Ralf Nass, MD; Suzan S. Pezzoli, BA; Mary Clancy Oliveri, MS; James T. Patrie, MS; Frank E. Harrell, PhD; Jody L. Clasey, PhD; Steven B. Heymsfield, MD; Mark A. Bach, MD; Mary Lee Vance, MD; Michael O. Thorner, MB, BS, DSc
The age-related decline of growth hormone secretion may play a role in sarcopenia and frailty.
In this randomized trial, 65 healthy older adults were assigned to receive placebo or MK-677, an oral ghrelin mimetic that increased pulsatile growth hormone secretion to young-adult levels. Over 1 year, lean fat-free mass increased 1.1 kg with MK-677 and decreased 0.5 kg with placebo. MK-677 did not affect strength and function, but insulin sensitivity declined and mean serum glucose levels increased 0.28 mmol/L (5 mg/dL).
This short-term trial was underpowered to detect functional changes and adverse events.
An oral ghrelin mimetic increases pulsatile growth hormone secretion and alters body composition in healthy older adults.
FBG= fasting blood glucose; HRT= hormone replacement therapy; MI= myocardial infarction.
Growth hormone and IGF-I data were not normally distributed and were analyzed on the natural logarithmic scale. Line graphs show geometric means and 95% CIs. Results of growth hormone deconvolution analysis are included in Appendix Table 1. A. Mean 24-hour GH levels. The dashed line indicates 24-hour mean GH level for young men and women combined (~1.3 g/L). *P < 0.001 for MK-677 versus placebo. B. Serum IGF-I levels. The lower dotted line indicates the lower limit of the IGF-I normal range for older adults (59 to 225 g/L), and the upper dashed line indicates the lower limit in adults age 21 to 25 years (116 to 358 g/L). C. Representative 24-hour GH profile in a 70-year-old man with a body mass index of 23.2 kg/m2 who received MK-677 for 1 year. His 24-hour mean GH levels were 0.37, 1.0, and 0.86 g/L at baseline, 6 months, and 12 months, respectively. The pulsatile pattern of GH secretion at baseline is maintained and enhanced at 6 and 12 months, primarily because of increased secretion per peak rather than peak frequency.
Graphs show arithmetic differences (95% CI). Asterisks indicates a significant difference (MK-677 vs. placebo) at 12 months. 4-C= 4-compartment model; CT= computed tomography; DXA= dual energy x-ray absorptiometry; ECW= extracellular water; FFM= fat-free mass; ICW= intracellular water; SC= subcutaneous; TASM= total appendicular skeletal mass; TBW= total body water. A. Changes in FFM (by 4-C model and by DXA) and TASM (by DXA). B. Changes in TBW, EBW, and ICW. The increase in TBW and ICW with MK-677 are consistent with the anabolic effects of the drug. C. Changes in abdominal visceral and abdominal SC fat cross-sectional areas by computed tomography. D. Changes in body weight and total fat by 4-C model and DXA.
Limb= appendicular lean soft tissue and appendicular fat; nonlimb= total minus limb.
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Feinberg School of Medicine of Northwestern University
November 12, 2008
Strategies for remaining as healthy adults
The study by Nass et. al. (1) elegantly reinforces the prevalent health strategy first proposed by an immigrant, Juan Ponce De Leon, in 1513 (2). Simply find the magic fountain, or the right pill, and perpetual youth and perhaps even immortality will be yours, without breaking a sweat, and oh, don't worry about the cost. A contrasting approach would cite the impressive data confirming the benefits of lifestyle changes, especially exercise, in preventing and reversing frailty, (3) which as a bonus reduces obesity, prevents falls and may even improve mental status. All this without decreasing insulin sensitivity or other potential long term side effects such as diabetes.
Perhaps any future studies testing ghrelin mimetic should include a "control group" using an aerobic and weight resistance exercise program combined with a diet intervention. One might reasonably predict that this latter group would outperform the pharmacologically enhanced cohort by a wide margin. They would also feel better and have lower costs while only expending sweat equity.
1. Nass R, Pezolli SS, Olivero JT; et. al. Effects of oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults. A randomized trial. Ann Intern Med. 2008;149:601-611
2. Olschki, L. Ponce De Leon's fountain of youth: History of a geographical Myth. The Hispanic Historical Review. Duke University Press, 1941. Durham NC. Vol XXVI #3 pp 361-385 3. Hall W. Centenarians: Metaphor becomes reality. Arch Intern Med. 2008;168:262-263
Dept. of Rheumatology, Kaiser Franz Josef Hospital, Vienna, Austria
To proof a concept of a drug without side effects
To the editors: I read with interest the study done by Nass et al (1), however, I want to address some critical issues with particular reference to adverse events: First, there is growing evidence, that IGF-1 is a cytokine involved in promotion and induction of oncogenesis in different types of tumors, as Ewing's sarcoma(rev. in 2) , Renal cell carcinoma (3), adenocarcinoma of the GI tract (e.g. colorectal carcinoma (4) and cholangiocellular carcinoma). I wonder why the authors do not report the results of screening methods (FOBT, abdominal ultrasound, colonoscopy) or staging of reported AEÂ´s. Second, MRI-imaging and biopsy of skeletal muscle in relation to the observed effects would have been of interest in context with a clinical trial trying to prove a concept. And finally, I think, that the study didn't focus on adverse events or economic issues as told in the objective. But, I wish I would have read a detailed discussion of the observed AEÂ´s. Non-pharmacologic treatment strategies for decreased muscle strength and increased (intra-) abdominal fat in the elderly have to be mentioned when talking about sarcopenia and increased blood glucose levels.
1. Nass R, et. al. Effects of oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults. A randomized trial. Ann Intern Med. 2008;149:601-611
2. Cironi L, et al. (2008) PLoS ONE 3(7): e2634. doi:10.1371/journal.pone.0002634
3. Jungwirth A, et al. Proc Natl Acad Sci U S A. 1997; 94(11):5810-3
4. Simmons JG et al. Am J Physiol Gastrointest Liver Physiol. 2007; 293(5): G995"“1003.
Universidad Nacional AutÃ³noma de MÃ©xico
November 13, 2008
Aging process is a disease
I read with interest the article by Nass and colleagues (1) in which the authors presented some clinical evidences of rejuvenation on 65 healthy older adults (men and women) ranging from 60 to 81 years of age, after daily administration of oral ghrelin (secretagogue product) during 1 year. Oral administration of MK-677 increased pulsatile growth hormone (GH)secretion and increased serum Insulin-like growth factor I(IGF-I, also known as somatomedin C) levels (2). In part, I agree with these authors,because through the blood flow the GH secretagogues (constituted by a combination of aminoacids, some peptides, vitamines and minerals) may reach to the producing hypothalamic nuclei of growth hormone-releasing hormone (GHRH) (3) and thus, increase the GH secretion from the adenohypophysis. However, these results may fail on older persons due to atherosclerotic plaques located at the mouths of the collateral branches originated from the supraclinoid carotids and circle of Willis (3,4 ). In contrast, a revascularization of the arcuate nucleus and surrounding nuclei by means of omental tissue can provoke rejuvenation (3), because through the omentum, the hypothalamus receives an increase in blood flow, oxygen, neurotransmitters, neurotrophic factors, cytokines and omental stem cells (3,5). For these reasons, I have postulated that aging is not a normal biological process but a disease.
1. Nass R,Pezzoli SS,Oliveri Co, et al.Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults. Ann Inter Med 2008;149(9):601-611.
2. Chapman IM,Bach MA,Cauter E,et al.Stimulation of the growth(GH)-insulin-like growth factor I axis by daily oral administration of a GH secretagogues(MK-677)in healthy subjects. J Clin Endocrinol Metab 1996;81:4249-4257.
3. Rafael H. Rejuvenation after omental transplantation on the optic chiasma and carotid bifurcation. Case Rep Clin Pract Rev 2006;7:48-51.www.amjcaserep.com
4. Rafael H. Hypothalamic ischemia and premature aging.Med Sci Monit 2007;13(7):LE9-10. www.medscimonit.com 5-Garcia-Gomez I,Goldsmith HS,Angulo J,et al.Angiogenic capacity of human omental stem cells. Neurol Res 2005;27(8):807-811.
Michael O. Thorner
University of Virginia Health System
December 15, 2008
Effects of an Oral Ghrelin Mimetic on Body Composition and Clinical Outcomes in Healthy Older Adults
We appreciate the thoughtful comments offered in response to our paper and offer some clarifications.
We believe that aging is not a disease, but a complex multi-system decline that occurs over decades. It is likely that MK-677 acts at multiple sites, including the hypothalamus, the pituitary and the periphery. We have no evidence that atherosclerosis impairs its action.
We did not perform other cancer screening in these healthy older adults. Subjects were carefully monitored with Pap smears and mammograms, as well as PSA levels in men. Adverse effects were reported in the results section. A study of this size cannot assess cancer risk, however, as of July 20, 2007 more than 600 adult patients had been exposed to MK-677 for 6-12 months. The combined incidence rate for malignancies in any MK-677 treatment group was similar to the incidence rate in the placebo groups in these studies (personal communication, Dimitris A. Papanicolaou). The cancer risk of growth hormone and IGF-I administration is controversial and has been extensively reviewed (1).
As outlined by Dr. Webster, the benefits of exercise are well established and always should be recommended. However, physiologic studies show that the effects of resistance training on intramuscular metabolic changes achieved in the elderly, as well as muscle growth response, are significantly lower when compared to a younger study population (2,3). Additional data suggest that in men over 80 years of age, the capacity to gain strength with resistance training is decreased because of the limited myocellular adaptive response.(4).
Furthermore, some elderly adults are not able to exercise because of significant muscle loss and frailty. Interventions that prevent or delay a decline in muscle mass would be desirable, given the expected demographic shift in the aging population. Our observations support a role for ghrelin mimetics to enhance growth hormone secretion; this resulted in both arrest of muscle mass loss, as well as an increase in muscle mass. The increase in appetite also may be important. Recent data from the Health ABC study demonstrate a significant association between change in lean mass in the elderly and dietary protein intake (5).
Long-term studies comparing the effects of exercise to a ghrelin mimetic alone or in combination with exercise are certainly needed in elderly subjects who are physically able to exercise. We emphasized that ours was a "˜proof-of-concept' study and now the definitive studies need to be designed and performed.
1. Consensus. Critical evaluation of the safety of recombinant human growth hormone administration: statement from the Growth Hormone Research Society. J. Clin. Endocrinol. Metab. 2001; 86:1868-1870. [PMID: 11344173]
2. Kosek DJ, Kim JS, Petrella JK, Cross JM, Bamman MM. Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults. J Appl Physiol. 2006;101:531-544. [PMID: 16614355].
3. Welle S, Thornton C, Statt M. Myofibrillar protein synthesis in young and old human subjects after three months of resistance training. Am J Physiol. 1995;268:E422-E427. [PMID: 7900788].
4. Slivka D, Raue U, Hollon C, Minchev K, Trappe S. Single muscle fiber adaptations to resistance training in old (>80 yr) men: evidence for limited skeletal muscle plasticity. Am J Physiol 2008;295:R273-280. [PMID: 18448613].
5. Houston DK, Nicklas BJ, Ding J, Harris TB, Tylavsky FA, Newman AB et al. Protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study. Am J Clin Nutr. 2008;87:150-155. [PMID: 17515911]
Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE, Clasey JL, 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;149:601-611. doi: 10.7326/0003-4819-149-9-200811040-00003
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Published: Ann Intern Med. 2008;149(9):601-611.
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