Merry Troy L, Kuhlow Doreen, Laube Beate, Pöhlmann Doris, Pfeiffer Andreas F H, Kahn C Ronald, Ristow Michael, Zarse Kim
Energy Metabolism Laboratory, Swiss Federal Institute of Technology (ETH) Zurich-Schwerzenbach, Schwerzenbach, Zurich, Switzerland.
School of Medical Sciences, University of Auckland, Auckland, New Zealand.
Aging Cell. 2017 Aug;16(4):761-772. doi: 10.1111/acel.12610. Epub 2017 May 22.
Impaired insulin/IGF1 signalling has been shown to extend lifespan in model organisms ranging from yeast to mammals. Here we sought to determine the effect of targeted disruption of the insulin receptor (IR) in non-neuronal tissues of adult mice on the lifespan. We induced hemizygous (PerIRKO ) or homozygous (PerIRKO ) disruption of the IR in peripheral tissue of 15-weeks-old mice using a tamoxifen-inducible Cre transgenic mouse with only peripheral tissue expression, and subsequently monitored glucose metabolism, insulin signalling and spontaneous death rates over 4 years. Complete peripheral IR disruption resulted in a diabetic phenotype with increased blood glucose and plasma insulin levels in young mice. Although blood glucose levels returned to normal, and fat mass was reduced in aged PerIRKO mice, their lifespan was reduced. By contrast, heterozygous disruption had no effect on lifespan. This was despite young male PerIRKO mice showing reduced fat mass and mild increase in hepatic insulin sensitivity. In conflict with findings in metazoans like Caenorhabditis elegans and Drosophila melanogaster, our results suggest that heterozygous impairment of the insulin signalling limited to peripheral tissues of adult mice fails to extend lifespan despite increased systemic insulin sensitivity, while homozygous impairment shortens lifespan.
胰岛素/胰岛素样生长因子1（IGF1）信号通路受损已被证明能延长从酵母到哺乳动物等模式生物的寿命。在此，我们试图确定成年小鼠非神经组织中胰岛素受体（IR）的靶向破坏对寿命的影响。我们使用仅在外周组织表达的他莫昔芬诱导型Cre转基因小鼠，在15周龄小鼠的外周组织中诱导IR的半合子（PerIRKO）或纯合子（PerIRKO）破坏，随后在4年多的时间里监测葡萄糖代谢、胰岛素信号传导和自然死亡率。完全外周IR破坏导致年轻小鼠出现糖尿病表型，血糖和血浆胰岛素水平升高。尽管老年PerIRKO小鼠的血糖水平恢复正常，脂肪量减少，但其寿命缩短。相比之下，杂合子破坏对寿命没有影响。尽管年轻雄性PerIRKO小鼠的脂肪量减少，肝脏胰岛素敏感性略有增加，但情况依然如此。与秀丽隐杆线虫和黑腹果蝇等后生动物的研究结果相反，我们的结果表明，仅限于成年小鼠外周组织的胰岛素信号杂合子损伤尽管会增加全身胰岛素敏感性，但并不能延长寿命，而纯合子损伤则会缩短寿命。
