Sonntag W E, Lynch C D, Bennett S A, Khan A S, Thornton P L, Cooney P T, Ingram R L, McShane T, Brunso-Bechtold J K
Department of Physiology and Pharmacology and the Sticht Center on Ageing, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1083, USA.
Neuroscience. 1999 Jan;88(1):269-79. doi: 10.1016/s0306-4522(98)00192-4.
Ageing in mammals is characterized by a decline in plasma levels of insulin-like growth factor-1 that appears to contribute to both structural and functional changes in a number of tissues. Although insulin-like growth factor-1 has been shown to provide trophic support for neurons and administration of insulin-like growth factor-1 to ageing animals reverses some aspects of brain ageing, age-related changes in insulin-like growth factor-1 or type 1 insulin-like growth factor receptors in brain have not been well documented. In this series of studies, insulin-like growth factor-1 messenger RNA and protein concentrations, and type 1 insulin-like growth factor receptor levels were analysed in young (three to four- and 10-12-month-old), middle-aged (19-20-month-old) and old (29-32-month-old) Fisher 344 x Brown Norway rats. Localization of insulin-like growth factor-1 messenger RNA throughout the lifespan revealed that expression was greatest in arteries, arterioles, and arteriolar anastomoses with greater than 80% of these vessels producing insulin-like growth factor-1 messenger RNA. High levels of expression were also noted in the meninges. No age-related changes were detected by either in situ hybridization or quantitative dot blot analysis of cortical tissue. However, analysis of insulin-like growth factor-1 protein levels in cortex analysed after saline perfusion indicated a 36.5% decrease between 11 and 32 months-of-age (P<0.05). Similarly, analysis of type 1 insulin-like growth factor receptor messenger RNA revealed no changes with age but levels of type 1 insulin-like growth factor receptors indicated a substantial decrease with age (31% in hippocampus and 20.8 and 27.3% in cortical layers II/III and V/VI, respectively). Our results indicate that (i) vasculature and meninges are an important source of insulin-like growth factor-1 for the brain and that expression continues throughout life, (ii) there are no changes in insulin-like growth factor-1 gene expression with age but insulin-like growth factor-1 protein levels decrease suggesting that translational deficiencies or deficits in the transport of insulin-like growth factor-1 through the blood-brain barrier contribute to the decline in brain insulin-like growth factor-1 with age, and (iii) type 1 insulin-like growth factor receptor messenger RNA is unchanged with age but type 1 insulin-like growth factor receptors decrease in several brain regions. We conclude that significant perturbations occur in the insulin-like growth factor-1 axis with age. Since other studies suggest that i.c.v. administration of insulin-like growth factor-1 reverses functional and cognitive deficiencies with age, alterations within the insulin-like growth factor-1 axis may be an important contributing factor in brain ageing.
哺乳动物的衰老特征是血浆中胰岛素样生长因子-1水平下降，这似乎导致了许多组织的结构和功能变化。尽管已证明胰岛素样生长因子-1为神经元提供营养支持，并且给衰老动物注射胰岛素样生长因子-1可逆转大脑衰老的某些方面，但大脑中胰岛素样生长因子-1或1型胰岛素样生长因子受体的年龄相关变化尚未得到充分记录。在这一系列研究中，分析了年轻（3至4个月和10至12个月大）、中年（19至20个月大）和老年（29至32个月大）的费希尔344×布朗挪威大鼠的胰岛素样生长因子-1信使核糖核酸和蛋白质浓度以及1型胰岛素样生长因子受体水平。对整个生命周期中胰岛素样生长因子-1信使核糖核酸的定位显示，动脉、小动脉和小动脉吻合处的表达最高，超过80%的这些血管产生胰岛素样生长因子-1信使核糖核酸。在脑膜中也观察到高水平的表达。通过原位杂交或皮质组织的定量斑点印迹分析未检测到与年龄相关的变化。然而，对生理盐水灌注后分析的皮质中胰岛素样生长因子-1蛋白水平的分析表明，11至32月龄之间下降了36.5%（P<0.05）。同样，对1型胰岛素样生长因子受体信使核糖核酸的分析显示，其水平不随年龄变化，但1型胰岛素样生长因子受体水平随年龄显著下降（海马体中下降31%，皮质层II/III和V/VI中分别下降20.8%和27.3%）。我们的结果表明：（i）血管系统和脑膜是大脑胰岛素样生长因子-1的重要来源，且其表达在整个生命过程中持续存在；（ii）胰岛素样生长因子-1基因表达不随年龄变化，但胰岛素样生长因子-1蛋白水平下降，这表明翻译缺陷或胰岛素样生长因子-1通过血脑屏障的转运不足导致大脑中胰岛素样生长因子-1随年龄下降；（iii）1型胰岛素样生长因子受体信使核糖核酸不随年龄变化，但在几个脑区中1型胰岛素样生长因子受体减少。我们得出结论，随着年龄增长，胰岛素样生长因子-1轴会发生显著扰动。由于其他研究表明，脑室内注射胰岛素样生长因子-1可逆转与年龄相关的功能和认知缺陷，因此胰岛素样生长因子-1轴内的改变可能是大脑衰老的一个重要促成因素。
