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Ghrelin Receptor (GHS‐R1A) Agonists Show Potential as Interventive Agents during Aging

Abstract:  Administration of an orally active agonist (MK‐0677) of the growth hormone secretagogue receptor (GHS‐R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS‐R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase‐2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPα preventing the age‐dependent formation of the C/EBPα‐Rb‐E2F4‐Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de‐repressed and C/EBPα regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS‐R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS‐R1a and dopamine receptor subtype‐1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS‐R and D1R form heterodimers, which modified G‐protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS‐R1a agonists to improve quality of life and maintain independence.