Masternak Michal M, Bartke Andrzej
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL USA.
Pathobiol Aging Age Relat Dis. 2012;2. doi: 10.3402/pba.v2i0.17293. Epub 2012 Apr 4.
Mutant animals characterized by extended longevity provide valuable tools to study the mechanisms of aging. Growth hormone and insulin-like growth factor-1 (IGF-1) constitute one of the well-established pathways involved in the regulation of aging and lifespan. Ames and Snell dwarf mice characterized by GH deficiency as well as growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice characterized by GH resistance live significantly longer than genetically normal animals. During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of anti-inflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines. This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human.
以长寿为特征的突变动物为研究衰老机制提供了有价值的工具。生长激素和胰岛素样生长因子-1（IGF-1）构成了参与衰老和寿命调节的成熟途径之一。以生长激素缺乏为特征的Ames和Snell侏儒小鼠以及以生长激素抵抗为特征的生长激素受体/生长激素结合蛋白敲除（GHRKO）小鼠的寿命明显长于基因正常的动物。在啮齿动物和人类的正常衰老过程中，胰岛素抵抗增加、代谢活动紊乱以及免疫系统功能下降。所有这些与年龄相关的过程都会促进炎症活动，导致长期的组织损伤和全身性慢性炎症。然而，对长寿突变体和限食动物的研究表明，促炎活性降低，抗炎脂肪因子如脂联素的水平升高。同时，这些动物的胰岛素信号传导和碳水化合物稳态得到改善，这与脂肪组织分泌谱的改变有关，包括抗炎脂肪因子的产生和释放增加。这表明减少促进健康代谢的炎症可能是长寿突变小鼠以及人类延长寿命的主要机制之一。
