Natural and Synthetic Growth Hormone Secretagogues: Endocrine and Nonendocrine Activities Suggesting Their Potential Usefulness as Anti-Aging Drug Interventions

Abstract

Human aging is associated with declining activity of the GH/IGF-I axis and the impressive similarity between consequences of GH deficiency in hypo-pituitary patients and age-related decline in structure functions and metabolism has been pointed out. The neologism somatopause has been therefore coined to indicate the potential link between the age-related decline in GH and IGF-I levels and changes in body composition, structure functions and metabolism which connote aging. This assumption led to clinical trials focusing on rhGH and/or rhIGF-I as potential anabolic drug interventions in elderly subjects. To restore the activity of GH/IGF-I axis with anabolic, anti-aging purposes, attention has been also paid to GH-releasing molecules such as GHRH and, particularly, to orally active, synthetic GH Secretagogues (GHS). At present, there is no definitive evidence that frail elderly subjects really benefit from restoring GH and IGF-I levels within the young adult range by treatment with rhGH, rhIGF-I, GHRH or GH Secretagogues. However, GHS would have perspectives as anti-aging intervention not only as function of their stimulatory effect on GH and, in turn, on IGF-I secretion. This evidence comes from studies on synthetic GHS and, more recently, on ghrelin, a natural GHS predominantly produced by the stomach. Besides their potent GH-releasing effect, ghrelin as well as synthetic GHS has other remarkable GH-independent activities, including (a) stimulation of lactotroph and corticotroph secretion; (b) orexant activity coupled with control of energy expenditure; (c) influence on sleep; (d) control of gastric motility and acid secretion; (e) influence on the endocrine pancreatic function and glucose metabolism; (f) cardiovascular actions including protection from ischemia and increase of the cardiac contractility in vivo and antiapoptotic effects in vitro; and (g) anti-proliferative effects in neoplastic thyroid, breast and lung cell lines. It is already clear that ghrelin is an hormone signaling the metabolic balance and managing the neuroendocrine and metabolic response to starvation; taking also into account its orexant activity, the potential interest of synthetic GHS acting as agonist or antagonist on the appetite is even obvious and would have perspectives in aging when either overweight or malnutrition are common and imply well-known clinical consequences. Cardiac ischemia and dilated cardiomyopathy are common in aging and the possibility that new GHS analogues are able to protect myocardial and, possibly, endothelial function has to be verified. Attention should be given also to the anti-proliferative effects of GHS analogues devoid of stimulatory effect on the activity of GH/IGF-I axis. In all, there is no present anti-aging drug intervention related to the GH/IGF-I axis; however, potential perspectives would come from orally active GHS not only as function of their stimulatory effect on GH and IGF-I secretion but because of their remarkable GH-independent activities.