Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin‐like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear. We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock‐down of Alk, or expression of dominant‐negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin‐like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism‐wide insulin‐like signalling. Finally, we show that TAE‐684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.

中文翻译：

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神经元酪氨酸激酶Alk是长寿的目标。

通过包括胰岛素样生长因子受体及其直向同源物在内的几种受体酪氨酸激酶（RTK）抑制信号传导，延长了来自不同进化分类群的生物的健康寿命。这就增加了其他RTK的可能性，包括那些已经针对其在癌症和发育生物学中的作用进行了深入研究的RTK，可能成为延长健康寿命的有希望的靶标。在这里，我们专注于间变性淋巴瘤激酶（Alk），一种在神经系统发育和多种癌症中已确立作用的RTK，但其对衰老的影响尚不清楚。我们发现，减少Alk信号传导的几种方法，包括其配体果冻肚（jeb）突变，Alk的RNAi敲除或成年神经元中显性负性Alk的表达，都可以延长女性的健康寿命，但不能延长男性的寿命，果蝇。此外，减少的Alk信号可随着年龄的增长而保留神经肌肉功能，增强对饥饿和异种生物胁迫的抵抗力，并改善夜间睡眠的巩固。我们进一步发现，对成年神经元中Alk信号的抑制作用可调节几种胰岛素样肽的表达，从而在神经元Alk信号与全生物体胰岛素样信号之间提供潜在的机理联系。最后，我们证明TAK-684是Alk的一种小分子抑制剂，可以延长果蝇的健康寿命，这表明Alk抑制剂的重新用途可能是促进健康衰老的策略的一个有希望的方向。