40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain.
40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain.
复制标题
DOI：
10.1530/jme-18-0093
复制
发表时间：
2018-07
影响因子：
3.5
通讯作者：
Milman S
中科院分区：
文献类型：
--
作者：
Gubbi S;Quipildor GF;Barzilai N;Huffman DM;Milman S
IGF-1 信号通路已成为从啮齿动物到人类衰老过程的主要调节因子。然而，鉴于 IGF-1 的多效作用，其在大脑衰老中的作用仍然复杂且有争议。虽然 IGF-1 显然对于中枢神经系统的正常发育至关重要，但关于其与认知功能以及脑血管和神经退行性疾病的关系，临床前和人体研究中出现了相互矛盾的证据。这篇综述深入研究了 IGF-1 在衰老大脑中的作用的证据现状，包括临床前和临床研究。对数据的广泛检查表明，IGF-1 确实可能在衰老的大脑中发挥相反的作用，具体取决于潜在的病理学和背景。一些证据表明，在以大脑中异常蛋白质沉积为特征的神经退行性疾病（例如阿尔茨海默病）中，减少 IGF-1 信号传导可能会起到保护作用，减缓疾病进展并增加病理蛋白的清除以维持细胞稳态。相比之下，诱导 IGF-1 缺乏也与认知和神经血管系统功能失调有关，这表明某些 IGF-1 信号传导可能是正常脑功能所必需的。此外，急性神经元损伤状态需要生长、修复和生存信号才能持续，通常证明 IGF-1 在这种情况下具有有益作用。认识到衰老大脑中 IGF-1 的双重（有时是对立的）“杰基尔博士”和“海德先生”特征，将使我们更深入地了解其影响，并设计出更有针对性的 IGF-1 相关干预措施。
The IGF-1 signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF-1, its role in the aging brain remains complex and controversial. While IGF-1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF-1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF-1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer’s disease, reducing IGF-1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF-1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF-1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF-1 in that context. Appreciating the dual, at times opposing “Dr. Jekyll” and “Mr. Hyde” characteristics of IGF-1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF-1-related interventions.