Healthy elderly persons who received the ghrelin mimetic MK-677 experienced a sustained increase in the amplitude of pulsatile growth hormone secretion and IGF-I levels to those seen in young adults. The likely mechanism was activation of the ghrelin receptor by MK-677, with feedback by IGF-I preventing excess growth hormone production. MK-677 increased fat-free mass by 1.6 kg relative to placebo. To provide perspective, an adult's average lifetime loss of fat-free mass is about 5.5 kg (
3). The concomitant increase in intracellular water, which reflects body cell mass (
25), was probably the mechanism for the increase in fat-free mass.
Ghrelin stimulates growth hormone secretion, but it also has effects that are not attributable to increased growth hormone levels. A ghrelin mimetic transiently increases appetite, a novel effect that might counteract physiologic anorexia, a cause of weight loss in elderly persons (
26–
27). Unlike growth hormone, which is lipolytic, ghrelin increases fat stores.
We found that body weight increased more in MK-677 recipients than in placebo recipients. Although total fat mass increased in both groups, limb fat and limb lean mass increased more in participants receiving MK-677 than in those receiving placebo. Surprisingly, thigh muscle cross-sectional area did not increase, although our study was not powered to detect small but potentially important differences because the single-slice computed tomography method that we used was insufficiently precise. Growth hormone reduces abdominal visceral fat in growth hormone deficient adults (
28) and abdominally obese, postmenopausal women (
29) but not in normal elderly participants (
30). Although MK-677 increased growth hormone levels, it did not affect abdominal visceral fat, possibly because its combined orexigenic and adipogenic effects counteracted the lipolytic effects of enhanced growth hormone.
Finally, although MK-677 did not reduce abdominal visceral fat, it did reduce low-density lipoprotein cholesterol levels at 12 months, an effect not seen with growth hormone in normal elderly participants (8).
Strength, function, and quality of life did not improve after administration of MK-677 in our small, healthy cohort result we should possibly have expected. Although strength improved in elderly patients with hypopituitarism after daily injections of growth hormone for 2 to 3 years (
31), growth hormone alone does not increase strength in healthy elderly persons (
8,
32–
33). Strength improved only in healthy older men receiving growth hormone plus testosterone for 26 weeks (
33). Finally, the relationship between strength and physical performance is nonlinear (
34); we speculate that increased physical capacity might substantially improve performance in frail adults but not healthy adults.
Sarcopenia is a hallmark of frailty (
35–
36) and is associated with increased mortality in elderly persons (
37–
40).
In our healthy sample, MK-677 counteracted 3 important factors that contribute to sarcopenia: reduced secretion of growth hormone, loss of fat-free mass, and inadequate food intake. We did not study patients with sarcopenia, and their response to a ghrelin mimetic is not known.
Of note, our participants tolerated daily administration of MK-677 for the 2-year study period. The most frequent side effects were mild, transient, lower-extremity edema; transient muscle pain; and increased appetite, which subsided in a few months. These effects of physiologically stimulated growth hormone secretion contrast with those of growth hormone administered by injection: edema, arthralgia, carpal tunnel syndrome, gynecomastia, and new-onset impaired fasting glucose and diabetes mellitus in some persons (8).
Both growth hormone and MK-677 increase insulin resistance and blood glucose in elderly persons (
22,
33,
41–
42). We found statistically significant but small increases in fasting blood glucose and HbA1c levels at 12 months. Considering the results of short-term studies with MK-677 (
9,
43), which found no statistically significant increase in serum cortisol, the small increase in serum cortisol that we found is unlikely to underlie the increase in fasting glucose level. In patients treated with growth hormone, bone mineral density initially decreases (
44); at least 18 months of treatment is needed to demonstrate an increase in bone mineral density (
45). Femoral neck bone mineral density decreased at 12 months in MK-677 recipients, which is consistent with the increased bone remodeling that occurs with growth hormone (
44). Fracture risk is the best measure of the effects of MK-677 on bone; however, this outcome would require studies of large samples over many years.
Our study has limitations. Its duration was relatively short, and the sample was small. Combining the results for men and women may have missed important sex effects. As a small, randomized study in healthy older adults, ours was a proof-of-concept study. It showed, apparently for the first time, that a drug can maintain the IGF-I levels and physiologic pattern of growth hormone secretion seen in young adults for at least 1 year and partially reverse age-related body composition changes.
Frailty is one of the scourges of elderly persons, and as researchers are beginning to learn about its causes, they are asking whether growth hormone deficiency is one of them. A systematic review (
8) concluded that the risks of exogenous growth hormone outweigh the benefits and that it is not the long-sought solution to frailty.
The promise of MK-677 is that it seems to restore endogenous growth hormone levels in a physiologic secretory pattern, unlike the single high-amplitude pulse observed after exogenous growth hormone administration. We believe that our study sets the stage for an adequately powered clinical trial of sufficient duration in a population vulnerable to frailty.
http://annals.org/article.aspx?articleid=743451
