Pierre Michel MD * Geneva Medical School, Geneva University, Geneva, Switzerland
The first articles devoted to “sarcopenia” appeared in the literature in 1993 by Evans and colleagues,1,2 and defined sarcopenia as “the agerelated loss in skeletal muscle mass, which results in decreased strength and aerobic capacity and thus functional capacity.” The same year, the word “sarcopenia” was used in other articles by Butler3 and Dehlin,4 who already began to mention, as did numerous other authors, the possible reversibility of this clinical condition.1,2,5 Twenty years later, 2290 articles have been published to date on the same topic and we still have the same questions6 concerning the following: the operationalized definition of sarcopenia, and the reversibility of this clinical condition. An operationalized definition of sarcopenia is urgently needed. Great progress toward a consensus definition was made in 2010 by the European Working Group on Sarcopenia in Older People (EWGSOP),7 and in 2011 by the International Working Group on Sarcopenia (IWGS),8 who jointly put forward the following definition: “Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function (strength or performance).” However, a universal working definition is still missing. A recent and complete review of the possible tools to diagnose sarcopenia concluded the following: Magnetic resonance imaging (MRI), computed tomography, and a 4-compartment model are gold standards for the assessment of muscle mass. A handheld dynamometer is a valid and reliable tool for evaluating muscle strength. The Short Physical Performance Battery (SPPB) and gait speed are reliable measures of physical performance.9 To measure muscle mass, strength, and physical performance in a general practitioner’s practice or in the home setting, a handheld dynamometer and gait speed over a short distance, or the SPPB and bioelectrical impedance analysis (BIA), can be used, as they are transportable tools and easy to implement in these specific settings.9 This approach seems reasonable and clear. However, numerous limitations exist: Handheld dynamometer: Measurements vary greatly, as demonstrated in the Survey of Health, Ageing and Retirement
The author declares no conflicts of interest. * Address correspondence to Jean-Pierre Michel, MD, Geneva Medical School, Geneva University, 40 A route de Malagnou, Geneva 1208, Switzerland. E-mail addresses: [email protected], [email protected] (J.-P. Michel).
in Europe (SHARE) study. Northern continental European countries had higher grip strength than southern European countries even when stratified by age and gender and controlling for height, weight, education, health, and socioeconomic status.10,11 BIA: Given that the validity of BIA is not optimal,12 one could argue that only muscle strength and physical performance need to be measured at first screening. If scores on these parameters are below normal, further assessment of muscle mass could be envisaged, for example, by dual-energy x-ray absorptiometry (DXA), which is a more valid alternative for the measurement of muscle mass.9 DXA: Based on a review of the literature, there is no consensus on DXA-derived sarcopenia cutoff points.13 Careful interpretation of appendicular skeletal muscle mass (ASMM) on DXA needs to take into account at the very least gender, race, height, and total body fat, to determine whether muscle mass is too low for an individual patient.13 An alternative proposal is the use of different cutoffs, for example, the 15th percentile (or 1 SD below the mean) of the ASMM index for young adults, and the 20th percentile of this index for an elderly reference population. This calculation was shown to be more effective in identifying cases of sarcopenia than subtracting 2 SD from the mean ASMM index of a young adult population.14 In this controversial context, although there is general agreement on the choice of methods, the agreement between the cutoff values proposed by the EWGSOP and IWGS to diagnose sarcopenia has been shown to be only fair, and the prevalence of sarcopenia varied widely depending on the different skeletal muscle mass indices used.15,16 The EWGSOP diagnostic strategy applied to healthy Japanese men (n ¼ 568) and women (n ¼ 1314) aged 65 to 89 years showed a prevalence of 21.8% and 22.1%, respectively.17 The use of the same EWGSOP criteria in 1421 ambulatory volunteers (553 men and 868 women) showed that sarcopenia can start at the age of 45, and affect from 22% to more than 60% of individuals in the oldest age groups.18 Ethnic and geographic variations in muscle mass, strength, and function are now well established19 and warrant further collaborative research using the same methods. To overcome this major problem, it also has been proposed that only “sarcopenia with limited mobility” be considered, which defines a person with muscle loss (with the caveats mentioned previously as to the appropriate method to determine it) and whose walking speed is slower than 1 m/s, or who walks less than 400 m during a 6-minute walk test. Indeed, the “limitation in mobility” should not clearly be a result of otherwise defined specific diseases of the muscle, peripheral
1525-8610/$ - see front matter Ó 2014 - American Medical Directors Association, Inc. All rights reserved. http://dx.doi.org/10.1016/j.jamda.2014.03.016
2
Editorial / JAMDA xxx (2014) 1e2
vascular disease with intermittent claudication, central and peripheral nervous system disorders, or cachexia.20 This approach is of interest in the search for a working definition that would be universally acceptable for clinical trials. Clinically significant interventions could be defined as an increase in the 6-minute walk distance of at least 50 meters, or an increase in walking speed of at least 0.1 m/s.20 Indeed, this possible working definition will limit clinical trials to severe sarcopenia, excluding pre-sarcopenia and sarcopenia,7 and could be very useful for selected clinical trials. A collaborative study is needed based on healthy volunteers aged 20 to 100 years and beyond, originating from different parts of the world. The methodology of such a study needs to be carefully planned and monitored. The comparison of controlled results obtained using the same types of BIA, DXA, MRI, and handheld dynamometer could provide the scientific community with interesting, valid, and generalizable results, which are indispensable for the development of an “international operationalized definition.” Sarcopenia Is Potentially Reversible The development of a universal, operationalized definition would certainly represent an important step forward in knowledge and clinical practice, but it should not interfere with the urgent need to clearly affirm to the whole scientific community that sarcopenia is reversible, and indeed, that its dramatic consequences can be reduced. Already, many encouraging studies have been published,21e23 raising hopes for the near future.24e26 After the excellent review published by Malafarina et al,27 the most important piece of information came from an international European Union Geriatric Medicine Society initiative that performed a wide literature review based on PubMed and Dialog databases, from January 2000 to October 2013, and using predefined search terms under the categories nutrition interventions and exercise interventions for sarcopenia.28 For intervention studies, only those that investigated muscle mass plus strength or function outcome measures consistent with the EWGSOP definition of sarcopenia were chosen. The application of widely selected key words identified 1577 abstracts on physical interventions, from which 175 full articles were extracted and read. Only 52 of them met the EWGSOPselected inclusion criteria (muscle mass and strength or function), and in these reports, average follow-up was 2.5 years. Cross-sectional studies on resistance training lasting more than 1 month that compared differences between active and sedentary groups, or that took exercise into account as a confounding variable showed a clear increase in muscle strength and muscle mass in the resistance training group. Surprisingly, the results were more pronounced in the older individuals than among their younger counterparts. The same selection process was applied to nutrition interventions. Among 2141 abstracts, 474 articles were selected and read. Only 14 studies met the inclusion criteria. A proteinenriched diet, amino acid and leucine supplements, and b-hydroxyb-methylbutyrate all had positive, albeit slightly different effects on muscle mass, strength, and performance. The selected studies unanimously showed that a combination of exercise and protein-based supplements had additive effects versus supplements alone.28 Therefore, clinicians should now be convinced that sarcopenia can be reversed in just a few months (3 to 6 months at least) through adapted training and physical exercises and adequate nutritional supplementation, and even more quickly with the combination of both interventions. These interventions will reduce the speed of onset of the frailty process29 and its consequences,30 without waiting for new drugs.
References 1. Evans WJ, Campbell WW. Sarcopenia and age-related changes in body composition and functional capacity J. Nutr 1993;123:465e468. 2. Roubenoff R, Evans WJ. Exercise and lean weight. Nutr Rev 1993;51:25. 3. Butler RN. Did you say ’sarcopenia’? Geriatrics 1993;48:11e12. 4. Dehlin O. [Sarcopeniaean old age disease possible to treat]. Lakartidningen 1993;90:1731. Swedish. 5. Fiatarone MA, Evans WJ. The etiology and reversibility of muscle dysfunction in the aged. J Gerontol 1993;48:77e83. 6. Roman D, Mahoney K, Mohamadi A. Sarcopenia: What’s in a name? J Am Med Dir Assoc 2013;14:80e82. 7. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010;39:412e423. 8. Fielding RA, Vellas B, Evans WJ, et al. Sarcopenia: An undiagnosed condition in older adults. Current consensus definition: Prevalence, etiology, and consequences. International Working Group on Sarcopenia. J Am Med Dir Assoc 2011;12:249e256. 9. Mijnarends DM, Meijers JMM, Halfens RJG, et al. Validity and reliability of tools to measure muscle mass, strength, and physical performance in communitydwelling older people: A systematic review. J Am Med Dir Assoc 2013;14: 170e178. 10. Andersen-Ranberg K, Person I, Frederiksen H, et al. Cross-national differences in grip strength among 50þ year-old Europeans: Results from the SHARE study. Eur J Ageing 2009;6:227e236. 11. Mohd Hairi F, Mackenbach JP, Andersen-Ranberg K, Avendano M. Does socioeconomic status predict grip strength in older Europeans? Results from the SHARE study in non-institutionalised men and women aged 50þ. J Epidemiol Community Health 2010;64:829e837. 12. Chang CI, Chen C-Y, Huang K-C, et al. Comparison of three BIA muscle indices for sarcopenia screening in old adults. Eur Geriatr Med 2013;4:145e149. 13. Visser M, Schaap L. Measurement of muscle mass, equations and cut-off points. In: Cruz-Jentoft AJ, editor. Sarcopenia. Chichester, UK: Wiley-Blackwell; 2013, pp. 205e225. 14. Coin A, Sarti S, Ruggiero E, et al. Prevalence of sarcopenia based on different diagnostic criteria using DEXA and appendicular skeletal muscle mass reference values in an Italian population aged 20 to 80. J Am Med Dir Assoc 2013; 14:507e512. 15. Lee WJ, Liu L-K, Peng L-N, et al. Comparisons of sarcopenia defined by IWGS and EWGSOP criteria among older people: Results from the I-Lan longitudinal aging study. J Am Med Dir Assoc 2013;14:528.e1e528.e7. 16. Chen Liang-Kung, Liu L-K, Woo Jean, et al. Sarcopenia in Asia: Consensus Report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc 2014; 15:95e101. 17. Yamada M, Nishiguchi S, Fukutani N. Prevalence of sarcopenia in communitydwelling Japanese older adults. J Am Med Dir Assoc 2013;14:911e915. 18. Cherin P, Veronska E, Fraoucene N, et al. Prevalence of sarcopenia among healthy ambulatory subjects: The sarcopenia begins from 45 years. Aging Clin Exp Res 2014;26:137e146. 19. Woo J, Arai H, Sayer AH, et al. Ethnic and geographic variations in muscle mass, muscle strength and physical performance measures. Eur Geriatr Med; 2014. In press. 20. Morley JE, Abbatecola AM, Argiles JM, et al. Sarcopenia with limited mobility: An international consensus. J Am Med Dir Assoc 2011;12:403e409. 21. Tieland M, Borgonjen-Van den Berg KJ, van Loon LJ, de Groot LC. Dietary protein intake in community-dwelling, frail, and institutionalized elderly people: Scope for improvement. Eur J Nutr 2012;51:173e179. 22. Tieland M, Dirks ML, van der Zwaluw N, et al. Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: A randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc 2012;13:713e719. 23. Singh NA, Quine S, Clemson LM, et al. Effects of high-intensity progressive resistance training and targeted multidisciplinary treatment of frailty on mortality and nursing home admissions after hip fracture: A randomized controlled trial. J Am Med Dir Assoc 2012;13:24e30. 24. Boirie Y. Fighting sarcopenia in older frail subjects: Protein fuel for strength, exercise for mass. J Am Med Dir Assoc 2013;14:140e143. 25. Cesari M. Perspective: Protein supplementation against sarcopenia and frailty: Future perspectives from novel data. J Am Med Dir Assoc 2013;14: 62e63. 26. Cruz-Jentoft AJ. Perspective: Protein and exercise for frailty and sarcopenia: Still learning. J Am Med Dir Assoc 2013;14:69e71. 27. Malafarina V, Uriz-Otano F, Iniesta R, Gil-Guerrero L. Effectiveness of nutritional supplementation on muscle mass in treatment of sarcopenia in old age: A systematic review. J Am Med Dir Assoc 2013;14:10e17. 28. Cruz-Jentoft AJ, Landi F, Schneider S, et al. Prevalence of and interventions for sarcopenia in ageing adultsda systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing; 2014. In press. 29. Cruz-Jentoft AJ, Michel JP. Sarcopenia: A useful paradigm for physical frailty. Eur Geriatr Med 2013;4:102e105. 30. Landi F, Liperoti R, Fusco D, et al. Sarcopenia and mortality among older nursing home residents. J Am Med Dir Assoc 2012;13:121e126.
JAMDA journal homepage: www.jamda.com
Editorial
Sarcopenia: There Is a Need for Some Steps Forward Jean-Pierre Michel MD * Geneva Medical School, Geneva University, Geneva, Switzerland
The first articles devoted to “sarcopenia” appeared in the literature in 1993 by Evans and colleagues,1,2 and defined sarcopenia as “the agerelated loss in skeletal muscle mass, which results in decreased strength and aerobic capacity and thus functional capacity.” The same year, the word “sarcopenia” was used in other articles by Butler3 and Dehlin,4 who already began to mention, as did numerous other authors, the possible reversibility of this clinical condition.1,2,5 Twenty years later, 2290 articles have been published to date on the same topic and we still have the same questions6 concerning the following: the operationalized definition of sarcopenia, and the reversibility of this clinical condition. An operationalized definition of sarcopenia is urgently needed. Great progress toward a consensus definition was made in 2010 by the European Working Group on Sarcopenia in Older People (EWGSOP),7 and in 2011 by the International Working Group on Sarcopenia (IWGS),8 who jointly put forward the following definition: “Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function (strength or performance).” However, a universal working definition is still missing. A recent and complete review of the possible tools to diagnose sarcopenia concluded the following: Magnetic resonance imaging (MRI), computed tomography, and a 4-compartment model are gold standards for the assessment of muscle mass. A handheld dynamometer is a valid and reliable tool for evaluating muscle strength. The Short Physical Performance Battery (SPPB) and gait speed are reliable measures of physical performance.9 To measure muscle mass, strength, and physical performance in a general practitioner’s practice or in the home setting, a handheld dynamometer and gait speed over a short distance, or the SPPB and bioelectrical impedance analysis (BIA), can be used, as they are transportable tools and easy to implement in these specific settings.9 This approach seems reasonable and clear. However, numerous limitations exist: Handheld dynamometer: Measurements vary greatly, as demonstrated in the Survey of Health, Ageing and Retirement
The author declares no conflicts of interest. * Address correspondence to Jean-Pierre Michel, MD, Geneva Medical School, Geneva University, 40 A route de Malagnou, Geneva 1208, Switzerland. E-mail addresses: [email protected], [email protected] (J.-P. Michel).
in Europe (SHARE) study. Northern continental European countries had higher grip strength than southern European countries even when stratified by age and gender and controlling for height, weight, education, health, and socioeconomic status.10,11 BIA: Given that the validity of BIA is not optimal,12 one could argue that only muscle strength and physical performance need to be measured at first screening. If scores on these parameters are below normal, further assessment of muscle mass could be envisaged, for example, by dual-energy x-ray absorptiometry (DXA), which is a more valid alternative for the measurement of muscle mass.9 DXA: Based on a review of the literature, there is no consensus on DXA-derived sarcopenia cutoff points.13 Careful interpretation of appendicular skeletal muscle mass (ASMM) on DXA needs to take into account at the very least gender, race, height, and total body fat, to determine whether muscle mass is too low for an individual patient.13 An alternative proposal is the use of different cutoffs, for example, the 15th percentile (or 1 SD below the mean) of the ASMM index for young adults, and the 20th percentile of this index for an elderly reference population. This calculation was shown to be more effective in identifying cases of sarcopenia than subtracting 2 SD from the mean ASMM index of a young adult population.14 In this controversial context, although there is general agreement on the choice of methods, the agreement between the cutoff values proposed by the EWGSOP and IWGS to diagnose sarcopenia has been shown to be only fair, and the prevalence of sarcopenia varied widely depending on the different skeletal muscle mass indices used.15,16 The EWGSOP diagnostic strategy applied to healthy Japanese men (n ¼ 568) and women (n ¼ 1314) aged 65 to 89 years showed a prevalence of 21.8% and 22.1%, respectively.17 The use of the same EWGSOP criteria in 1421 ambulatory volunteers (553 men and 868 women) showed that sarcopenia can start at the age of 45, and affect from 22% to more than 60% of individuals in the oldest age groups.18 Ethnic and geographic variations in muscle mass, strength, and function are now well established19 and warrant further collaborative research using the same methods. To overcome this major problem, it also has been proposed that only “sarcopenia with limited mobility” be considered, which defines a person with muscle loss (with the caveats mentioned previously as to the appropriate method to determine it) and whose walking speed is slower than 1 m/s, or who walks less than 400 m during a 6-minute walk test. Indeed, the “limitation in mobility” should not clearly be a result of otherwise defined specific diseases of the muscle, peripheral
1525-8610/$ - see front matter Ó 2014 - American Medical Directors Association, Inc. All rights reserved. http://dx.doi.org/10.1016/j.jamda.2014.03.016
2
Editorial / JAMDA xxx (2014) 1e2
vascular disease with intermittent claudication, central and peripheral nervous system disorders, or cachexia.20 This approach is of interest in the search for a working definition that would be universally acceptable for clinical trials. Clinically significant interventions could be defined as an increase in the 6-minute walk distance of at least 50 meters, or an increase in walking speed of at least 0.1 m/s.20 Indeed, this possible working definition will limit clinical trials to severe sarcopenia, excluding pre-sarcopenia and sarcopenia,7 and could be very useful for selected clinical trials. A collaborative study is needed based on healthy volunteers aged 20 to 100 years and beyond, originating from different parts of the world. The methodology of such a study needs to be carefully planned and monitored. The comparison of controlled results obtained using the same types of BIA, DXA, MRI, and handheld dynamometer could provide the scientific community with interesting, valid, and generalizable results, which are indispensable for the development of an “international operationalized definition.” Sarcopenia Is Potentially Reversible The development of a universal, operationalized definition would certainly represent an important step forward in knowledge and clinical practice, but it should not interfere with the urgent need to clearly affirm to the whole scientific community that sarcopenia is reversible, and indeed, that its dramatic consequences can be reduced. Already, many encouraging studies have been published,21e23 raising hopes for the near future.24e26 After the excellent review published by Malafarina et al,27 the most important piece of information came from an international European Union Geriatric Medicine Society initiative that performed a wide literature review based on PubMed and Dialog databases, from January 2000 to October 2013, and using predefined search terms under the categories nutrition interventions and exercise interventions for sarcopenia.28 For intervention studies, only those that investigated muscle mass plus strength or function outcome measures consistent with the EWGSOP definition of sarcopenia were chosen. The application of widely selected key words identified 1577 abstracts on physical interventions, from which 175 full articles were extracted and read. Only 52 of them met the EWGSOPselected inclusion criteria (muscle mass and strength or function), and in these reports, average follow-up was 2.5 years. Cross-sectional studies on resistance training lasting more than 1 month that compared differences between active and sedentary groups, or that took exercise into account as a confounding variable showed a clear increase in muscle strength and muscle mass in the resistance training group. Surprisingly, the results were more pronounced in the older individuals than among their younger counterparts. The same selection process was applied to nutrition interventions. Among 2141 abstracts, 474 articles were selected and read. Only 14 studies met the inclusion criteria. A proteinenriched diet, amino acid and leucine supplements, and b-hydroxyb-methylbutyrate all had positive, albeit slightly different effects on muscle mass, strength, and performance. The selected studies unanimously showed that a combination of exercise and protein-based supplements had additive effects versus supplements alone.28 Therefore, clinicians should now be convinced that sarcopenia can be reversed in just a few months (3 to 6 months at least) through adapted training and physical exercises and adequate nutritional supplementation, and even more quickly with the combination of both interventions. These interventions will reduce the speed of onset of the frailty process29 and its consequences,30 without waiting for new drugs.
References 1. Evans WJ, Campbell WW. Sarcopenia and age-related changes in body composition and functional capacity J. Nutr 1993;123:465e468. 2. Roubenoff R, Evans WJ. Exercise and lean weight. Nutr Rev 1993;51:25. 3. Butler RN. Did you say ’sarcopenia’? Geriatrics 1993;48:11e12. 4. Dehlin O. [Sarcopeniaean old age disease possible to treat]. Lakartidningen 1993;90:1731. Swedish. 5. Fiatarone MA, Evans WJ. The etiology and reversibility of muscle dysfunction in the aged. J Gerontol 1993;48:77e83. 6. Roman D, Mahoney K, Mohamadi A. Sarcopenia: What’s in a name? J Am Med Dir Assoc 2013;14:80e82. 7. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010;39:412e423. 8. Fielding RA, Vellas B, Evans WJ, et al. Sarcopenia: An undiagnosed condition in older adults. Current consensus definition: Prevalence, etiology, and consequences. International Working Group on Sarcopenia. J Am Med Dir Assoc 2011;12:249e256. 9. Mijnarends DM, Meijers JMM, Halfens RJG, et al. Validity and reliability of tools to measure muscle mass, strength, and physical performance in communitydwelling older people: A systematic review. J Am Med Dir Assoc 2013;14: 170e178. 10. Andersen-Ranberg K, Person I, Frederiksen H, et al. Cross-national differences in grip strength among 50þ year-old Europeans: Results from the SHARE study. Eur J Ageing 2009;6:227e236. 11. Mohd Hairi F, Mackenbach JP, Andersen-Ranberg K, Avendano M. Does socioeconomic status predict grip strength in older Europeans? Results from the SHARE study in non-institutionalised men and women aged 50þ. J Epidemiol Community Health 2010;64:829e837. 12. Chang CI, Chen C-Y, Huang K-C, et al. Comparison of three BIA muscle indices for sarcopenia screening in old adults. Eur Geriatr Med 2013;4:145e149. 13. Visser M, Schaap L. Measurement of muscle mass, equations and cut-off points. In: Cruz-Jentoft AJ, editor. Sarcopenia. Chichester, UK: Wiley-Blackwell; 2013, pp. 205e225. 14. Coin A, Sarti S, Ruggiero E, et al. Prevalence of sarcopenia based on different diagnostic criteria using DEXA and appendicular skeletal muscle mass reference values in an Italian population aged 20 to 80. J Am Med Dir Assoc 2013; 14:507e512. 15. Lee WJ, Liu L-K, Peng L-N, et al. Comparisons of sarcopenia defined by IWGS and EWGSOP criteria among older people: Results from the I-Lan longitudinal aging study. J Am Med Dir Assoc 2013;14:528.e1e528.e7. 16. Chen Liang-Kung, Liu L-K, Woo Jean, et al. Sarcopenia in Asia: Consensus Report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc 2014; 15:95e101. 17. Yamada M, Nishiguchi S, Fukutani N. Prevalence of sarcopenia in communitydwelling Japanese older adults. J Am Med Dir Assoc 2013;14:911e915. 18. Cherin P, Veronska E, Fraoucene N, et al. Prevalence of sarcopenia among healthy ambulatory subjects: The sarcopenia begins from 45 years. Aging Clin Exp Res 2014;26:137e146. 19. Woo J, Arai H, Sayer AH, et al. Ethnic and geographic variations in muscle mass, muscle strength and physical performance measures. Eur Geriatr Med; 2014. In press. 20. Morley JE, Abbatecola AM, Argiles JM, et al. Sarcopenia with limited mobility: An international consensus. J Am Med Dir Assoc 2011;12:403e409. 21. Tieland M, Borgonjen-Van den Berg KJ, van Loon LJ, de Groot LC. Dietary protein intake in community-dwelling, frail, and institutionalized elderly people: Scope for improvement. Eur J Nutr 2012;51:173e179. 22. Tieland M, Dirks ML, van der Zwaluw N, et al. Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: A randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc 2012;13:713e719. 23. Singh NA, Quine S, Clemson LM, et al. Effects of high-intensity progressive resistance training and targeted multidisciplinary treatment of frailty on mortality and nursing home admissions after hip fracture: A randomized controlled trial. J Am Med Dir Assoc 2012;13:24e30. 24. Boirie Y. Fighting sarcopenia in older frail subjects: Protein fuel for strength, exercise for mass. J Am Med Dir Assoc 2013;14:140e143. 25. Cesari M. Perspective: Protein supplementation against sarcopenia and frailty: Future perspectives from novel data. J Am Med Dir Assoc 2013;14: 62e63. 26. Cruz-Jentoft AJ. Perspective: Protein and exercise for frailty and sarcopenia: Still learning. J Am Med Dir Assoc 2013;14:69e71. 27. Malafarina V, Uriz-Otano F, Iniesta R, Gil-Guerrero L. Effectiveness of nutritional supplementation on muscle mass in treatment of sarcopenia in old age: A systematic review. J Am Med Dir Assoc 2013;14:10e17. 28. Cruz-Jentoft AJ, Landi F, Schneider S, et al. Prevalence of and interventions for sarcopenia in ageing adultsda systematic review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing; 2014. In press. 29. Cruz-Jentoft AJ, Michel JP. Sarcopenia: A useful paradigm for physical frailty. Eur Geriatr Med 2013;4:102e105. 30. Landi F, Liperoti R, Fusco D, et al. Sarcopenia and mortality among older nursing home residents. J Am Med Dir Assoc 2012;13:121e126.
