PDF(Pubmed)
Abstract：
Pharmacological therapies are promising interventions to slow down aging and reduce multimorbidity in the elderly. Studies in animal models are the first step toward translation of candidate molecules into human therapies, as they aim to elucidate the molecular pathways, cellular mechanisms, and tissue pathologies involved in the anti-aging effects. Trametinib, an allosteric inhibitor of MEK within the Ras/MAPK (Ras/Mitogen-Activated Protein Kinase) pathway and currently used as an anti-cancer treatment, emerged as a geroprotector candidate because it extended lifespan in the fruit fly Drosophila melanogaster. Here, we confirm that trametinib consistently and robustly extends female lifespan, and reduces intestinal stem cell (ISC) proliferation, tumor formation, tissue dysplasia, and barrier disruption in guts in aged flies. In contrast, pro-longevity effects of trametinib are weak and inconsistent in males, and it does not influence gut homeostasis. Inhibition of the Ras/MAPK pathway specifically in ISCs is sufficient to partially recapitulate the effects of trametinib. Moreover, in ISCs, trametinib decreases the activity of the RNA polymerase III (Pol III), a conserved enzyme synthesizing transfer RNAs and other short, non-coding RNAs, and whose inhibition also extends lifespan and reduces gut pathology. Finally, we show that the pro-longevity effect of trametinib in ISCs is partially mediated by Maf1, a repressor of Pol III, suggesting a life-limiting Ras/MAPK-Maf1-Pol III axis in these cells. The mechanism of action described in this work paves the way for further studies on the anti-aging effects of trametinib in mammals and shows its potential for clinical application in humans.
摘要：
药物疗法是有希望的干预措施，可以减缓老年人的衰老并减少多发病率。动物模型研究是将候选分子转化为人类疗法的第一步，因为他们旨在阐明分子途径，细胞机制，以及与抗衰老作用有关的组织病理学。曲美替尼,Ras/MAPK（Ras/丝裂原激活蛋白激酶）途径内的MEK变构抑制剂，目前用作抗癌治疗，由于它延长了果蝇果蝇的寿命，因此成为了年龄保护者。这里,我们证实，trametinib持续和有力地延长女性寿命，并减少肠干细胞（ISC）的增殖，肿瘤形成，组织发育不良,和年老苍蝇肠道屏障的破坏。相比之下,Trametinib的促长寿作用在男性中微弱且不一致，它不会影响肠道稳态。在ISC中特异性抑制Ras/MAPK途径足以部分概括曲美替尼的作用。此外，在ISC中，曲美替尼降低RNA聚合酶III（PolIII）的活性，一个保守的酶合成转移RNA和其他短，非编码RNA，其抑制作用也能延长寿命并减少肠道病理。最后,我们表明曲美替尼在ISC中的促长寿作用部分由PolIII的阻遏物Maf1介导，提示这些细胞中存在生命限制性的Ras/MAPK-Maf1-PolIII轴。这项工作中描述的作用机制为进一步研究曲美替尼在哺乳动物中的抗衰老作用铺平了道路，并显示了其在人类中的临床应用潜力。
