The neuronal receptor tyrosine kinase Alk is a target for longevity.
The neuronal receptor tyrosine kinase Alk is a target for longevity.
复制标题
神经元受体酪氨酸激酶 Alk 是长寿的目标。
DOI：
10.1111/acel.13137
复制
发表时间：
2020
期刊：
影响因子：
7.8
通讯作者：
Woodling NS
中科院分区：
文献类型：
--
作者：
Woodling NS
通过几种受体酪氨酸激酶(RTK)抑制信号，包括胰岛素样生长因子受体及其同源物，延长了来自不同进化类群的生物体的健康寿命。这增加了其他RTK的可能性，包括那些已经因其在癌症和发育生物学中的作用而得到充分研究的RTK，可能是延长健康寿命的有希望的目标。在这里，我们关注间变性淋巴瘤激酶(ALK)，它是一种RTK，在神经系统发育和多种癌症中具有既定的作用，但其对衰老的影响尚不清楚。我们发现，几种减少ALK信号的方法，包括其配体果冻腹部(JEB)的突变，ALK的RNAi击倒，或在成年神经元中表达显性负ALK，可以延长雌性果蝇的健康寿命，但不能延长雄性果蝇的健康寿命。此外，随着年龄的增长，ALK信号的减少可以保护神经肌肉功能，提高对饥饿和外来压力的抵抗力，并改善夜间睡眠巩固。我们进一步发现，抑制成年神经元中的ALK信号可以调节几个胰岛素样肽的表达，在神经元ALK信号和整个生物体的胰岛素样信号之间提供了潜在的机制联系。最后，我们证明了ALK的小分子抑制剂Tae-684可以延长果蝇的健康寿命，这表明ALK抑制剂的再利用可能是促进健康衰老的一个有前途的方向。
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 inDrosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.