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Pharmacologic Options for the Treatment of Sarcopenia

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Abstract

Sarcopenia is now clinically defined as a loss of muscle mass coupled with functional deterioration (either walking speed or distance or grip strength). Based on the FRAX studies suggesting that the questions without bone mineral density can be used to screen for osteoporosis, there is now a valid simple questionnaire to screen for sarcopenia, i.e., the SARC-F. Numerous factors have been implicated in the pathophysiology of sarcopenia. These include genetic factors, mitochondrial defects, decreased anabolic hormones (e.g., testosterone, vitamin D, growth hormone and insulin growth hormone-1), inflammatory cytokine excess, insulin resistance, decreased protein intake and activity, poor blood flow to muscle and deficiency of growth derived factor-11. Over the last decade, there has been a remarkable increase in our understanding of the molecular biology of muscle, resulting in a marked increase in potential future targets for the treatment of sarcopenia. At present, resistance exercise, protein supplementation, and vitamin D have been established as the basic treatment of sarcopenia. High-dose testosterone increases muscle power and function, but has a number of potentially limiting side effects. Other drugs in clinical development include selective androgen receptor molecules, ghrelin agonists, myostatin antibodies, activin IIR antagonists, angiotensin converting enzyme inhibitors, beta antagonists, and fast skeletal muscle troponin activators. As sarcopenia is a major predictor of frailty, hip fracture, disability, and mortality in older persons, the development of drugs to treat it is eagerly awaited.

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References

  1. Rosenberg IH, Roubenoff R (1995) Stalking sarcopenia. Ann Intern Med 123:727–728

    Article  CAS  PubMed  Google Scholar 

  2. Clark BC, Manini TM (2008) Sarcopenia =/= dynapenia. J Gerontol A Biol Sci Med Sci 63:829–834

    Article  PubMed  Google Scholar 

  3. Barbat-Artigas S, Rolland Y, Vellas B, Aubertin-Leheudre M (2013) Muscle quantity is not synonymous with muscle quality. J Am Med Dir Assoc 14:852.e1-7. doi:10.1016/j.jamda.2013.06.003

    Article  PubMed  Google Scholar 

  4. Manini TM, Clark BC (2012) Dynapenia and aging: an update. J Gerontol A 67:28–40

    Article  Google Scholar 

  5. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y et al (2010) Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on sarcopenia in older people. Age Ageing 39:412–423

    Article  PubMed  PubMed Central  Google Scholar 

  6. Landi F, Cruz-Jentoft AJ, Liperoti R, Russo A, Giovannini S, Tosato M, Capoluongo E, Bernabei R, Onder G (2013) Sarcopenia and mortality risk in frail older persons aged 80 years and older: results from ilSIRENTE study. Age Ageing 42:203–209

    Article  PubMed  Google Scholar 

  7. Landi F, Liperoti R, Fusco D, Mastropaolo S, Quattrociocchi D, Proia A, Tosato M, Bernabei R, Onder G (2012) Sarcopenia and mortality among older nursing home residents. J Am Med Dir Assoc 13:121–126

    Article  PubMed  Google Scholar 

  8. Lee WJ, Liu LK, Peng LN, Lin MH, Chen LK, ILAS Research Group (2013) 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 14:528.e1-7

    PubMed  Google Scholar 

  9. Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, Newman AB, Abellan van Kan G et al (2011) Sarcopenia: An undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International Working Group on Sarcopenia. J Am Med Dir Assoc 12:249–256

    Article  PubMed  Google Scholar 

  10. Morley JE, Abbatecola AM, Argiles JM, Baracos V, Bauer J, Bhasin S, Cederholm T, Coats AJ, Cummings SR, Society on Sarcopenia, Cachexia and Wasting Disorders Trialist Workshop et al (2011) Sarcopenia with limited mobility: An international consensus. J Am Med Dir Assoc 12:403–409

    Article  PubMed  Google Scholar 

  11. Dam TT, Peters KW, Fragala M, Cawthon PM, Harris TB, McLean R, Shardell M, Alley DE, Kenny A, Ferrucci L, Guralnik J, Kiel DP, Kritchevsky S, Vassileva MT, Studenski S (2014) An evidence-based comparison of operational criteria for the presence of sarcopenia. J Gerontol A 69:584–590

    Article  Google Scholar 

  12. Chen LK, Liu LK, Woo J, Assantachai P, Auyeung TW, Bahyah KS, Chou MY, Chen LY, Hsu PS, Krairit O, Lee JS, Lee WJ, Lee Y, Ck Liang, Limpawattana P, Lin CS, Peng LN, Satake S, Suzuki T, Won CW, Wu CH, Wu SN, Zhang T, Zeng P, Akishita M, Arai H (2014) Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc 15:95–101

    Article  PubMed  Google Scholar 

  13. Woo J, Leung J, Morley JE (2014) Defining sarcopenia in terms of incident adverse outcomes. J Am Med Dir. doi:10.1016/jamda.2014.11.013

    Google Scholar 

  14. Kanis JA, McCloskey E, Johansson H, Oden A, Leslie WD (2012) FRAX® with and without bone mineral density. Calcif Tissue Int 90:1–13

    Article  CAS  PubMed  Google Scholar 

  15. Malmstrom TK, Morley JE (2013) SARC-F: a simple questionnaire to rapidly diagnose sarcopenia. J Am Med Dir Assoc 14:531–532

    Article  PubMed  Google Scholar 

  16. Woo J, Leung J, Morley JE (2014) Validating the SARC-F: a suitable community screening tool for sarcopenia? J Am Med Dir Assoc 15:630–634

    Article  PubMed  Google Scholar 

  17. Cao L, Chen S, Zou C, Ding X, Gao L, Liao Z, Liu G, Malmstrom TK, Morley JE, Flaherty JH, An Y, Dong B (2014) A pilot study of the SARC-F scale on screening sarcopenia and physical disability in the Chinese older people. J Nutr Health Aging 18:277–283

    Article  CAS  PubMed  Google Scholar 

  18. Malmstrom TK, Simonsick EM, Ferrucci L, Miller DK, Morley JE (2015) SARC-F: a symptom score to predict persons with sarcopenia at risk for poor functional outcomes. J Cachexia Sarc Muscle. doi:10.1002/jcsm.12048

  19. Argiles JM, Anker SD, Evans WJ, Morley JE, Fearon KC, Strasser F, Muscaritoli M, Baracos VE (2010) Consensus on cachexia definitions. J Am Med Dir Assoc 11:229–230

    Article  PubMed  Google Scholar 

  20. Purves-Smith FM, Sgarioto N, Hepple RT (2014) Fiber typing in aging muscle. Exerc Sport Sci Rev 42:45–52

    Article  PubMed  Google Scholar 

  21. Hepple RT (2003) Sarcopenia: a critical perspective. Sci Aging Knowl Environ 45:31

    Google Scholar 

  22. Drey M, Grosch C, Neuwirth C, Bauer JM, Sieber CC (2013) The motor unit number index (MUNIX) in sarcopenic patients. Exp Gerontol 48:381–384

    Article  CAS  PubMed  Google Scholar 

  23. Hettwer S, Dahinden P, Kucsera S, Farina C, Ahmed S, Fariello R et al (2013) Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients. Exp Gerontol 48:69–75

    Article  CAS  PubMed  Google Scholar 

  24. Drey M, Krieger B, Sieber CC, Bauer JM, Hettwer S, Bertsch T, DISARCO Group (2014) Motoneuron loss is associated with sarcopenia. J Am Med Dir Assoc 15:435–439

    Article  PubMed  Google Scholar 

  25. McNeil CJ, Doherty TJ, Stashuk DW, Rice CL (2005) Motor unit number estimates in the tibialis anterior muscle of young, old, and very old men. Muscle Nerve 31:461–467

    Article  PubMed  Google Scholar 

  26. Guillet C, Auguste P, Mayo W, Kreher P, Gascan H (1999) Ciliary neurotrophic factor is a regulator of muscular strength in aging. J Neurosci 19:1257–1262

    CAS  PubMed  Google Scholar 

  27. Arking DE, Fallin DM, Fried LP, Li T, Beamer BA, Xue QL, Chakravarti A, Walston J (2006) Variation in the ciliary neurotrophic factor gene and muscle strength in older Caucasian women. J Am Geriatr Soc 54:823–826

    Article  PubMed  Google Scholar 

  28. Demontis F, Piccirillo R, Goldberg AL, Perrimon N (2013) The influence of skeletal muscle on systemic aging and lifespan. Aging Cell 12:943–949

    Article  CAS  PubMed  Google Scholar 

  29. Iizuka K, Machida T, Hirafuji M (2014) Skeletal muscle is an endocrine organ. J Pharmacol Sci 125:125–131

    Article  CAS  PubMed  Google Scholar 

  30. Yoon JH, Kim J, Song P, Lee TG, Suh PG, Ryu SH (2012) Secretomics for skeletal muscle cells: a discovery of novel regulators? Adv Biol Regul 52:340–350

    Article  CAS  PubMed  Google Scholar 

  31. Pal M, Febbraio MA, Whitham M (2014) From cytokine to myokine: The emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol 92:331–339

    Article  CAS  PubMed  Google Scholar 

  32. Pistilli EE, Quinn LS (2013) From anabolic to oxidative: reconsidering the roles of Il-15 and IL-15Rα in skeletal muscle. Exerc Sport Sci Rev 41:100–106

    Article  PubMed  Google Scholar 

  33. Morley JE, von Haehling S, Anker SD, Vellas B (2014) From sarcopenia to frailty: a road less travelled. J Cachexia Sarcopenia Muscle 5:5–8

    Article  PubMed  PubMed Central  Google Scholar 

  34. Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, Cesari M, Chumlea WC, Doehner W, Evans J et al (2013) Frailty consensus: a call to action. J Am Med Dir Assoc 14:392–397

    Article  PubMed  PubMed Central  Google Scholar 

  35. Garatachea N, Lucia A (2013) Genes and the ageing muscle: a review on genetic association studies. Age 35:207–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stewart CEH, Rittweger J (2006) Adaptive processes in skeletal muscle: molecular regulators and genetic influences. J Musculoskelet Neuronal Interact 6:783–786

    Google Scholar 

  37. Seto JT, Quinlan KG, Lek M, Zheng XF, Garton F, MacArthur DG et al (2013) ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling. J Clin Invest 123:4255–4263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Seto JT, Chan S, Turner N, MacArthur DG, Raftery JM, Berman YD et al (2011) The effect of α-actinin-3 deficiency on muscle aging. Exp Gerontol 46:292–302

    Article  CAS  PubMed  Google Scholar 

  39. Dennis RA, Zhu H, Kortebein PM, Bush HM, Harvey JF, Sullivan DH, Peterson CA (2009) Muscle expression of genes associated with inflammation, growth, and remodeling is strongly correlated in older adults with resistance training outcomes. Physiol Genomics 38:169–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Windelinckx A, De Mars G, Huygens W, Peeters MW, Vincent B, Wijmenga C, Lambrechts D et al (2011) Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene. Eur J Hum Genet 19:208–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Conte M, Vasuri F, Trisolino G, Bellavista E, Santoro A, Degiovanni A et al (2013) Increased Plin2 expression in human skeletal muscle is associated with sarcopenia and muscle weakness. PLoS ONE 8(8):e73709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rolland Y, Lauwers-Cances V, Crostini C, Abellan van Kan G, Janssen I, Morley JE, Vellas B (2009) Difficulties with physical function associated with obesity, sarcopenia, and sarcopenic-obesity in community-dwelling elderly women. EPIDOS Study 89:1895–1900

    CAS  Google Scholar 

  43. Baumgartner RN, Wayne SJ, Waters DL, Janssen I, Gallagher D, Morley JE (2004) Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly. Obes Res 12:1995–2004

    Article  PubMed  Google Scholar 

  44. Amold A-S, Egger A, Handschin C (2011) PGC-1α and myokines in the aging muscle—a mini-review. Gerontology 57:37–43

    Article  CAS  Google Scholar 

  45. Ling C, Poulsen P, Carlsson E, Ridderstrale M, Almgren P, Wojtaszewski J, Beck-Nielsen H, Groop L, Vaag A (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest 114:1518–1526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sandri M, Lin J, Handschin C, Yang W, Zp Arany, Lecker SH, Goldberg AL, Spiegelman BM (2006) PGC-1α protects skeletal muscle from atrophy by suppressing fox03 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA 103:16260–16265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hepple RT (2014) Mitochondrial involvement and impact in aging skeletal muscle. Front Aging Neurosci 6:211. doi:10.3389/fnagi.2014.00211

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Marzetti E, Calvani R, Cesari M, Buford TW, Lorenzi M, Behnke BJ, Leeuwenburgh C (2013) Mitochondrial dysfunction and sarcopenia of aging: From signaling pathways to clinical trials. Int J Biochem Cell Biol 45:2288–2301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Coen PM, Jubrias SA, Distefano G, Amati F, Mackey DC, Glynn NW et al (2013) Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J Gerontol A 68:447–455

    Article  Google Scholar 

  50. Wang CH, Kao CH, Chen YF, Wei YH, Tsai TF (2014) Cisd2 mediates lifespan: Is there an interconnection among Ca2+ homeostasis, autophagy, and lifespan? Free Radic Res 48:1109–1114

    Article  CAS  PubMed  Google Scholar 

  51. Wu CY, Chen YF, Wang CH, Kao CH, Zhuang HW, Chen CC, Chen LK et al (2012) A persistent level of Cisd2 extends healthy lifespan and delays aging in mice. Hum Mol Genet 21:3956–3968

    Article  CAS  PubMed  Google Scholar 

  52. Lawrenson L, Poole JG, Kim J, Brown C, Patel P, Richardson RS (2003) Vascular and metabolic response to isolated small muscle mass exercise: effect of age. Am J Physiol Heart Circ Physiol 285:H1023–H1031. doi:10.1152/ajpheart.00135.2003

    Article  CAS  PubMed  Google Scholar 

  53. Donato AJ, Uberoi A, Wray DW, Nishiyama S, Lawrenson L, Richardson RS (2006) Differential effects of aging on limb blood flow in humans. Am J Physiol Heart Circ Physiol 290:H272–H278

    Article  CAS  PubMed  Google Scholar 

  54. Seals DR, Jablonski KL, Donato AJ (2011) Aging and vascular endothelial function in humans. Clin Sci 120:357–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Behnke BJ, Delp MD, Dougherty PJ, Musch TI, Poole DC (2005) Effects of aging on microvascular oxygen pressures in rat skeletal muscle. Respir Physiol Neurobiol 146:259–268

    Article  PubMed  Google Scholar 

  56. Cohen S, Nathan JA, Goldberg AL (2015) Muscle wasting in disease: molecular mechanisms and promising therapies. Nature 14:58–74

    CAS  Google Scholar 

  57. Cohen S, Brault JJ, Gygi SP, Glass DJ, Valenzuela DM, Geratner C, Latres E, Goldberg AL (2009) During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J Cell Biol 185:1083–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cohen S, Zhai B, Gygi SP, Goldberg AL (2012) Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J Cell Biol 198:575–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Verdijk LB, Koopmans R, Schaart G, Meijer K, Savelberg HHCM, van Loon LJC (2007) Satellite cell content is specifically reduced in type II skeletal muscle fibers in the elderly. Am J Physiol Endocrinol Metab 292:E151–E157

    Article  CAS  PubMed  Google Scholar 

  60. McGregoe RA, Poppitt SD, Cameron-Smith D (2014) Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans. Ageing Res Rev 17:25–33

    Article  CAS  Google Scholar 

  61. Rivas DA, Lessard SJ, Rice NP, Lustgarten MS, So K, Goodyear LJ, Parnell LD, Fielding RA (2014) Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling. FASEB J 28:4133–4147

    Article  CAS  PubMed  Google Scholar 

  62. Barbierato M, Zusso M, Skaper SD, Giusti P (2015) MicroRNAs: emerging role in the endogenous mu opioid system. CNS Neurol Disord Drug Targets 14:239–250

    Article  CAS  PubMed  Google Scholar 

  63. Alieva AKH, Filatova EV, Karabonov AV, Illarioshkin SN, Limborska SA, Shadrina MI, Slominsky PA (2015) miRNA expression is highly sensitive to a drug therapy in Parkinson’s disease. Parkinsonism Relat Disord 21:72–74

    Article  PubMed  Google Scholar 

  64. Kern H, Barberi L, Löfler S, Sbardella S, Burggraf S, Fruhmann H et al (2014) Electrical stimulation counteracts muscle decline in seniors. Front Aging Neurosci. doi:10.3389/fnagi.2014.00189

    PubMed  PubMed Central  Google Scholar 

  65. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433(7027):760–764

    Article  CAS  PubMed  Google Scholar 

  66. Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C et al (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344(6184):649–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sinha I, Sinha-Hikim AP, Wagers AJ, Sinha-Hikim I (2014) Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res 357(3):815–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fuster G, Busquets S, Almendro V, Lopez-Soriano FJ, Argiles JM (2007) Antiproteolytic effects of plasma from hibernating bears: a new approach for muscle wasting therapy? Clin Nutr 26:658–661

    Article  CAS  PubMed  Google Scholar 

  69. Bodine SC (2013) Hibernation: The search for treatments to prevent disuse-induced skeletal muscle atrophy. Exper Neurol 248:129–135

    Article  Google Scholar 

  70. Andres-Mateos E, Brinkmeier H, Burks TN, Mejias R, Files DC, Steinberger M, Soleimani A et al (2013) Activation of serum/glucocorticoid-induced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy. EMBO Mol Med 5:80–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Valenzuela T (2012) Efficacy of progressive resistance training interventions in older adults in nursing homes: a systematic review. J Am Med Dir Assoc 13:418–428

    Article  PubMed  Google Scholar 

  72. Cadone Cadore EL, Izquierdo M (2013) New strategies for the concurrent strength-, power-, and endurance-training prescription in elderly individuals. J Am Med Dir Assoc 14:623–624

    Article  PubMed  Google Scholar 

  73. Singh NA, Quine S, Clemson LM, Williams EJ, Williamson DA, Stavrinos TM et al (2012) 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 13:24–30

    Article  PubMed  Google Scholar 

  74. Pahor M, Guralnik JM, Ambrosius WT, Blair S, Bonds DE, Church TS et al (2014) Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA 311(23):2387–2396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yamada M, Arai H, Sonoda T, Aoyama T (2012) Community-based exercise program is cost-effective by preventing care and disability in Japanese frail older adults. J Am Med Dir Assoc 13:507–511

    Article  PubMed  Google Scholar 

  76. Bauer J, Biolo G, Cederholm T, Cesari M, Cruz-Jentoft AJ, Morley JE et al (2013) Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE study group. J Am Med Dir Assoc 14:542–559

    Article  PubMed  Google Scholar 

  77. Malafarina V, Uriz-Otano F, Iniesta R, Gil-Guerrero L (2013) Effectiveness of nutritional supplementation on muscle mass in treatment of sarcopenia in old age: a systematic review. J Am Med Dir Assoc 14:10–17

    Article  PubMed  Google Scholar 

  78. Boirie Y (2013) Fighting sarcopenia in older frail subjects: protein fuel for strength, exercise for mass. J Am Med Dir Assoc 14:140–143

    Article  PubMed  Google Scholar 

  79. Tieland M, van de Rest O, Dirks ML, van der Zwaluw N, Mensink M, van Loon LJ et al (2012) Protein supplementation improves physical performance in frail elderly people: a randomized, double-blind, placebo-controlled trial. J Am Med Dir Assoc 13:720–726

    Article  PubMed  Google Scholar 

  80. Cermak NM, de Groot LC, van Loon LJ (2013) Perspective: Protein supplementation during prolonged resistance type exercise training augments skeletal muscle mass and strength gains. J Am Med Dir Assoc 14:71–72

    Article  PubMed  Google Scholar 

  81. Gryson C, Ratel S, Rance M, Penando S, Bonhomme C, Le Ruyet P, Duclos M, Boirie Y, Walrand S (2014) Four-month course of soluble mil proteins interacts with exercise to improve muscle strength and delay fatigue in elderly participants. J Am Med Dir Assoc 15:958.e1-9

    Article  PubMed  Google Scholar 

  82. Ferrando AA, Paddon-Jones D, Hays NP, Kortebein P, Ronsen O, Williams RH, McComb A, Symons TB, Wolfe RR, Evans W (2010) EAA supplementation to increase nitrogen intake improves muscle function during bed rest in the elderly. Clin Nutr 29:18–23

    Article  CAS  PubMed  Google Scholar 

  83. Bauer JM, Verlaan S, Bautmans I, Brandt K, Donini LM, Maggio M, et al. (2015) Effects of a vitamin D and leucine-enriched whey protein nutritional supplement on measures of sarcopenia in older adults. The PROVIDE study: a randomized, double-blind, placebo-controlled trial. J Am Med Dir (in press)

  84. Morley JE, Argiles JM, Evans WJ, Bhasin S, Cella D, Deutz NE et al (2010) Nutritional recommendations for the management of sarcopenia. J Am Med Dir Assoc 11:391–396

    Article  PubMed  PubMed Central  Google Scholar 

  85. Van Wetering C, Hoogendoorn M, Broekhuizen R, Geraerts-Keeris GJ, de Munck DR, Rutten-van Molken MP et al (2010) Efficacy and costs of nutritional rehabilitation in muscle-wasted patients with chronic obstructive pulmonary disease in a community-based setting: a prespecified subgroup analysis of the INTERCOM trial. J Am Med Dir Assoc 11:179–187

    Article  PubMed  Google Scholar 

  86. Tieland M, Dirks ML, van der Zwaluw N, Verdijk LB, van de Rest O, de Groot LC, van Loon LJ (2012) 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 13:713–719

    Article  PubMed  Google Scholar 

  87. Beaudart C, Buckinx F, Rabenda V, Gillain S, Cavalier E, Slomian J et al (2014) The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 99:4336–4345

    Article  CAS  PubMed  Google Scholar 

  88. Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi MM et al (2011) Clinical review: the effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011(96):2997–3006

    Article  CAS  Google Scholar 

  89. Morley JE (2011) Should frailty be treated with testosterone? Aging Male 14:1–3

    Article  PubMed  Google Scholar 

  90. Morley JE, Fe Kaiser, Perry HM 3rd, Patrick P, Morley PM, Stauber PM, Vellas B, Baumgartner RN, Garry PJ (1997) Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 46:410–413

    Article  CAS  PubMed  Google Scholar 

  91. Baumgartner RN, Dl Waters, Gallagher D, Morley JE, Garry PJ (1999) Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 107:123–136

    Article  CAS  PubMed  Google Scholar 

  92. Morley JE, Perry HM 3rd, Kaiser FE, Kraenzle D, Jensen J, Houston K, Mattammal M, Perry HM Jr (1993) Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc 41:149–152

    Article  CAS  PubMed  Google Scholar 

  93. Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ et al (2005) Exogenous testosterone (T) alone or with finasteride increses physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 90:1502–1510

    Article  CAS  PubMed  Google Scholar 

  94. Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C (1997) Testosterone replacement in older hypogonadal men: A 12-month randomized controlled trial. J Clin Endocrinol Metab 82:1661–1667

    Article  CAS  PubMed  Google Scholar 

  95. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE (2003) Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A 58:618–625

    Article  Google Scholar 

  96. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE et al (2005) Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrniol Metab 90:678–688

    Article  CAS  Google Scholar 

  97. Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA et al (2010) Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 95:639–650

    Article  CAS  PubMed  Google Scholar 

  98. Kenny AM, Kleppinger A, Annis K, Rathier M, Browner B, Judge JO et al (2010) Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am Geriatr Soc 58:1134–1143

    Article  PubMed  PubMed Central  Google Scholar 

  99. Travison TG, Basaria S, Storer TW, Jette AM, Miciek R, Farwell WR et al (2011) Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci 66:1090–1099

    Article  PubMed  CAS  Google Scholar 

  100. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M et al (2009) Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 54:919–927

    Article  CAS  PubMed  Google Scholar 

  101. Iellamo F, Volterrano M, Caminiti G, Karam R, Massaro R, Fini M et al (2010) Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol 56:1310–1316

    Article  CAS  PubMed  Google Scholar 

  102. Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS (2006) Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 27:57–64

    Article  CAS  PubMed  Google Scholar 

  103. Stout M, Tew GA, Doll H, Zwierska I, Woodroofe N, Channer KS, Saxton JM (2012) Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J 164:893–901

    Article  CAS  PubMed  Google Scholar 

  104. Morley JE, Perry HM 3rd (2003) Androgens and women at the menopause and beyond. J Gerontol A Biol Sci Med Sci 58:M409–M416

    Article  PubMed  Google Scholar 

  105. Chapman IM, Visvanathan R, Hammond AJ, Morley JE, Field JB, Tai K et al (2009) Effect of testosterone and a nutritional supplement, alone and in combination, on hospital admissions in undernourished older men and women. Am J Clin Nutr 89:880–889

    Article  CAS  PubMed  Google Scholar 

  106. Wolfe R, Ferrando A, Sheffield-Moore M, Urban R (2000) Testosterone and muscle protein metabolism. Mayo Clin Proc 75(Suppl):S55–S59

    CAS  PubMed  Google Scholar 

  107. Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR, Urban RJ (2003) Differential anabolic effects of testosterone and amino acid feeding in older men. J Clin Endocrinol Metab 88:358–362

    Article  CAS  PubMed  Google Scholar 

  108. Kovacheva EL, Hikim AP, Shen R, Sinha I, Sinha-Hikim I (2010) Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways. Endocrniology 151:628–638

    Article  CAS  Google Scholar 

  109. Harin MT, Siddiqui AM, Armbrecht HJ, Kevorkian RT, Kim MJ, Haas MJ, Mazza A, Kumar VB, Green M, Banks WA, Morley JE (2011) Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscle. Int J Androl 34:55–68

    Article  CAS  Google Scholar 

  110. Morley JE (2013) Scientific overview of hormone treatment used for rejuvenation. Fertil Steril 99:1807–1813

    Article  CAS  PubMed  Google Scholar 

  111. Carona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, Maggi M (2014) Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf 13:1327–1351

    Article  CAS  Google Scholar 

  112. Mogentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM (2015) Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 90:224–251

    Article  CAS  Google Scholar 

  113. Borst SE, Shuster JJ, Zou B, Ye F, Jia H, Wokhlu A, Yarrow JF (2014) Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Med 12:211–215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Morley JE, Malmstrom TK, Rodriguez-Manas L, Sinclair AJ (2014) Frailty, sarcopenia and disabetes. J Am Med Dir Assoc 15:853–859

    Article  PubMed  Google Scholar 

  115. Landi F, Onder G, Bernabei R (2013) Sarcopenia and diabetes: two sides of the same coin. J Am Med Dir Assoc 14:540–541

    Article  PubMed  Google Scholar 

  116. Leenders M, Verdijk LB, van der Hoeven L, Adam JJ, van Kranenburg J, Nilwik R, van Loon LJ (2013) Patients with type 2 diabetes show a greater decline in muscle mass, muscle strength, and functional capacity with aging. J Am Med Dir Assoc 14:585–592

    Article  PubMed  Google Scholar 

  117. Muraleedharan V, March H, Kapoor D, Channer KS, Jones TH (2013) Tesosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 169:725–733

    Article  CAS  PubMed  Google Scholar 

  118. Nieschlag E (2015) Current topics in testosterone replacement of hypogonadal men. Best Pract Res Clin Endocrinol Metab 29:77–90

    Article  CAS  PubMed  Google Scholar 

  119. Irwig MS (2014) Bone health in hypogonadal men. Curr Opin Urol 24:608–613

    Article  PubMed  Google Scholar 

  120. Sharma S, Arneja A, McLean L, Duerksen D, Leslie W, Sciberras D, Lertzman M (2008) Anabolic steroids in COPD: a review and preliminary results of a randomized trial. Chron Respir Dis 5:169–176

    Article  CAS  PubMed  Google Scholar 

  121. Frisoli A Jr, Chaves PH, Pinheiro MM, Vl Szejnfeld (2005) The effect of nandrolone decanoate on bone mineral density, muscle mass, and hemoglobin levels in elderly women with osteoporosis: a double-blind, randomized, placebo-controlled clinical trial. J Gerontol A 60:648–653

    Article  Google Scholar 

  122. Macdonald JH, Marcora SM, Jibani MM, Kumwenda MJ, Ahmed W, Lemmey AB (2007) Nandrolone decanoate as anabolic therapy in chronic kidney disease: a randomized phase II dose-finding study. Nephron Clin Pract 106:c125–c135

    Article  CAS  PubMed  Google Scholar 

  123. Farooqi V, van den Berg ME, Cameron ID, Crotty M (2014) Anabolic steroids for rehabilitation after hip fracture in older people. Cochrane Database Syst Rev 10:CD008887

    PubMed  Google Scholar 

  124. Papanicolaou DA, Ather SN, Zhu H, Zhou Y, Lutkiewicz J, Scott BB, Chandler J (2013) A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. J Nutr Health Aging 17:533–543

    Article  CAS  PubMed  Google Scholar 

  125. Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y et al (2009) Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit. J Med Chem 52:3598–3617

    Article  CAS  Google Scholar 

  126. Bhasin S, Jasuja R (2009) Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care 12:232–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Basario S, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R et al (2013) The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J Gerontol A 68:87–95

    Article  CAS  Google Scholar 

  128. Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST et al (2011) The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle 2:153–161

    Article  PubMed  PubMed Central  Google Scholar 

  129. Dobs AS, Boccia RV, Croot CC, Gabrial NY, Dalton JT, Hancock ML et al (2013) Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomized controlled phase 2 trial. Lancet Oncol 14:335–345

    Article  CAS  PubMed  Google Scholar 

  130. Steiner MS (2013) Enobosarm, a selective androgen receptor modulator, increases lean body mass in advanced non-small cell lung cancer patients in two pivotal, international phase 3 trials. J Cachexia Sarcopenia Muscle 4:69. doi:10.1007/s13539-013-0123-9

    Google Scholar 

  131. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF et al (1990) Effects of human growth hormone in men over 60 years old. N Engl J Med 323:1–6

    Article  CAS  PubMed  Google Scholar 

  132. Cohn L, Feller AG, Draper MW, Rudman IW, Rudman D (1993) Carpal tunnel syndrome and gynaecomastia druing growth hormone treatment of elderly men with low circulating IGF-1 concentrations. Clin Endocrniol (Oxf) 39:417–425

    Article  CAS  Google Scholar 

  133. Kim MJ, Morley JE (2005) The hormonal fountains of youth: myth or reality? J Endocrinol Invest 28(11):5–14

    CAS  PubMed  Google Scholar 

  134. Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE et al (2002) Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 288:2282–2292

    Article  CAS  PubMed  Google Scholar 

  135. Kaiser FE, Silver AJ, Morley JE (1991) The effect of recombinant human growth hormone on malnourished older individuals. J Am Geriatr Soc 39:235–240

    Article  CAS  PubMed  Google Scholar 

  136. Liu H, Bravata DM, Olkin I, Nayak S, Roberts B, Am Garber, Hoffman AR (2007) Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 146:104–115

    Article  PubMed  Google Scholar 

  137. Giannoulis MG, Martin FC, Nair KS, Umpleby AM, Sonksen P (2012) Hormone replacement therapy and physical function in healthy older men. Time to talk hormones? Endocr Rev 33:314–377

    Article  CAS  PubMed  Google Scholar 

  138. Sullivan DH, Carter WJ, Warr WR, Williams LH (1998) Side effects resulting from the use of growth hormone and insulin-like growth factor-1 as combined therapy to frail elderly patients. J Gerontol A 53:M183–M187

    Article  CAS  Google Scholar 

  139. Gaskin FS, Farr SA, Banks WA, Kumar VB, Morley JE (2008) Ghrelin-induced feeding is dependent on nitric oxide. Peptides 24:913–918

    Article  CAS  Google Scholar 

  140. Argiles JM, Stemmler B (2013) The potential of ghrelin in the treatment of cancer cachexia. Expert Opin Biol Ther 13:67–76

    Article  CAS  PubMed  Google Scholar 

  141. Miyazaki T, Tanaka N, Hirai H, Yokobori T, Sano A, Sakai M et al (2012) Ghrelin level and body weight loss after esophagectomy for esophageal cancer. J Surg Res 176:74–78

    Article  CAS  PubMed  Google Scholar 

  142. Garcia JM, Boccia RV, Graham CD, Yan Y, Duus EM, Allen S, Friend J (2015) Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomized, placebo-controlled, double-blind trials. Lancet Oncol 16:108–116

    Article  CAS  PubMed  Google Scholar 

  143. Temel J, Bondarde S, Jain M, Yun Y, Duus E, Allen S et al (2013) Efficacy and safety results from a phase II study of anamorelin HC21, a ghrelin receptor agonist, in NSCLC patients. J Cachexia Sarcopenia Muscle 4:334

    Google Scholar 

  144. White HK, Petrie CD, Landschulz W, MacLean D, Taylor A, Lyles K et al (2009) Effects of an oral growth hormone scretagogue in older adults. J Clin Endocrinol Metab 94:1198–1206

    Article  CAS  PubMed  Google Scholar 

  145. Adunsky A, Chandler J, Heyden N, Lutkiewicz J, Scott BB, Berd Y et al (2011) MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fractures: a multicenter, randomized, placebo-controlled phase IIb study. Arch Gerontol Geriatr 53:183–189

    Article  CAS  PubMed  Google Scholar 

  146. Elkina Y, vono Haehling S, Anker SD, Springer J (2011) The role of muyostatin in muscle wasting: an overview. J Cachexia Sarcopenia Muscle 2:143–151

    Article  PubMed  PubMed Central  Google Scholar 

  147. Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W, Braun T, Tobin JF, Lee SJ (2004) Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 350:2682–2688

    Article  CAS  PubMed  Google Scholar 

  148. Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K (2010) Effects of oral cretine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrniol 317:25–30

    Article  CAS  Google Scholar 

  149. Walter MC, Reilich P, Lochmuller H, Kohnen R, Schlotter B, Hautmann H, Dunkl E et al (2002) Creatine monohydrate in myotonic dystrophy: a double-blind, placebo-controlled clinical study. J Neurol 249:1717–1722

    Article  CAS  PubMed  Google Scholar 

  150. Tsuchida K (2008) Targeting myostatin for therapies against muscle-wasting disorders. Curr Opin Drug Discov Devel 11:487–494

    CAS  PubMed  Google Scholar 

  151. Wagner KR, Fleckenstein JL, Amato AA, Barhn RJ, Bushby K, Eagle M, Florence JM, King WM et al (2008) A phase I/II Trial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol 63:561–571

    Article  CAS  PubMed  Google Scholar 

  152. Padhi D, Higano CS, Shore ND, Sieber P, Rasmussen E, Smith MR (2014) Pharmacological inhibition of myostatin and changes in lean body mass and lower extremity muscle size in patients receiving androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 99:E1967–E1975

    Article  CAS  PubMed  Google Scholar 

  153. Fajardo RJ, Manoharan RK, Pearsall RS, Davies MV, Marvell T, Monnell TE et al (2010) Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis). Bone 46:64–71

    Article  CAS  PubMed  Google Scholar 

  154. Attie KM, Brogstein NG, Yang Y, Condon CH, Wilson DM, Pearsall AE et al (2013) A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve 47:416–423

    Article  CAS  PubMed  Google Scholar 

  155. Amato AA, Sivakumar K, Goyal N, David WS, Salajegheh M, Praestgaard J, Lach-Trifilieff E, Trendelenburg AU, Laurent D, Glass DJ, Roubenoff R, Tseng BS, Greenberg SA (2014) Treatment of Sporadic inclusion body myositis with bimagrumab. Neurology 83:2239–2246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Potsch MS, Tschirner A, Palus S, von Haehling S, Doehner W, Beadle J, Coats AJ, Anker SD, Springer J (2014) The anabolic catabolic transforming agenda (ACTA) espindolol increases muscle mass and decreases fat mass in old rats. J Cachexia Sarcopenia Muscle 5:149–158

    Article  PubMed  PubMed Central  Google Scholar 

  157. Steward Coats AJ, Srinivasan Surendran J, Chicarmana H, Vangipuram SR, Bhatt NN, Jain M et al (2011) The ACT-ONE trial, a multicenter, randomized, double-blind, placebo-controlled dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design. J Cachexia Sarcopenia Muscle 2:201–207

    Article  Google Scholar 

  158. Hutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME (2002) Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomized double blind placebo controlled trial. Heart 88:373–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sumukadas D, Witham MD, Struthers AD, McMurdo ME (2007) Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ 177:867–874

    Article  PubMed  PubMed Central  Google Scholar 

  160. Sumukadas D, Band M, Miller S, Cvoro V, Witham M, Struthers A, McConnachie A, Lloud SM, McMurdo M (2014) Do ACE inhibitors improve the response to exercise training in functionally impaired older adults? A randomized controlled trial. J Gerontol A 69:736–743

    Article  CAS  Google Scholar 

  161. Peters R, Beckett N, Burch L, de Vernejoul MC, Liu L, Duggan J et al (2010) The effect of treatment based on diuretic (indapamide) ± ACE inhibitor (perindopril) on fractures in the hypertension in the very elderly trial (HYVET). Age Ageing 39:609–616

    Article  PubMed  Google Scholar 

  162. Malik F (2013) Fast skeletal muscle troponin activators and their application to disease-preclinical characterization. In: Abstracts, 7th Cachexia Conference, Kobe. p 50

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The author declares that there were no funds received from any entity for the writing of this article. The author has received grants from Nestle (Purina) and Kemin that are not related to this work. The author is on the speaker’s bureau and has been a consultant for Nutricia and received consultant fees from Nutricia, Sanofi-Aventis, Astellas, Boehringer-Ingelheim, Merck, and Akros, none of which have any influence on the writing of this article.

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Morley, J.E. Pharmacologic Options for the Treatment of Sarcopenia. Calcif Tissue Int 98, 319–333 (2016). https://doi.org/10.1007/s00223-015-0022-5

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