Hadem Ibanylla Kynjai Hynniewta, Sharma Ramesh
Department of Biochemistry, North-Eastern Hill University, Shillong, 793 022, India.
Cell Mol Neurobiol. 2017 Aug;37(6):985-993. doi: 10.1007/s10571-016-0431-7. Epub 2016 Oct 7.
Time-dependent alterations in several biological processes of an organism may be characterized as aging. One of the effects of aging is the decline in cognitive functions. Dietary restriction (DR), an intervention where the consumption of food is lessened but without malnutrition, is a well-established mechanism that has a wide range of important outcomes including improved health span, delayed aging, and extension of lifespan of various species. It also plays a beneficial role in protecting against age-dependent deterioration of cognitive functions, and has neuroprotective properties against neurodegenerative diseases. Insulin-like growth factor (IGF)-1 plays an important role in the regulation of cellular and tissue functions, and relating to the aging process the most important pathway of IGF-1 is the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt/PKB) signaling cascade. Although many have studied the changes in the level of IGF-1 and its effect on neural proliferation, the downstream signaling proteins have not been fully elucidated. Hence in the present investigation, the IGF-1 gene expression and the normal endogenous levels of IGF1R (IGF-1 receptor), PI3K, Akt, pAkt, and pFoxO in the hippocampus of young, adult, and old mice were determined using real-time PCR and Western blot analyses. The effects of DR on these protein levels were also studied. Results showed a decrease in the levels of IGF-1, IGF1R, PI3K, and pAkt, while pFoxO level increased with respect to age. Under DR, these protein levels are maintained in adult mice, but old mice displayed diminished expression levels of these proteins as compared to ad libitum-fed mice. Maintenance of PI3K/Akt pathway results in the phosphorylation of FoxOs, necessary for the enhancement of neural proliferation and survival in adult mice. The down-regulation of IGF-I signaling, as observed in old mice, leads to increasing the activity of FoxO factors that may be important for the neuroprotective effects seen with DR.
生物体中几个生物过程随时间的变化可被描述为衰老。衰老的影响之一是认知功能的下降。饮食限制（DR）是一种减少食物摄入量但不导致营养不良的干预措施，是一种已被充分证实的机制，具有广泛的重要结果，包括改善健康寿命、延缓衰老以及延长各种物种的寿命。它在预防认知功能的年龄依赖性衰退方面也发挥着有益作用，并且对神经退行性疾病具有神经保护特性。胰岛素样生长因子（IGF）-1在细胞和组织功能的调节中起重要作用，与衰老过程相关，IGF-1最重要的途径是磷脂酰肌醇3激酶（PI3K）和蛋白激酶B（Akt/PKB）信号级联。尽管许多人研究了IGF-1水平的变化及其对神经增殖的影响，但其下游信号蛋白尚未完全阐明。因此，在本研究中，使用实时PCR和蛋白质印迹分析测定了年轻、成年和老年小鼠海马中IGF-1基因表达以及IGF1R（IGF-1受体）、PI3K、Akt、pAkt和pFoxO的正常内源性水平。还研究了饮食限制对这些蛋白质水平的影响。结果显示，随着年龄增长，IGF-1、IGF1R、PI3K和pAkt水平下降，而pFoxO水平升高。在饮食限制条件下，成年小鼠中这些蛋白质水平得以维持，但与自由进食的小鼠相比，老年小鼠中这些蛋白质的表达水平降低。PI3K/Akt途径的维持导致FoxOs磷酸化，这对于成年小鼠神经增殖和存活的增强是必要的。如在老年小鼠中观察到的，IGF-I信号的下调导致FoxO因子活性增加，这可能对饮食限制所见的神经保护作用很重要。
