MK-0677 reversed age-related GH amplitude decline and GHS-R conserved 400 million years
Background
Age-related growth hormone deficiency is characterised by reduced amplitude of pulsatile GH secretion, contributing to declines in body composition, bone density, and metabolic function in older adults. Endogenous GH releasing hormone (GHRH) acts via its own receptor, but a structurally distinct family of synthetic GH secretagogues — including peptides and small-molecule mimetics — was found to operate through a separate, orphan receptor. Understanding the GHS-R (GH secretagogue receptor) and whether an endogenous ligand exists became a central question in GH-axis pharmacology. The evolutionary conservation of receptor–ligand binding pockets across distant vertebrate species is a key indicator that an endogenous physiological role remains to be fully characterised.
Study Design
MK-0677 was administered once daily, chronically, to human subjects aged 70–90 years to assess restoration of GH pulse amplitude. Separately, [(35)S-MK-0677 was synthesised and deployed as a radioligand to characterise and clone the GHS-R. The GHS-R gene was subsequently sequenced and compared across human and rat. To identify receptor family members (GPR38, GPR39, FM3), human genomic libraries were screened. Pufferfish (Spheroides nephelus) genomic libraries were exploited as a compact vertebrate genome to clone three full-length GHS-R homologues and test their activation by hexapeptide and non-peptide ligands.
Results
Chronic once-daily MK-0677 in subjects aged 70–90 years reversed the age-related reduction in GH pulse amplitude, restoring a physiological profile typical of young adults. The GHS-R was confirmed as a unique G-protein coupled receptor distinct from the GHRH receptor. Deduced protein sequences of the GHS-R were 96% identical between human and rat. Three family members — GPR38, GPR39, and FM3 — were isolated from human genomic libraries. Three full-length GHS-R-homologous clones were recovered from the pufferfish genome, and the clone with highest sequence homology to the human receptor was functionally activated by both hexapeptide and non-peptide ligands.
The
GHS-Rligand-binding pocket has remained structurally and functionally conserved across approximately 400 million years of vertebrate evolution, strongly implying an endogenous natural ligand with a conserved physiological role.
Key Findings
- MK-0677 once-daily in 70–90-year-olds restored youthful GH pulse amplitude profiles
- GHS-R deduced protein sequence is 96% identical between human and rat
- Three GHS-R family members (GPR38, GPR39, FM3) isolated from human genomic libraries
- Three GHS-R homologues cloned from pufferfish; highest-homology clone activated by hexapeptide and non-peptide ligands
- GHS-R ligand-binding pocket conserved across approximately 400 million years of vertebrate evolution
Why It Matters
The existence of a deeply conserved GHS-R strongly supports the eventual identification of an endogenous ghrelin-axis ligand, providing a rational pharmacological target for reversing age-related GH decline. For clinicians and researchers, once-daily MK-0677 already demonstrated functional GH restoration in elderly humans, moving this class beyond purely preclinical interest. The 96% human–rat receptor homology validates rodent models for mechanistic GHS-R studies, while pufferfish cross-species activation data raise confidence that GHS-R agonists are engaging a fundamentally preserved binding pocket rather than a species-specific artifact. Protocol-wise, the chronic once-daily dosing regimen confirmed in elderly subjects sets a precedent for long-duration GH secretagogue administration strategies.
TitrateLab articles covering MK-677
Written by TitrateLab, separately from the study summarized above.
