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Ghrelin in Health and Disease pp 199–211Cite as

Ghrelin Receptor Agonists in Cachexia of Human Aging

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Part of the book series: Contemporary Endocrinology ((COE,volume 10))

Abstract

Frailty is one of the key features of aging and it is associated with a loss of function, an increased risk of falls, and ultimately loss of the ability to live independently. Based on the demographic shift of the older population, as a result of the aging of the baby boomers, interventions to slow or delay the development of frailty will be of increasing importance. One of the physiologic correlates of frailty is the cachexia of aging. The underlying mechanism of the cachexia of aging is cytokine-associated wasting of protein and energy stores and ghrelin receptor agonists target some of these mechanisms. Clinical trials have shown that ghrelin receptor agonists have orexigenic effects, enhance GH secretion, and increase lean body mass and limb fat mass in the elderly. The potential benefits of ghrelin receptor agonists in the treatment of cachexia of aging and of cachexia secondary to various diseases are reviewed.

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References

  1. Butler RN. Population aging and health. BMJ. 1997;315:1082–4.

    Article  PubMed  CAS  Google Scholar 

  2. CDC. Public health and aging:trends in aging-United States and worldwide. JAMA. 2003; 289:1371–73.

    Google Scholar 

  3. Michel JP, Newton JL, Kirkwood TB. Medical challenges of improving the quality of a longer life. JAMA. 2008;299:688–90.

    Article  PubMed  Google Scholar 

  4. Ory MG, Cox DM. Forging ahead: linking health and behavior to improve quality of life in older people. Soc Indic Res. 1994;33:89–120.

    Article  Google Scholar 

  5. Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporosis Int. 1997;7:407–13.

    Article  CAS  Google Scholar 

  6. Tinetti ME. Prevention of falls and fall injuries in elderly persons: a research agenda. Prev Med. 1994;23:756–62.

    Article  PubMed  CAS  Google Scholar 

  7. Leveille SG, Guralnik JM, Ferrucci L, Langlois JA. Aging successfully until death in old age: opportunities for increasing active life expectancy. Am J Epidemiol. 1999;149:654–64.

    Article  PubMed  CAS  Google Scholar 

  8. Fried LP, Guralnik JM. Disability in older adults: evidence regarding significance, etiology, and risk. J Am Geriatr Soc. 1997;45:92–100.

    PubMed  CAS  Google Scholar 

  9. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–56.

    Article  PubMed  CAS  Google Scholar 

  10. Espinoza S, Walston JD. Frailty in older adults: insights and interventions. Cleve Clin J Med. 2005;72:1105–12.

    Article  PubMed  Google Scholar 

  11. Morley KC, Cornish JL, Li KM, McGregor IS. Preexposure to MDMA (“Ecstasy”) delays acquisition but facilitates MDMA-induced reinstatement of amphetamine self-administration behavior in rats. Pharmacol Biochem Behav. 2004;79:331–42.

    Article  PubMed  CAS  Google Scholar 

  12. Kotler DP. Cachexia. Ann Intern Med. 2000;133:622–34.

    PubMed  CAS  Google Scholar 

  13. Rosenbaum K, Wang J, Pierson Jr RN, Kotler DP. Time-dependent variation in weight and body composition in healthy adults. JPEN J Parenter Enteral Nutr. 2000;24:52–5.

    Article  PubMed  CAS  Google Scholar 

  14. Yeh SS, Schuster MW. Geriatric cachexia: the role of cytokines. Am J Clin Nutr. 1999; 70:183–97.

    PubMed  CAS  Google Scholar 

  15. Morley JE, Baumgartner RN. Cytokine-related aging process. J Gerontol A Biol Sci Med Sci. 2004;59:M924–9.

    Article  PubMed  Google Scholar 

  16. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–70.

    Article  PubMed  CAS  Google Scholar 

  17. Cappola AR, Xue QL, Ferrucci L, Guralnik JM, Volpato S, Fried LP. Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J Clin Endocrinol Metab. 2003;88:2019–25.

    Article  PubMed  CAS  Google Scholar 

  18. Sullivan DH, Morley JE, Johnson LE, et al. The GAIN (Geriatric Anorexia Nutrition) registry: the impact of appetite and weight on mortality in a long-term care population. J Nutr Health Aging. 2002;6:275–81.

    PubMed  CAS  Google Scholar 

  19. Ritchie CS, Locher JL, Roth DL, McVie T, Sawyer P, Allman R. Unintentional weight loss predicts decline in activities of daily living function and life-space mobility over 4 years among community-dwelling older adults. J Gerontol A Biol Sci Med Sci. 2008;63:67–75.

    Article  PubMed  Google Scholar 

  20. Argiles JM, Busquets S, Felipe A, Lopez-Soriano FJ. Molecular mechanisms involved in muscle wasting in cancer and ageing: cachexia versus sarcopenia. Int J Biochem Cell Biol. 2005; 37:1084–104.

    Article  PubMed  CAS  Google Scholar 

  21. Conn MP, Bowers CY. A new receptor for growth hormone-release peptide. Science. 1996; 273:923.

    Article  PubMed  CAS  Google Scholar 

  22. Bowers CY, Chang JK, Fong TTW. A synthetic pentapeptide which specifically releases GH, in vitro. Proceedings of the 59th Meeting of The Endocrine Society. Chicago; 1977.

    Google Scholar 

  23. Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984;114:1537–45.

    Article  PubMed  CAS  Google Scholar 

  24. Chapman IM, Hartman ML, Pezzoli SS, Thorner MO. Enhancement of pulsatile growth hormone secretion by continuous infusion of a growth hormone-releasing peptide mimetic, L-692,429, in older adults—a clinical research center study. J Clin Endocrinol Metab. 1996;81:2874–80.

    Article  PubMed  CAS  Google Scholar 

  25. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273:974–7.

    Article  PubMed  CAS  Google Scholar 

  26. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–60.

    Article  PubMed  CAS  Google Scholar 

  27. Kojima M, Hosoda H, Matsuo H, Kangawa K. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab. 2001; 12:118–22.

    Article  PubMed  CAS  Google Scholar 

  28. Guerlavais V, Boeglin D, Mousseaux D, et al. New active series of growth hormone secretagogues. J Med Chem. 2003;46:1191–203.

    Article  PubMed  CAS  Google Scholar 

  29. Bednarek MA, Feighner SD, Pong SS, et al. Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem. 2000;43:4370–6.

    Article  PubMed  CAS  Google Scholar 

  30. Matsumoto M, Hosoda H, Kitajima Y, et al. Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun. 2001;287:142–6.

    Article  PubMed  CAS  Google Scholar 

  31. Tschoep M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908–13.

    Article  Google Scholar 

  32. Tschoep M, Tataranni PA, Weyer C et al. Circulating human ghrelin and the regulation of energy balance. Proceedings of the 83rd Meeting of The Endocrine Society. Denver, CO; 2001:129.

    Google Scholar 

  33. Smith RG. Development of growth hormone secretagogues. Endocrinol Rev. 2005;26:346–60.

    Article  CAS  Google Scholar 

  34. Torsello A, Luoni M, Schweiger F, et al. Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release. Eur J Pharmacol. 1998;360:123–9.

    Article  PubMed  CAS  Google Scholar 

  35. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002;87:2988–91.

    Article  PubMed  CAS  Google Scholar 

  36. van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocrinol Rev. 2004;25:426–57.

    Article  Google Scholar 

  37. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol. 2003;23:7973–81.

    Article  PubMed  CAS  Google Scholar 

  38. Zhao TJ, Liang G, Li RL, et al. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA. 2010;107: 7467–72.

    Article  PubMed  CAS  Google Scholar 

  39. Nass RM, Gaylinn BD, Rogol AD, Thorner MO. Ghrelin and growth hormone: story in reverse. Proc Natl Acad Sci U S A. 2010;107:8501–2.

    Article  PubMed  CAS  Google Scholar 

  40. Liu J, Prudom CE, Nass R, et al. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J Clin Endocrinol Metab. 2008; 93:1980–7.

    Article  PubMed  CAS  Google Scholar 

  41. Dixit VD, Schaffer EM, Pyle RS, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest. 2004; 114:57–66.

    PubMed  CAS  Google Scholar 

  42. Li WG, Gavrila D, Liu X, et al. Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells. Circulation. 2004;109:2221–6.

    Article  PubMed  CAS  Google Scholar 

  43. Rigamonti AE, Pincelli AI, Corra B, et al. Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients. J Endocrinol. 2002;175:R1–5.

    Article  PubMed  CAS  Google Scholar 

  44. Nass R, Liu J, Pezzoli SS, Oliveri MC, Gaylinn BD, Thorner MO. 24-h Mean acyl-ghrelin levels are decreased in older adults. 4th International Congress of the GRS and the IGF Society. Genoa, Italy; 2008:51.

    Google Scholar 

  45. Nagaya N, Itoh T, Murakami S, et al. Treatment of cachexia with ghrelin in patients with COPD. Chest. 2005;128:1187–93.

    Article  PubMed  CAS  Google Scholar 

  46. Nagaya N, Kojima M, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia. Intern Med. 2006;45:127–34.

    Article  PubMed  Google Scholar 

  47. Vestergaard ET, Hansen TK, Gormsen LC, et al. Constant intravenous ghrelin infusion in healthy young men: clinical pharmacokinetics and metabolic effects. Am J Physiol Endocrinol Metab. 2007;292:E1829–36.

    Article  PubMed  CAS  Google Scholar 

  48. Murphy MG, Plunkett LM, Gertz BJ, et al. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998;83:320–5.

    Article  PubMed  CAS  Google Scholar 

  49. Chapman IM, Bach MA, Van Cauter E, et al. Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 1996;81:4249–57.

    Article  PubMed  CAS  Google Scholar 

  50. Svensson J, Lonn L, Jansson JO, et al. Two-month treatment of obese subjects with the oral growth hormone (GH) secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab. 1998;83:362–9.

    Article  PubMed  CAS  Google Scholar 

  51. Murphy MG, Weiss S, McClung M, et al. Effect of alendronate and MK-677 (a growth hormone secretagogue), individually and in combination, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab. 2001; 86:1116–25.

    Article  PubMed  CAS  Google Scholar 

  52. Bach MA, Rockwood K, Zetterberg C, et al. The effects of MK-0677, an oral growth hormone secretagogue, in patients with hip fracture. J Am Geriatr Soc. 2004;52:516–23.

    Article  PubMed  Google Scholar 

  53. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008; 149: 601–11.

    PubMed  Google Scholar 

  54. White HK, Petrie CD, Landschulz W, et al. Effects of an oral growth hormone secretagogue in older adults. J Clin Endocrinol Metab. 2009;94:1198–206.

    Article  PubMed  CAS  Google Scholar 

  55. Garcia JM, Polvino WJ. Effect on body weight and safety of RC-1291, a novel, orally available ghrelin mimetic and growth hormone secretagogue: results of a phase I, randomized, placebo-controlled, multiple-dose study in healthy volunteers. Oncologist. 2007;12:594–600.

    Article  PubMed  CAS  Google Scholar 

  56. Garcia J, Boccia RV, Graham C, Kumor K, Polvino W. A phase II randomized, placebo-controlled, double-blind study of the efficacy and safety of RC-1291 (RC) for the treatment of cancer cachexia [abstract]. J Clin Oncol. 2007;S25.

    Google Scholar 

  57. Piccoli F, Degen L, MacLean C, et al. Pharmacokinetics and pharmacodynamic effects of an oral ghrelin agonist in healthy subjects. J Clin Endocrinol Metab. 2007;92:1814–20.

    Article  PubMed  CAS  Google Scholar 

  58. MacLean CM, Casanova AT, Baselgia-Jeker L, et al. Effect of food on the pharmacokinetics and pharmacodynamics of an oral ghrelin agonist (ARD-07) in healthy subjects. J Clin Pharmacol. 2009;49:553–9.

    Article  PubMed  CAS  Google Scholar 

  59. Lasseter KC, Shaughnessy L, Cummings D, et al. Ghrelin agonist (TZP-101): safety, pharmacokinetics and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study. J Clin Pharmacol. 2008;48:193–202.

    Article  PubMed  CAS  Google Scholar 

  60. Zdravkovic M, Sogaard B, Ynddal L, et al. The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN073, a novel orally active growth hormone secretagogue in healthy male volunteers. Growth Horm IGF Res. 2000;10:193–8.

    Article  PubMed  CAS  Google Scholar 

  61. Gertner J. SUN 11031 (synthetic human ghrelin) improves lean body mass and function in advanced COPD cachexia in a placebo controlled trial. 5th International Congress of the GRS and IGF Society. New York; 2010.

    Google Scholar 

  62. Roddam AW, Allen NE, Appleby P, et al. Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann Intern Med. 2008;149:461–71.

    PubMed  Google Scholar 

  63. van Bunderen CC, van Nieuwpoort IC, van Schoor NM, Deeg DJ, Lips P, Drent ML. The association of serum insulin-like growth factor-I with mortality, cardiovascular disease, and cancer in the elderly: a population-based study. J Clin Endocrinol Metab. 2010;95:4616–24.

    Article  PubMed  Google Scholar 

  64. Holly J. Insulin-like growth factors (IGFs) and IGF binding proteins in PSA-detected prostate cancer: a population-based case control study. 5th International Congress of the GRS and IGF Society. New York; 2010.

    Google Scholar 

  65. Koo GC, Huang C, Camacho R, et al. Immune enhancing effect of a growth hormone secretagogue. J Immunol. 2001;166:4195–201.

    PubMed  CAS  Google Scholar 

  66. Svensson J, Fowelin J, Landin K, Bengtsson BA, Johansson JO. Effects of seven years of GH-replacement therapy on insulin sensitivity in GH-deficient adults. J Clin Endocrinol Metab. 2002;87:2121–7.

    Article  PubMed  CAS  Google Scholar 

  67. Strasser F, Lutz TA, Maeder MT, et al. Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study. Br J Cancer. 2008;98:300–8.

    Article  PubMed  CAS  Google Scholar 

  68. Neary NM, Small CJ, Wren AM, et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2004; 89:2832–6.

    Article  PubMed  CAS  Google Scholar 

  69. Broglio F, Gianotti L, Destefanis S, et al. The endocrine response to acute ghrelin administration is blunted in patients with anorexia nervosa, a ghrelin hypersecretory state. Clin Endocrinol. 2004;60:592–9.

    Article  CAS  Google Scholar 

  70. Miljic D, Pekic S, Djurovic M, et al. Ghrelin has partial or no effect on appetite, growth hormone, prolactin, and cortisol release in patients with anorexia nervosa. J Clin Endocrinol Metab. 2006;91:1491–5.

    Article  PubMed  CAS  Google Scholar 

  71. Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785–92.

    Article  PubMed  CAS  Google Scholar 

  72. Golden AG, Daiello LA, Silverman MA, Llorente M, Preston RA. University of Miami Division of Clinical Pharmacology Therapeutic Rounds: medications used to treat anorexia in the frail elderly. Am J Ther. 2003;10:292–8.

    Article  PubMed  Google Scholar 

  73. Lambert CP, Sullivan DH, Freeling SA, Lindquist DM, Evans WJ. Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men: a randomized controlled trial. J Clin Endocrinol Metab. 2002; 87:2100–6.

    Article  PubMed  CAS  Google Scholar 

  74. Evans WJ. Editorial: megestrol acetate use for weight gain should be carefully considered. J Clin Endocrinol Metab. 2007;92:420–1.

    Article  PubMed  CAS  Google Scholar 

  75. Wilson MM, Philpot C, Morley JE. Anorexia of aging in long term care: is dronabinol an effective appetite stimulant?—a pilot study. J Nutr Health Aging. 2007;11:195–8.

    PubMed  CAS  Google Scholar 

  76. Bhasin S, Wu F. Making a diagnosis of androgen deficiency in adult men: what to do until all the facts are in? Nat Clin Pract Endocrinol Metab. 2006;2:529.

    Article  PubMed  Google Scholar 

  77. Sattler FR, Castaneda-Sceppa C, Binder EF, et al. Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab. 2009;94: 1991–2001.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Endocrinology, University of Virginia, University Hospital, Charlottesville, VA, USA

    Ralf Nass M.D.

  2. Department of Medicine, University of Virginia, 450 Ray C Hunt Drive, Charlottesville, VA, 22908-1411, USA

    Michael O. Thorner M.B., B.S., D.Sc.

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  1. Ralf Nass M.D.
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Correspondence to Michael O. Thorner M.B., B.S., D.Sc. .

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Editors and Affiliations

  1. , Department of Metabolism and Aging, The Scripps Research Institute Florida, Scripps Way 3B3 130, Jupiter, 33458, Florida, USA

    Roy G. Smith

  2. , Department of Medicine, University of Virginia, Ray C Hunt Drive 450, Charlottesville, 22908, Virginia, USA

    Michael O. Thorner

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Nass, R., Thorner, M.O. (2012). Ghrelin Receptor Agonists in Cachexia of Human Aging. In: Smith, R., Thorner, M. (eds) Ghrelin in Health and Disease. Contemporary Endocrinology, vol 10. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-903-7_11

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