{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:53:01Z","timestamp":1790880781348,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2007,11,28]],"date-time":"2007-11-28T00:00:00Z","timestamp":1196208000000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of the New York Academy of Sciences"],"published-print":{"date-parts":[[2007,11]]},"abstract":"<jats:p><jats:bold><jats:sc>Abstract<\/jats:sc>:\u2002<\/jats:bold>  <jats:bold>Administration of an orally active agonist (MK\u20100677) of the growth hormone secretagogue receptor (GHS\u2010R1a) 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\u2010R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4\/cdk6 activity and increased protein phosphatase\u20102A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C\/EBP\u03b1 preventing the age\u2010dependent formation of the C\/EBP\u03b1\u2010Rb\u2010E2F4\u2010Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de\u2010repressed and C\/EBP\u03b1 regulated expression of <jats:italic>Pepck<\/jats:italic>, 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\u2010R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS\u2010R1a and dopamine receptor subtype\u20101 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS\u2010R and D1R form heterodimers, which modified G\u2010protein 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\u2010R1a agonists to improve quality of life and maintain independence.<\/jats:bold> <\/jats:p>","DOI":"10.1196\/annals.1404.023","type":"journal-article","created":{"date-parts":[[2007,12,5]],"date-time":"2007-12-05T02:57:04Z","timestamp":1196823424000},"page":"147-164","source":"Crossref","is-referenced-by-count":25,"title":["Ghrelin Receptor (GHS\u2010R1A) Agonists Show Potential as Interventive Agents during Aging"],"prefix":"10.1111","volume":"1119","author":[{"given":"ROY G.","family":"SMITH","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YUXIANG","family":"SUN","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HONG","family":"JIANG","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ROSIE","family":"ALBARRAN\u2010ZECKLER","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"NIKOLAI","family":"TIMCHENKO","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,11,28]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2004-0019"},{"key":"e_1_2_7_3_2","first-page":"261","article-title":"Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland","volume":"51","author":"Smith R.G.","year":"1996","journal-title":"Rec. 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