Smith Roy G, Sun Yuxiang, Jiang Hong, Albarran-Zeckler Rosie, Timchenko Nikolai
Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, MS: BCM M230, Houston, TX 77030, USA.
Ann N Y Acad Sci. 2007 Nov;1119:147-64. doi: 10.1196/annals.1404.023.
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/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha 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.
给老年受试者施用生长激素促分泌素受体（GHS-R1a）的口服活性激动剂（MK-0677），可将内源性间歇性生长激素（GH）释放的幅度恢复至年轻成年人的水平。功能益处包括增加瘦体重和骨密度，并适度改善力量。在老年小鼠中，类似的激动剂可部分恢复胸腺功能，并减少肿瘤细胞生长和转移。用内源性GHS-R1a激动剂胃饥饿素治疗老年小鼠可恢复年轻的肝脏表型。其机制涉及抑制细胞周期蛋白D3:cdk4/cdk6活性，并增加肝细胞核中蛋白磷酸酶-2A（PP2A）的活性，从而稳定转录因子C/EBPα的去磷酸化形式，防止C/EBPα-Rb-E2F4-Brm核复合物的年龄依赖性形成。通过抑制该复合物的形成，E2F靶基因的抑制被解除，糖异生调节因子Pepck的C/EBPα调节表达恢复正常，从而恢复年轻的肝脏表型。在大脑中，衰老与多巴胺功能下降有关。我们研究了GHS-R1a对多巴胺作用的潜在神经调节作用。在海马体、皮质、黑质和腹侧被盖区鉴定出共表达GHS-R1a和多巴胺受体亚型-1（D1R）的神经元。细胞培养研究表明，在胃饥饿素和多巴胺存在的情况下，GHS-R和D1R形成异二聚体，修饰G蛋白信号转导，导致多巴胺信号放大。我们推测，衰老与内源性胃饥饿素信号不足有关，通过使用GHS-R1a激动剂进行干预可以挽救这种不足，从而改善生活质量并维持独立性。
