Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the “insulin paradox”). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.

降低的胰岛素/胰岛素样生长因子（IGF）信号传导（IIS）可以延长蠕虫，果蝇和小鼠的健康寿命，但也会产生不利影响（“胰岛素悖论”）。IIS的慢性，中度降低可缓解果蝇与年龄相关的神经传递的下降巨纤维系统（GFS），一种简单的逃避反应神经元回路，通过增加将间隙连接蛋白内毒素摇动B靶向间隙连接（GJs）来实现。当减少IIS时，在培养的人类细胞中也会刺激GJ的内体再循环。此外，提高回收的小鸟苷三磷酸酶（GTPase）Rab4或Rab11的活性足以在培养的人细胞和果蝇中IIS升高时维持GJ，并挽救与年龄有关的GJ和GFS功能的丧失。因此，降低的IIS会增加神经元和其他细胞类型中GJ的内体再循环，这表明了针对与衰老相关的神经元疾病进行治疗干预的细胞机制。