Sarcopenia

Sarcopenia
Classification and external resources
ICD-10 M62.84
ICD-9-CM xxx

Sarcopenia is the degenerative loss of skeletal muscle mass (0.5–1% loss per year after the age of 50), quality, and strength associated with aging.[1] Sarcopenia is a component of the frailty syndrome. It is often a component of cachexia. It can also exist independently of cachexia; whereas cachexia includes malaise and is secondary to an underlying pathosis (such as cancer), sarcopenia may occur in healthy people and does not necessarily include malaise. The term is from Greek σάρξ sarx, "flesh" and πενία penia, "poverty".

Classification

Sarcopenia is not a disease or a syndrome, and it is not always even a medical sign, because the degree to which it is normal (physiologic) versus abnormal (pathologic) is not determined. As of 2009 there is no generally accepted definition of sarcopenia in the medical literature.[2]

The European Working Group on Sarcopenia in Older People (EWGSOP) developed a clinical definition and consensus diagnostic criteria for age-related sarcopenia, using the presence of low muscle mass and either low muscular strength or low physical performance.[3] Severe sarcopenia requires the presence of all three conditions.[3]

Signs and symptoms

Sarcopenia is characterized first by a muscle atrophy (a decrease in the size of the muscle), along with a reduction in muscle tissue quality, characterized by such factors as replacement of muscle fibres with fat, an increase in fibrosis, changes in muscle metabolism, oxidative stress, and degeneration of the neuromuscular junction and leading to progressive loss of muscle function and frailty.[4] Sarcopenia is determined by two factors: initial amount of muscle mass and rate at which aging decreases muscle mass. Due to the loss of independence associated with loss of muscle strength, the threshold at which muscle wasting becomes a disease is different pathologically from person to person.[5]

Simple circumference measurement does not provide enough data to determine whether or not an individual is suffering from severe sarcopenia. Sarcopenia is also marked by a decrease in the circumference of distinct types of muscle fibers. Skeletal muscle has different fiber-types, which are characterized by expression of distinct myosin variants. During sarcopenia, there is a decrease in "type 2" fiber circumference (Type II), with little to no decrease in "type I" fiber circumference (Type I), and deinervated type 2 fibers are often converted to type 1 fibers by reinnervation by slow type 1 fiber motor nerves.[6]

Causes

Satellite cells are small mononuclear cells that abut the muscle fiber. Satellite cells are normally activated upon injury or exercise. These cells then differentiate and fuse into the muscle fiber, helping to maintain its function. One theory is that sarcopenia is in part caused by a failure in satellite cell activation.[4]

Extreme muscle loss is often a result of both diminishing anabolic signals, such as growth hormone and testosterone, and promotion of catabolic signals, such as pro-inflammatory cytokines.[4]

Oxidized proteins increase in skeletal muscle with age and leads to a buildup of lipofuscin and cross-linked proteins that are normally removed via the proteolysis system. These proteins compile in the skeletal muscle tissue, but are dysfunctional. This leads to an accumulation of non-contractile material in the skeletal muscle. This helps explain why muscle strength decreases severely, as well as muscle mass, in sarcopenia.[5]

One group has suggested that the evolutionary basis for the failure of the body to maintain muscle mass and function with age is that the genes governing these traits were selected in a Late Paleolithic environment in which there was a very high level of obligatory muscular effort, and that these genetic parameters are therefore ill-matched to a modern lifestyle characterized by high levels of lifelong sedentary behavior.[7]

Epidemiological research into the developmental origins of health and disease has shown that early environmental influences on growth and development may have long-term consequences for human health. Low birth weight, a marker of a poor early environment, is associated with reduced muscle mass and strength in adult life.[8][9][10][11][12] One study has shown that lower birth weight is associated with a significant decrease in muscle fibre score, suggesting that developmental influences on muscle morphology may explain the widely reported associations between lower birth weight and sarcopenia.[13]

Diagnosis

A working definition for diagnosis was proposed in 1998 by Baumgartner et al which uses a measure of lean body mass as determined by dual energy X-ray absorptiometry (DEXA) compared to a normal reference population. His working definition uses a cut point of 2 standard deviations below the mean of lean mass for gender specific healthy young adults.[14]

This methodology shows it is predictive of negative outcomes and it is also a method familiar to most clinicians. This latter point is especially true for those that treat the geriatric population, given its similarity to the 1996 World Health Organization (WHO) methodology for definitive diagnosis of osteoporosis, which also uses DEXA, but uses a measure of lean mass rather than bone mineral density (BMD). DEXA is widely used already in clinical settings in developed countries to identify and monitor severity of osteoporosis. And the degree of sarcopenia can be measured using DEXA in patients being evaluated for osteoporosis, at the same time with the same scan, with no added cost or radiation exposure to the patient.

Since Baumgartner's working definition first appeared, some consensus groups have refined the definition, including the recent joint effort of the European Society on Clinician Nutrition and Metabolism (ESPEN) Special Interest Groups (SIG) on geriatric nutrition and on cachexia-anorexia in chronic wasting diseases. Their consensus definition is:[15]

  1. A low muscle mass, >2 standard deviations below that mean measured in young adults (aged 18–39 years in the 3rd NHANES population) of the same sex and ethnic background, and
  2. Low gait speed (e.g. a walking speed below 0.8 m/s in the 4-m walking test).[15]

Management

Exercise

Lack of exercise is thought to be a significant risk factor for sarcopenia.[16] Even highly trained athletes experience its effects; master-class athletes who continue to train and compete throughout their adult lives exhibit a progressive loss of muscle mass and strength, and records in speed and strength events decline progressively after age 30.[4][17]

Master-class athletes maintain a high level of fitness throughout their lifespan. Even among master athletes, performance of marathon runners and weight lifters declines after approximately 40 years of age, with peak levels of performance decreased by approximately 50% by 80 years of age.[18] However a gradual loss of muscle fibres begins only at approximately 50 years of age.[18]

Exercise is of interest in treatment of sarcopenia; evidence indicates increased ability and capacity of skeletal muscle to synthesize proteins in response to short-term resistance exercise.[19] A 2009 Cochrane review also found evidence that in older adults progressive resistance training can improve physical performance (gait speed) and muscular strength,[20] which are two key components of sarcopenia.

Medication

As of July 2015, there are no approved medications for the treatment of sarcopenia;[1] however, β-hydroxy β-methylbutyrate (HMB), a metabolite of leucine which is sold as a dietary supplement, has demonstrated efficacy in preventing the loss of muscle mass in individuals with sarcopenia.[1][21][22] A growing body of evidence supports the efficacy of HMB as a treatment for reducing, or even reversing, the loss of muscle mass, muscle function, and muscle strength in hypercatabolic disease states such as cancer cachexia;[23][24][25] consequently, as of June 2016 it is recommended that both the prevention and treatment of sarcopenia and muscle wasting in general include supplementation with HMB, regular resistance exercise, and consumption of a high-protein diet.[23][24] Based upon a meta-analysis of seven randomized controlled trials that was published in 2015, HMB supplementation has efficacy as a treatment for preserving lean muscle mass in older adults.[note 1][22] More research is needed to determine the precise effects of HMB on muscle strength and function in this age group.[22]

DHEA and human growth hormone have been shown to have little to no effect in this setting. Growth hormone increases muscle protein synthesis and increases muscle mass, but does not lead to gains in strength and function in most studies.[26] This, and the similar lack of efficacy of its effector insulin-like growth factor 1 (IGF-1), may be due to local resistance to IGF-1 in aging muscle, resulting from inflammation and other age changes.[26]

Testosterone or other anabolic steroids have also been investigated for treatment of sarcopenia, and seem to have some positive effects on muscle strength and mass, but cause several side effects and raise concerns of prostate cancer in men and virilization in women.[26][27] Additionally, recent studies suggest testosterone treatments may induce adverse cardiovascular events.[28][29][30] Other approved medications under investigation as possible treatments for sarcopenia include ghrelin, vitamin D, angiotensin converting enzyme inhibitors, and eicosapentaenoic acid.[26][27]

Epidemiology

A study, in community dwelling older adults with an average age of 67 years, found the UK prevalence of sarcopenia to be 4.6% in men and 7.9% in women using the EWGSOP approach.[31] Another study, conducted in the United States among older adults with an average age of 70.1 years, found the prevalence of sarcopenia to be 36.5%.[32]

Society and culture

Due to the lessened physical activity and increased longevity of industrialized populations, sarcopenia is emerging as a major health concern. Sarcopenia may progress to the extent that an older person may lose his or her ability to live independently. Furthermore, sarcopenia is an important independent predictor of disability in population-based studies, linked to poor balance, gait speed, falls, and fractures. Sarcopenia can be thought of as a muscular analog of osteoporosis, which is loss of bone, also caused by inactivity and counteracted by exercise. The combination of osteoporosis and sarcopenia results in the significant frailty often seen in the elderly population.

Research directions

Many opportunities remain for further refinement of reference populations by ethnic groups, and to further correlate the degrees of severity of sarcopenia to overt declines in functional performance (preferably using verified functional tests), as well as incidence of hospitalization admissions, morbidity, and mortality. The body of research points toward severe sarcopenia being predictive of negative outcomes, similar to those already shown to exist with frailty syndrome, as defined by the criteria set forth in 2001 by Fried et al.[33]

Future research should aim to gain a deeper understanding of the molecular and cellular mechanisms of sarcopenia and the application of a lifecourse approach to understanding aetiology as well as to informing the optimal timing of interventions.[34]

New pharmaceutical therapies in clinical development include myostatin and the selective androgen receptor modulators (SARMs).[35] Nonsteriodal SARMs are of particular interest, given they exhibit significant selectivity between the anabolic effects of testosterone on muscle, but with little to no evidence of androgenic effects (such as prostate stimulation in men).[35]

MT-102, the first-in-class anabolic catabolic transforming agent (ACTA), has recently been tested in a Phase-II clinical study for treating cachexia in late-stage cancer patients. The study data show significant increases in body weight in patients treated with 10 mg of MT-102 twice daily over the study period of 16 weeks compared to significant decrease in body weight in patients receiving placebo treatment.[36] In preclinical models, MT-102 has also shown benefits in reversing sarcopenia in elderly animals.[37] Future clinical studies will investigate sarcopenia as potential second indication for MT-102.

Novartis proposes the use of a new molecule BYM338 Bimagrumab for treatment of sarcopenia and plans to make a FDA submission in 2019.[38]

Clinical practice

However, diagnosis can be difficult due to the comprehensive measurements used in research that are not always practical in healthcare settings. Hand grip strength alone has also been advocated as a clinical marker of sarcopenia that is simple and cost effective and has good predictive power, although it does not provide comprehensive information.[39]

Exercise remains the intervention of choice for sarcopenia but translation of findings into clinical practice is challenging. The type, duration and intensity of exercise are variable between studies, so an ‘off the shelf’ exercise prescription for sarcopenia remains an aspiration.[40]

The role of nutrition in preventing and treating sarcopenia is less clear. Large, well-designed studies of nutrition particularly in combination with exercise are needed, ideally across healthcare settings. For now, basing nutritional guidance on the evidence available from the wider health context is probably the best approach with little contention in the goals of replacing vitamin D where deficient, and ensuring an adequate intake of calories and protein, although there is debate about whether currently recommended protein intake levels are optimal.[39][40]

See also

Notes

  1. ↑ The estimated standard mean difference effect size for the increase in muscle mass in the HMB treatment groups relative to controls was 0.352 kilograms (0.78 lb) with a 95% confidence interval of 0.11–0.594 kilograms (0.24–1.31 lb).[22] The studies included in the meta-analysis had durations of 2–12 months and the majority of studies lasted 2–3 months.[22]

References

  1. 1 2 3 Phillips SM (July 2015). "Nutritional supplements in support of resistance exercise to counter age-related sarcopenia". Adv. Nutr. 6 (4): 452–460. doi:10.3945/an.115.008367. PMC 4496741Freely accessible. PMID 26178029.
  2. ↑ Visser M (October 2009). "Towards a definition of sarcopenia--results from epidemiologic studies" (PDF). J Nutr Health Aging (Review). 13 (8): 713–6. doi:10.1007/s12603-009-0202-y. PMID 19657555.
  3. 1 2 Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. (July 2010). "Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People". Age Ageing. 39 (4): 412–23. doi:10.1093/ageing/afq034. PMC 2886201Freely accessible. PMID 20392703.
  4. 1 2 3 4 Ryall JG, Schertzer JD, Lynch GS (August 2008). "Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness". Biogerontology (Review). 9 (4): 213–28. doi:10.1007/s10522-008-9131-0. PMID 18299960.
  5. 1 2 Marcell TJ (October 2003). "Sarcopenia: causes, consequences, and preventions". J. Gerontol. A Biol. Sci. Med. Sci. (Review). 58 (10): M911–6. doi:10.1093/gerona/58.10.m911. PMID 14570858.
  6. ↑ Doherty TJ (2003). "Invited review: Aging and sarcopenia". J Appl Physiol (Review). 95 (4): 1717–27. doi:10.1152/japplphysiol.00347.2003. PMID 12970377.
  7. ↑ Booth FW, Chakravarthy MV, Spangenburg EE (September 2002). "Exercise and gene expression: physiological regulation of the human genome through physical activity". J. Physiol. (Lond.) (Review). 543 (Pt 2): 399–411. doi:10.1113/jphysiol.2002.019265. PMC 2290514Freely accessible. PMID 12205177.
  8. ↑ Sayer, Avan Aihie; Syddall, Holly E.; Gilbody, Helen J.; Dennison, Elaine M.; Cooper, Cyrus (2004-09-01). "Does Sarcopenia Originate in Early Life? Findings From the Hertfordshire Cohort Study". The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 59 (9): M930–M934. doi:10.1093/gerona/59.9.M930. ISSN 1079-5006. PMID 15472158.
  9. ↑ Sayer, Avan Aihie; Dennison, Elaine M.; Syddall, Holly E.; Jameson, Karen; Martin, Helen J.; Cooper, Cyrus (2008-08-01). "The Developmental Origins of Sarcopenia: Using Peripheral Quantitative Computed Tomography to Assess Muscle Size in Older People". The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 63 (8): 835–840. doi:10.1093/gerona/63.8.835. ISSN 1079-5006. PMC 2652118Freely accessible. PMID 18772471.
  10. ↑ Gale, Catharine R.; Martyn, Christopher N.; Kellingray, Samantha; Eastell, Richard; Cooper, Cyrus (2013-07-02). "Intrauterine Programming of Adult Body Composition 1". The Journal of Clinical Endocrinology & Metabolism. 86 (1): 267–272. doi:10.1210/jcem.86.1.7155.
  11. ↑ Kuh, Diana; Hardy, Rebecca; Butterworth, Suzanne; Okell, Lucy; Wadsworth, Michael; Cooper, Cyrus; Sayer, Avan Aihie (2006-07-01). "Developmental Origins of Midlife Grip Strength: Findings From a Birth Cohort Study". The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 61 (7): 702–706. doi:10.1093/gerona/61.7.702. ISSN 1079-5006. PMID 16870632.
  12. ↑ Ylihärsilä, H.; Kajantie, E.; Osmond, C.; Forsén, T.; Barker, D. J. P.; Eriksson, J. G. (2007-03-13). "Birth size, adult body composition and muscle strength in later life". International Journal of Obesity. 31 (9): 1392–1399. doi:10.1038/sj.ijo.0803612. ISSN 0307-0565.
  13. ↑ Patel, H. P.; Jameson, K. A.; Syddall, H. E.; Martin, H. J.; Stewart, C. E.; Cooper, C.; Sayer, A. A. (2012-01-01). "Developmental Influences, Muscle Morphology, and Sarcopenia in Community-Dwelling Older Men". The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 67A (1): 82–87. doi:10.1093/gerona/glr020. ISSN 1079-5006. PMID 21357193.
  14. ↑ Baumgartner RN, Koehler KM, Gallagher D, et al. (April 1998). "Epidemiology of sarcopenia among the elderly in New Mexico". Am. J. Epidemiol. (Comparative study). 147 (8): 755–63. PMID 9554417.
  15. 1 2 Muscaritoli M, Anker S, Argilés J, et al. (2010). "Consensus definition of sarcopenia, cachexia and pre-cachexia: Joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics"". Clinical Nutrition. 29 (2): 154–159. doi:10.1016/j.clnu.2009.12.004. PMID 20060626.
  16. ↑ Abate M, Di Iorio A, Di Renzo D, Paganelli R, Saggini R, Abate G (September 2007). "Frailty in the elderly: the physical dimension". Eura Medicophys. 43 (3): 407–15. PMID 17117147.
  17. ↑ Faulkner JA, Larkin LM, Claflin DR, Brooks SV (November 2007). "Age-related changes in the structure and function of skeletal muscles". Clin. Exp. Pharmacol. Physiol. (Review). 34 (11): 1091–6. doi:10.1111/j.1440-1681.2007.04752.x. PMID 17880359.
  18. 1 2 Faulkner JA, Larkin LM, Claflin DR, Brooks SV (November 2007). "Age-related changes in the structure and function of skeletal muscles". Clin. Exp. Pharmacol. Physiol. 34: 1091–6. doi:10.1111/j.1440-1681.2007.04752.x. PMID 17880359.
  19. ↑ Yarasheski KE (October 2003). "Exercise, aging, and muscle protein metabolism". J. Gerontol. A Biol. Sci. Med. Sci. (Review). 58 (10): M918–22. doi:10.1093/gerona/58.10.m918. PMID 14570859.
  20. ↑ Liu, Chiung-ju; Latham, Nancy K (2009-07-08). Cochrane Database of Systematic Reviews. John Wiley & Sons. doi:10.1002/14651858.cd002759.pub2. ISSN 1465-1858.
  21. ↑ Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention". Mol. Aspects Med. doi:10.1016/j.mam.2016.04.006. PMID 27106402. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people.
  22. 1 2 3 4 5 Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K (September 2015). "Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis". Arch. Gerontol. Geriatr. 61 (2): 168–175. doi:10.1016/j.archger.2015.06.020. PMID 26169182. RESULTS: A total of seven randomized controlled trials were included, in which 147 older adults received HMB intervention and 140 were assigned to control groups. The meta-analysis showed greater muscle mass gain in the intervention groups compared with the control groups (standard mean difference=0.352kg; 95% confidence interval: 0.11, 0.594; Z value=2.85; P=0.004). There were no significant fat mass changes between intervention and control groups (standard mean difference=-0.08kg; 95% confidence interval: -0.32, 0.159; Z value=0.66; P=0.511).
    CONCLUSION: Beta-hydroxy-beta-methylbutyrate supplementation contributed to preservation of muscle mass in older adults. HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors. Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults.
  23. 1 2 Brioche T, Pagano AF, Py G, Chopard A (April 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention". Mol. Aspects Med. doi:10.1016/j.mam.2016.04.006. PMID 27106402. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is cheap (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people. ... 3 g of CaHMB taken three times a day (1 g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013).
  24. 1 2 Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (June 2016). "Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease". J. Am. Med. Dir. Assoc. doi:10.1016/j.jamda.2016.04.019. PMID 27324808. Studies suggest dietary protein and leucine or its metabolite b-hydroxy b-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. ... These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia.65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84 A growing body of evidence suggests HMB may help slow, or even reverse, the muscle loss experienced in sarcopenia and improve measures of muscle strength.44, 65, 72, 76, 77, 78, 79, 80, 81, 82, 83, 84 However, dietary leucine does not provide a large amount of HMB: only a small portion, as little as 5%, of catabolized leucine is metabolized into HMB.85 Thus, although dietary leucine itself can lead to a modest stimulation of protein synthesis by producing a small amount of HMB, direct ingestion of HMB more potently affects such signaling, resulting in demonstrable muscle mass accretion.71, 80 Indeed, a vast number of studies have found that supplementation of HMB to the diet may reverse some of the muscle loss seen in sarcopenia and in hypercatabolic disease.65, 72, 83, 86, 87 The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation.68 ...
    Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB.
  25. ↑ Mullin GE (February 2014). "Nutrition supplements for athletes: potential application to malnutrition". Nutr. Clin. Pract. 29 (1): 146–147. doi:10.1177/0884533613516130. PMID 24336486. There are a number of nutrition products on the market that are touted to improve sports performance. HMB appears to be the most promising and to have clinical applications to improve muscle mass and function. Continued research using this nutraceutical to prevent and/or improve malnutrition in the setting of muscle wasting is warranted.
  26. 1 2 3 4 Kunihiro, Sakuma; Akihiko Yamaguchi (May 28, 2012). "Sarcopenia and Age-Related Endocrine Function". International Journal of Endocrinology. 2012: 127362. doi:10.1155/2012/127362. PMC 3368374Freely accessible. PMID 22690213.
  27. 1 2 Wakabayashi, H; Sakuma K (November 11, 2013). "Comprehensive Approach to Sarcopenia Treatment". Curr Clin Pharmacol. 9 (2): 171–80. doi:10.2174/1574884708666131111192845. PMID 24219006.
  28. ↑ Finkle, WD; Greenland, S; Ridgeway, GK; Adams, JL; Frasco, MA; Cook, MB; Fraumeni, JF Jr; Hoover, RN (Jan 29, 2014). "Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.". PLoS ONE. 9 (1): e85805. doi:10.1371/journal.pone.0085805. PMC 3905977Freely accessible. PMID 24489673. Retrieved 2 June 2014.
  29. ↑ Vigen R; O'Donnell CI; Barón AE; Grunwald GK; Maddox TM; Bradley SM; Barqawi A; Woning G; Wierman ME; Plomondon ME; Rumsfeld JS; Ho PM (Nov 6, 2013). "Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels". JAMA. 310 (17): 1829–36. doi:10.1001/jama.2013.280386. PMID 24193080.
  30. ↑ Basaria, S.; Coviello, A.D.; Travison, T.G. (June 2010). "Adverse Events Associated with Testosterone Administration". The New England Journal of Medicine. 363 (2): 109–122. doi:10.1056/NEJMoa1000485. PMC 3440621Freely accessible. PMID 20592293.
  31. ↑ Patel, Harnish P.; Syddall, Holly Emma; Jameson, Karen; Robinson, Sian; Denison, Hayley; Roberts, Helen C.; Edwards, Mark; Dennison, Elaine; Cooper, Cyrus (2013-05-01). "Prevalence of sarcopenia in community-dwelling older people in the UK using the European Working Group on Sarcopenia in Older People (EWGSOP) definition: findings from the Hertfordshire Cohort Study (HCS)". Age and Ageing. 42 (3): 378–384. doi:10.1093/ageing/afs197. ISSN 0002-0729. PMC 3633365Freely accessible. PMID 23384705.
  32. ↑ "Sarcopenia and mortality among a population-based sample of community-dwelling older adults". Journal of Cachexia, Sarcopenia and Muscle. doi:10.1002/jcsm.12073.
  33. ↑ Fried LP, Tangen CM, Walston J, et al. (2001). "Frailty in Older Adults: Evidence for a Phenotype.". J Gerontol a Biol Sci Med Sci. 56 (3): M146–56. doi:10.1093/gerona/56.3.m146. PMID 11253156.
  34. ↑ Sayer, Avan Aihie; Robinson, Sian M.; Patel, Harnish P.; Shavlakadze, Tea; Cooper, Cyrus; Grounds, Miranda D. (2013-03-01). "New horizons in the pathogenesis, diagnosis and management of sarcopenia". Age and Ageing. 42 (2): 145–150. doi:10.1093/ageing/afs191. ISSN 0002-0729. PMC 3575121Freely accessible. PMID 23315797.
  35. 1 2 Lynch, Gordon S (November 2004). "Emerging drugs for sarcopenia: age-related muscle wasting". Expert Opinion on Emerging Drugs. 9 (2): 345–61. doi:10.1517/14728214.9.2.345. PMID 15571490.
  36. ↑ see press release on businesswire from 12 November 2013 "Mid-Stage Clinical Study of Wasting Disease Therapeutic MT-102 Shows Reversal of Cancer-Related Wasting"
  37. ↑ Pötsch MS, Tschirner A, Palus S, von Haehling S, Doehner W, Beadle J, Coats AJ, Anker SD, Springer J (Nov 2013). "The anabolic catabolic transforming agent (ACTA) espindolol increases muscle mass and decreases fat mass in old rats". J Cachexia Sarcopenia Muscle. 5 (Online ahead of print): 149–58. doi:10.1007/s13539-013-0125-7. PMC 4053568Freely accessible. PMID 24272787. Retrieved 28 April 2014.
  38. ↑ http://www.novartis.com/downloads/innovation/planned-filings.pdf
  39. 1 2 Sayer, A. A. "Sarcopenia". BMJ. 341 (aug10 2): c4097–c4097. doi:10.1136/bmj.c4097.
  40. 1 2 Sayer, Avan Aihie (2014-11-01). "Sarcopenia the new geriatric giant: time to translate research findings into clinical practice". Age and Ageing. 43 (6): 736–737. doi:10.1093/ageing/afu118. ISSN 0002-0729. PMID 25227204.

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