The Journal of Nutrition, Health & Aging© Volume 12, Number 7, 2008
SARCOPENIA: DIAGNOSIS AND TREATMENT
SARCOPENIA: DIAGNOSIS AND TREATMENT J.E. MORLEY Division of Geriatric Medicine, Saint Louis University School of Medicine and GRECC, VA Medical Center St. Louis, Missouri. Contact: John E. Morley, M.B., B.Ch. Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, Email:
[email protected]
In 1931, Critchley noted that with aging there was a loss of muscle mass which was most marked in the hands and feet (1). This age-related loss of muscle mass was called sarcopenia (from the Greek: sarx for flesh and penia for loss) by Irving Rosenberg (2). While originally sarcopenia was considered to be a generalized loss of muscle, it is now more conventionally used as a level of muscle loss substantially less than that seen in normal young persons, similar to the terms osteopenia and osteoporosis for bone (3). While it is recognized that the factors that cause strength loss are different from those producing muscle loss (4), sarcopenia usually results in a decline in strength and power leading to frailty and disability. The International Academy for Nutrition and Aging definition for frailty is strongly related to sarcopenia (Table 1) (5, 6). Table 1 The International Academy of Nutrition and Aging Screen for Frailty Fatigue Resistance (cannot climb 1 flight of stairs) Aerobic (cannot walk one block) Illnesses (more than 5) Loss of weight (greater than 5% in 1 year)
Sarcopenia is very common in older persons with a prevalence from 5 to 13% in persons aged 60 to 70 years and of 11 to 50% in persons over 80 years of age (5, 6, 7, 8, 9, 10, 11, 12). The large variability in prevalence is related to the differences in measurement and cut-offs used to define sarcopenia. Sarcopenia is approximately twice as common as frailty (13). In the United States, it can be estimated that there are roughly 3.6 million persons with frailty. Janssen et al. (14) utilized the NHANES data to demonstrate that sarcopenia was strongly associated with disability. They calculated that the total cost to the American Health System of sarcopenia was approximately $18.4 billion. Subsequently it has been recognized that persons who lose muscle, but remain obese, are at very high risk of disability and mortality (15). This condition is called “obese sarcopenia” or the “fat frail.” In addition, when muscle contains large amounts of fat as demonstrated by attenuation on magnetic resonance imaging, there is increased likelihood of poor outcomes (16). This condition is termed myosteatosis.
Received March 7, 2008 Accepted for publication March 17, 2008
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Diagnosis The measurement of skeletal muscle mass is fraught with difficulty with al available methods having some drawbacks. The methods used to measure muscle mass are outlined in Table 2. Most studies measure appendicular muscle mass and correct this for height. About 75% of muscle mass is appendicular and approximately 60% of fat free mass is muscle. Table 2 Methods to Estimate Sarcopenia Approach
Problems
Cost
DEXA
Cannot distinguish muscle from organ protein Problem when abdominal fat is present
$$$
Bioelectrical Impedance
Problems with hydration status
$$
Anthropometry
Operator dependent Crude approximation
$
Urinary creatine/ Creatinine
Physical activity Non-muscle sources Renal clearance
$
CT or MRI
Cross-sectional
$$$$
Neutron Activation Cannot distinguish muscle from organ protein Limited availability
$$$
As already alluded to, aging is associated with changes in muscle composition and quality. With aging there is a decrease in both muscle fiber size and number. With aging, there is a greater loss of Type II fibers and an increase in hybrid type I and II fibers (17, 18). Changes in the muscle result in a slowing of twitch contraction time and a slowing of maximum shortening speed. For these reasons, it is important to measure muscle strength and power as well as mass. The Jamar dynamometer remains an excellent method for measuring upper arm strength in persons without arthritis. Lower limb strength and/or power can be obtained by measuring walking speed or stair climbing. The use of the Cybex and similar machines is useful for research, but requires expensive equipment and technical skill. Ultrasonic studies have shown that changes in tendons with alteration in pennation angles plays an important role in the ability to generate power (19). Electromyography can be used
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THE JOURNAL OF NUTRITION, HEALTH & AGING© to determine loss in motor units. It should be recognized that loss of executive function interacts with sarcopenia to produce falls – “the dual tasking” effect. The trigger to screen for sarcopenia should be a loss of muscle mass of 5% or greater over a year or less (20). Sarcopenia is one of the four major causes of weight loss (21). The other causes are anorexia (22, 23), cachexia (24) and dehydration (25). Loss of muscle mass leads to “masked” renal failure. This is important as renal failure is a common cause of cachexia (26). Differentiating the different causes of weight loss can be difficult as shown in Table 3. Table 3 Comparison of Sarcopenia, Cachexia and Anorexia
Weight loss Fat free mass Proteolysis Fat Mass Anorexia Cytokines
Sarcopenia
Cachexia
Anorexia
Mild Moderate Loss Increased Increased or Normal No Elevated or Normal
Severe Severe Loss Markedly Increased Marked Loss Yes Markedly Elevated
Moderate Mild Loss Normal Loss Yes Normal
Management The key to managing sarcopenia is physical activity coupled with adequate nutritional intake. At present, the only available drug therapy for sarcopenia is anabolic steroids. Numerous other drugs are at various stages of development (Table 4). Table 4 Management of Sarcopenia 1. 2.
Physical exercise – Aerobic/Resistant High protein supplement
3.
Anabolic steroids
4. 5. 6.
Selective Androgen Receptor Molecules (SARMs) Angiotensin Converting Enzyme Inhibitors Developmental
- casein - leucine - testosterone - nandrolone - ostarine - prindopril - antimyostatin - ghrelin agonists
Physical Activity Manini et al. (27) found that in 70 to 80 year olds high total energy expenditure leads to increased longevity. In this study, stair climbing was a major factor in producing increased total energy expenditure. Higher levels of physical activity attenuate the development of sarcopenia (28). When older persons undergo a period of enforced bed rest, they lose muscle at a greater rate than do young persons (29). Both aerobic and resistance exercise increase muscle mass and strength and decrease the rate of fat accumulation (30, 31, 32). Exercise decreases the rate of development of disability and frailty (33, 34). Spontaneous Physical Fun (SPF) is an important component of maintaining muscle mass. Spontaneous physical activity is 453
related to orexin levels in the hypothalamus of rodents (35). Older persons who get out of the house once a day do better than those who stay indoors (36). SPF includes stair climbing, walking, dancing and gardening. It needs to be done in combination with a regular exercise routine. Nutrition Low calorie and protein intake in older persons is associated with the development of frailty (37). Calories are essential for muscles to generate adequate energy. Thus, older persons with the physiological anorexia of aging or pathological causes of anorexia need to be aggressively treated to allow maintenance of an adequate calorie intake (38, 39, 40). Depression is a common, treatable cause of anorexia (41, 42, 43). Caloric supplements should be given between and not with meals (43a). The Recommended Daily Allowance of 0.8 g/kg body weight/daily of protein is insufficient to maintain nitrogen balance in older persons (44). To prevent sarcopenia older persons need between 1.2 to 1.5 g/kg daily. Essential amino acids such as leucine are not only building blocks but increase protein anabolism and decrease protein breakdown (45). There are now studies that demonstrate that creatine acts synergistically with resistance exercise to increase strength in older persons (46, 47). Anabolic Steroids Since 1889 when “Pud” Galvin, a pitcher for the Pittsburgh Steelers, used Brown-Sequard Elixir, sports persons have used anabolic steroids to improve performance. Total testosterone decreases by 1% per year and bioavailable testosterone by 2% per year from the age of 30 years in males (48, 49). Testosterone levels decrease rapidly from 20 to 45 years in women (50). A number of studies have shown that testosterone, even in eugonadal males, increased muscle mass (51, 52, 53). High doses of testosterone in hypogonadal older males increase strength (54, 55, 56) and improve physical performance (57). Testosterone increases muscle mass and strength by stimulating satellite cell production as well as muscle protein synthesis (58). Testosterone also increases muscle mass in postmenopausal women (50). Testosterone in combination with a caloric supplement decreased hospitalization in frail older men and women (59). Dehydroepiandrosterone (DHEA) levels decline steeply with aging and lower levels are associated with low muscle mass and strength in postmenopausal women (60). However, 50g of DHEA for a year failed to improve muscle mass or strength in males and females (61). Nandrolone, an injectable anabolic steroid, increases muscle mass and performance in older persons (62). It is similarly effective to increase muscle performance in patients with AIDS, COPD and renal failure (63, 64, 65). Recently, a number of selective androgen receptor molecules (SARMs) have been developed. These agents can be ingested orally and build muscle and promote bone. One of these agents
The Journal of Nutrition, Health & Aging© Volume 12, Number 7, 2008
SARCOPENIA: DIAGNOSIS AND TREATMENT is ostarine (66). Ostarine increased fat free mass and power as measured by stair climb in healthy older males and females with a mean age of 64.8 years (67). Vitamin D Low levels of vitamin D (less than 30 ng/ml) are associated with sarcopenia and declines in muscle strength (68, 69). Low vitamin D is an independent predictor of falls (70). Vitamin D replacement in persons with low levels increases strength and performance (71). Vitamin D levels fall longitudinally with age (72). Low vitamin D levels are particularly common in older persons residing in nursing homes (73, 74, 75). All older persons with sarcopenia should have vitamin D levels measured and, if low, vitamin D needs to be replaced. Growth Hormone In malnourished older persons growth hormone produces nitrogen retention and improves walking speed (76, 77). However, there is limited evidence that growth hormone can increase strength (78). For this reason, growth hormone is not recommended for the treatment of sarcopenia. Ghrelin is a hormone that is produced from the fundus of the stomach and causes increased appetite, growth hormone release and improved memory (79, 80). Ghrelin increased handgrip strength in patients with heart failure (81).
Conclusion Sarcopenia should be diagnosed by geriatricians. Diagnosis requires a DEXA measurement of fat free mass using the appendicular levels corrected for height squared. Ultrasound measurement of muscles and tendon angle may be an acceptable alternative. Basic treatment consists of aerobic and resistance exercise together with a high protein (leucine and creatine) supplement between meals. 25(OH) vitamin D levels should be measured and, if low, need to be aggressively replaced. A total or preferably free or bioavailable testosterone level should be obtained in males (96). If low, testosterone replacement at 100 mg a week intra-muscular is advised. In females nandrolone may be a reasonable alternative. A brachial/ankle Doppler should be obtained and if suggestive of peripheral vascular disease, the patient should be treated for atherosclerosis. This approach is summarized in Figure 1. Figure 1 Possible Approach to the Management of Sarcopenia
Angiotensin Converting Enzyme (ACE) Inhibitors There is epidemiological and animal studies supporting the use of ACE inhibitors for the treatment of sarcopenia (82, 83). Persons with the II ACE genotype have low ACE activity and better endurance performance in response to exercise training (84). Heart failure patients receiving an ACE inhibitor had improved exercise capacity (85). In a double blind controlled trial, 130 persons over 65 years of age received perindopril or placebo for 20 weeks (86). In this study perindopril increased walking distance by 31.4 meters. Other Factors High levels of cytokines, especially interleukin-6, result in a loss of muscle mass and decreased performance (87, 88, 89). There is however, no studies demonstrating that cytokine inhibitors improve muscle function. Myostatin inhibits muscle growth (90). Myostatin antibodies are in clinical trials to try and reverse sarcopenia. The metabolic syndrome and diabetes are associated with a decline in muscle strength, increased falls and hip fracture (91, 92, 93). Adequate control of diabetes and hypertriglyceridemia should be obtained in persons with sarcopenia. Loss of motor units is associated with loss of muscle mass and power (94). This may be due to declining ciliary neurotrophic factor levels with aging (95). Topiramate may improve nerve growth.
References 1. 2. 3. 4.
454
Critchley M. The neurology of old age. Nutrition. 2001;17:660-663. Rosenberg IH. Sarcopenia: Origins and clinical relevance. J Nutr. 1997;127(Suppl 5):S990-S991. Morley JE. Anorexia, sarcopenia, and aging. Nutrition. 2001;17:660-663. Rolland YM, Perry HM 3rd, Patrick P, et al. Loss of appendicular muscle mass and loss of muscle strength in young postmenopausal women. J Gerontol A Biol Sci Med Sci. 2007;62:330-335.
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THE JOURNAL OF NUTRITION, HEALTH & AGING© 5. 6. 7.
8.
9. 10. 11. 12.
13. 14. 15.
16. 17. 18. 19. 20.
21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.
37.
38. 39. 40.
Baumgartner RN, Koehler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998;147:755-763. Morley JE, Baumgartner RN, Roubenoff R, et al. Sarcopenia. J Lab Clin Med. 2001;137:231-243. Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc. 2002;50:889-896. Tanko LB, Movsesyan L, Mouritzen U, Christiansen C, Svendsen OL. Appendicular lean tissue mass and the prevalence of sarcopenia among healthy women. Metabolism. 2002;51:69-74. Melton LJ, Khosla S, Crowson CS, O’Connor MD, O’Fallon WM, Riggs BL. Epidemiology of sarcopenia. J Am Geriatr Soc. 2000;48:625-630. Gillette-Guyonnet S, Hourhashemi F, et al. Body composition in French women 75+ years of age: the EPIDOS study. Mech Ageing Dev. 2003;124:311-316. Castillo EM, Goodman-Gruen D, Kritz-Silverstein D, et al. Sarcopenia in elderly men and women: The Rancho Bernardo Study. Am J Prev Med. 2003;25:226-231. Ianuzzi-Sucich M, Prestwood KM, Kenny AM. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J Gerontol A Biol Sci Med Sci. 2002;57:M2771-M777. Morley JE, Kim MJ, Haren MT, Kevorkian R, Banks WA. Frailty and the aging male. Aging Male. 2005;8:135-140. Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R. The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc. 2004;52:80-85. Baumgartner RN, Wayne SJ, Waters DL et al. Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly. Obes Res. 2004;12:1995-2004. Goodpaster BH, Carlson CL, Visser M, et al. Attenuation of skeletal muscle and strength in the elderly: The Health ABC Study. J Appl Physiol. 2001;90:2157-2163. Larsson L. Histochemical characteristics of human skeletal muscle during aging. Acta Physiol Scand. 1983;117:469-471. Reeves ND, Narici MB, Maganaris CN. Myotendinous plasticity to ageing and resistance exercise in humans. Exp Physiol. 2006;91:483-498. Narici MV, Maganaris CN. Adaptability of elderly human muscles and tendons to increased loading. J Anat. 2006;208:433-443. Thomas DR, Ashmen W, Morley JE, Evans WJ. Nutritional management in longterm care: development of a clinical guideline. Council for Nutritional Strategies in Long-Term Care. J Gerontol A BIol Sci Med Sci. 2000;55:M725-M734. Morley JE. Weight loss in the nursing home. J Am Med Dir Assoc. 2007;8:201-204. Morley JE. Weight loss in older persons: new therapeutic approaches. Curr Pharm Des. 2007;13:3637-3647. Morley JE. Anorexia and weight loss in older persons. J Gerontol A Biol Sci Med Sci. 2003;58:131-137. Morley JE, Thomas DR, Wilson MM. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr. 2006;83:735-743. Thomas DR, Cote TR, Lawhorne L, et al. Understanding clinical dehydration and its treatment. J Am Med Dir Assoc. 2008;9: june issue (In Press) Kalantar-Zadeh K, Horwich TB, Oreopoulos A, et al. Risk factor paradox in wasting diseases. Curr Opin Clin Nutr Metab Care. 2007;10:433-442. Manini TM, Everhart JE, Patel KV, et al. Daily activity energy expenditure and mortality among older adults. JAMA. 2006;296:171-179. Hughes VA, Roubenoff R, Wood M, et al. Anthropometric assessment of 10-y changes in body composition in the elderly. Am J Clin Nutr. 2004;80:475-482. Kortebien P, Ferrando A, Lombeida J, et al. Effect of 1 days of bed rest on skeletal muscle in healthy older adults. JAMA. 2007;297:1772-1774. Roubenoff R. Physical activity, inflammation, and muscle loss. Nutr Rev. 2007;65(12 Pt 2):S208-S212. Frankel JE, Bean JF, Frontera WR. Exercise in the elderly: research and clinical practice. Clin Geriatr Med. 2006;22:239-256. Singh MA. Exercise to prevent and treat functional disability. Clin Geriatr Med. 2002;18:431-462. Heath JM, Stuart MR. Prescribing exercise for frail elders. J Am Board Fam Pract. 2002;15:218-228. van Kan GA, Rolland YM, Morley JE, Vellas B. Frailty: toward a clinical definition. J Am Med Dir Assoc. 2008;9:71-72. Kotz CM, Wang C, Teske JA, et al. Orexin A mediation of time spent moving in rats: neural mechanisms. Neuroscience. 2006;142:29-36. Simonsick EM, Guralnik JM, Volpato S, et al. Just get out the door! Importance of walking outside the home for maintaining mobility; findings from the women’s health and aging study. J Am Geriatr Soc. 2005;53:198-203. Bartali B, Frongillo EA, Bandinelli S, et al. Low nutrient intake is an essential component of frailty in older persons. J Gerontol A Biol Sci Med Sci. 2006;61:589593. Chapman IM, MacIntosh CG, Morley JE, Horowitz M. The anorexia of ageing. Biogerontology. 2002;3:67-71. Hays NP, Roberts SB. The anorexia of aging in humans. Physiol Behav. 2006;88:257-266. Morley JE. Decreased food intake with aging. J Gerontol A Biol Sci Med Sci.
455
41. 42. 43. 44.
45.
46. 47.
48.
49.
50. 51. 52.
53.
54.
55.
56.
57.
58.
59. 60.
61.
62.
63.
64. 65.
66.
67.
68.
2001;56(Spec 2):81-88. Morley JE. Weight loss in the nursing home. J Am Med Dir Assoc. 2007;8:201-204. Morley JE. Kraenzle D. Causes of weight loss in a community nursing home. J Am Geriatr Soc. 1994;42:583-585. Cabrera MA, Mesas AE, Garcia AR, de Andrade SM. Malnutrition and depression among community-dwelling elderly people. J Am Med Dir Assoc. 2007;8:582-584. Volpi E, Sheffield-Moore M, Rasmussen BB, Wolfe RR. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA. 2001;286:1206-1212. Paddon-Jones D, Sheffield-Moore M, Urban RJ, et al. Essential amino acid and carbohydrate supplementation ameliorates muscle protein loss in humans during 28 days bedrest. J Clin Endocrinol Metab. 2004;89:4351-4358. Candow DG, Chilibeck PD. Effect of creatine supplementation during resistance training on muscle accretion in the elderly. J Nutr Health Aging. 2007;11:185-188. Olsen S, Aagaard P, Kadi F, et al. Creatine supplementation augments the increase in satellite cell and myonuclei number in human muscle induced by strength training. J Physiol. 2006;573(Pt 2):525-534. Morley JE, Kaiser FE, Perry HM 3rd, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46:410-413. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrionl Metab. 2002;87:589-598. Morley JE, Perry HM 3rd. Androgens and women at the menopause and beyond. J Gerontol A BIol Sci Med Sci. 2003;58:M409-M416. Morley JE. The diagnosis of late life hypogonadism. Aging Male. 2007;10:217-220. Wittert GA, Chapman IM, Haren MT, et al. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci. 2003;58:618-625. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:2647-2653. Morley JE, Perry HM 3rd, Kaiser FE, et al. Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc. 1993;41:149-152. Ottenbacher KJ, Ottenbacher ME, Ottenbacher AJ, et al. Androgen treatment and muscle strength in elderly men: a meta-analysis. J Am Geriatr Soc. 2006;54:16661673. Sih R, Morley JE, Kaiser FE, et al. Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997;82:1661-1667. Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab. 2005;90:1502-1510. Bhasin S, Taylor WE, Singh R, et al. The mechanisms of androgen effects of body composition: mesenchymal pluripotent cellas the target of androgen action. J Gerontol A Biol Sci Med Sic. 2003;58:M1103-M1110. Chapman IM. Anorexia abstracts, 4th Cachexia Conference. Tampa, Florida, March 1, 2007. www.cachexia.org Haren MT, Malmstrom TK, Banks WA, et al. Lower serum DHEAs levels are associated with a higher degree of physical disability and depressive symptoms in middle-aged to older African American women. Maturitas. 2007;57:347-360. Percheron G, Hogrel JY, Denot-Ledunois S, et al. Effect of 1-year oral administration of dehydroepiandrosterone to 60- to 80-year-old individuals on muscle function and cross-sectional area: a double-blind placebo-controlled trial. Arch Intern med. 2003;163:720-727. Frisoli A Jr., Chaves PH, Pinheiro MM, Szejnfeld VL. 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 Biol Sci Med Sci. 2005;60:648-653. MacDonald JH, Marcora SM, Jibani MM, et al. Nandrolone decanoate as anabolic therapy in chronic kidney disease: a randomized phase II dose-finding study. Nephron Clin pract. 2007;106:c125-c135. Gold J, Batterham MJ, Rekers H, et al. Effects of nandrolone decanoate compared with placebo or testosterone on HIV-associated wasting. HIV Med. 2006;7:146-155. Creutzberg EC, Wouters EF, Mostert R, et cl. A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest. 2003;124:1733-1742. Gao W, Dalton JT, Ockham’s razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase? Mol Interv. 2007;7:1013. Evans WJ, Smith M, Morley JE, et al. Ostarine increases lean body mass and improves physical performance in healthy elderly subjects: Implications for cancer cachexia patients. 2007 Annual Meeting Proceedings Part I. J Clin Oncol 2007;25(18S):9119. Visser M, Deeg DJH, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): The
The Journal of Nutrition, Health & Aging© Volume 12, Number 7, 2008
SARCOPENIA: DIAGNOSIS AND TREATMENT 69. 70. 71. 72. 73. 74.
75. 76.
77. 78. 79. 80. 81.
82.
83.
Longitudinal Aging Study Amsterdam. J Clin Endocrin Metab. 2003;88:5766-5772. Morley JE. Should all long-term care residents receive vitamin D? J Am Med Dir Assoc. 2007;8:69-70. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA. 2004;291:1999-2006. Heath KM, Elovic EP. Vitamin D deficiency: implications in the rehabilitation setting. Am J Phys Med Rehabil. 2006;85:916-923. Perry HM 3rd, Horowitz M, Morley JE, et al. Longitudinal changes in serum 25hydroxyvitamin D in older people. Metabolism. 1999;48:1028-1032. Drinka PJ, Krause PF, Nest LJ, Goodman BM. J Am Med Dir Assoc. 2007;8:76-79. Hamid Z, Riggs A, Spencer T, Redman C, Bodenner D. Vitamin D deficiency in residents of academic long-term care facilities despite having been prescribed vitamin D. J Am Med Dir Assoc. 2007;8:71-75. Munir J, Wright RJ, Carr DB. A quality improvement study on calcium and vitamin D supplementation in long-term care. J Am med Dir Assoc. 2006;7:305-309. Chu LW, Lam KS, Tam SC et al. A randomized controlled trial of low-dose recombinant human growth hormone in the treatment of malnourished elderly medical patients: J Clin Endocrinol Metab. 2001;86:1913-1920. Kaiser FE, Silver AJ, Morley JE. The effect of recombinant human growth hormone on malnourished older individuals. J Am Geriatr Soc. 1991;39:235-240. Morley JE. Growth hormone: fountain of youth or death hormone? J Am Geriatr Soc. 1999;47:1475-1476. Gaskin FS, Farr SA, Banks WA, et al. Ghrelin-induced feeding is dependent on nitric oxide. Peptides. 2003;24:913-918. Diano S, Farr SA, Benoit SC, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006;9:381-388. Nagaya N, Moriya J, Yasumura Y, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation. 2004;110:3674-3679. Carter CS, Onder G, Kritchevsky SB, Pahor M. Angiotensin-converting enzyme inhibition intervention in elderly persons: effects on body composition and physical performance. J Gerontol A Biol Sci Med Sci. 2005;60:1437-1446. Onder G, Vedova CD, Pahor M. Effects of ACE inhibitors on skeletal muscle. Curr
84.
85.
86.
87.
88. 89. 90. 91. 92. 93. 94. 95. 96.
456
Pharm Des. 2006;12:2057-2064. Frederiksen H, Bathum L, Worm C, et al. ACE genotype and physical training effects: a randomized study among elderly Danes. Aging Clin Exp Res. 2003;15:284291. Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect of perindopril on physical function in elderly people with functional impairment: a randomized controlled trial. CMAJ. 2007;177:867-874. Hutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomized double blind placebo controlled trial. Heart. 2002;88:373377. Ferrucci L, Penninx BWJH, Volpato S, et al. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J Am Geriatr Soc. 2002;50:1947-1954. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, latelife diseases, and frailty. Ann Rev Med. 2000;51:245-270. Morley JE, Baumgartner RN. Cytokine-related aging process. J Gerontol A BIol Sci Med Sci. 2004;59:M924-M929. McNally EM. Powerful genes—myostatin regulation of human muscle mass. N Engl J Med. 2004;350:2642-2644. Mazza AD, Morley JE. Metabolic syndrome and the older male population. Aging Male. 2007;10:3-8. Mazza AD, Morley JE. Update on diabetes in the elderly and the application of current therapeutics. J Am Med Dir Assoc. 2007;8:489-492. Patel S, Hyer S, Tweed K, et al. Risk factors for fractures and falls in older women with type 2 diabetes mellitus. Calcif Tissue Int. 2008;82:87-91. Doherty TJ, Vandervoort AA, Brown WF. Effects of ageing on the motor unit: a brief review. Can J Appl Physiol. 1993;18:331-358. Guillet C, Auguste P, Mayo W, et al. Ciliary neurotrophic factor is a regulator of muscular strength in aging. J Neurosci. 1999;19:1257-1262. Morley JE, Patrick P, Perry HM 3rd. Evaluation of assays available to measure free testosterone. Metabolism. 2002;51:554-559.