The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity.
The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity.
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DOI：
10.1016/j.cell.2015.06.023
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发表时间：
2015-07-02
期刊：
影响因子：
64.5
通讯作者：
Partridge L
中科院分区：
文献类型：
--
作者：
Slack C;Alic N;Foley A;Cabecinha M;Hoddinott MP;Partridge L
确定老化背后的分子机制及其药理操作是改善人类终身健康的关键目标。在这里，我们确定了Ras-Erk-ETS信号在果蝇衰老中的关键作用。我们发现Ras的抑制足以延长胰岛素/IGF-1 （IIS）信号传导降低下游的寿命。此外，Ras或Erk活性的直接降低导致寿命延长。我们发现e - 26 （ETS）转录抑制因子，前部开放（Aop），是IIS或Ras衰减减少导致的寿命延长的核心。重要的是，我们证明了成人发病的药物曲美替尼（一种高度特异性的Ras-Erk-ETS信号抑制剂）可以延长寿命。Ras-Erk-ETS通路作为动物衰老的药理学靶点的发现，以及该通路高度的进化保守性，表明抑制Ras-Erk-ETS信号传导可能为哺乳动物抗衰老干预提供一个有效的靶点。Ras- erk信号的衰减通过Aop转录因子延长寿命，使用Ras- erk信号抑制剂曲美替尼治疗，延长寿命Ras- erk - ets信号可能为哺乳动物抗衰老干预提供靶点，Ras抑制与胰岛素/IGF-1信号减少引起的寿命有关。在成年果蝇中，Mek激酶抑制剂曲美替尼对Ras信号的药理抑制可以延长寿命，揭示了中年抗衰老干预的新潜在靶点。
Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals. Reduced insulin/IGF-1 (IIS) signaling involves Ras inhibition for longevity Attenuation of Ras-Erk signaling extends lifespan via the Aop transcription factor Treatment with trametinib, an inhibitor of Ras-Erk signaling, extends lifespan Ras-Erk-ETS signaling may provide targets for anti-aging interventions in mammals Ras inhibition is implicated in the longevity that arises from reduced insulin/IGF-1 signaling. In adult flies, pharmacological inhibition of Ras signaling using the Mek kinase inhibitor, trametinib, extends lifespan, revealing a new potential target for midlife anti-aging interventions.