Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells.
Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells.
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DOI：
10.1073/pnas.2311313121
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发表时间：
2024-01-23
影响因子：
11.1
通讯作者：
Partridge, Linda
中科院分区：
文献类型：
--
作者：
Urena, Enric;Xu, Bowen;Regan, Jennifer C.;Atilano, Magda L.;Minkley, Lucy J.;Filer, Danny;Lu, Yu-Xuan;Bolukbasi, Ekin;Khericha, Mobina;Alic, Nazif;Partridge, Linda
由于医学、卫生和营养等方面的进步，人类的预期寿命在过去几十年中显着增加。然而，这种人口变化导致与年龄相关的疾病患病率增加，例如癌症、心血管和神经退行性疾病。在动物模型中，衰老是可塑的，药物干预可以减少与年龄相关的病理的发生率。在这里，我们证明曲美替尼（一种抗癌剂）可以延长雌性果蝇的寿命并改善肠道健康。这种效应是通过抑制 RNA 聚合酶 III 介导的，RNA 聚合酶 III 是一种保守酶，可合成短的非编码 RNA，如 tRNA（转移 RNA）。我们的研究结果增进了对曲美替尼在动物中的抗衰老特性的理解，并证实了其作为老年保护干预措施的潜力。药物疗法是延缓衰老和减少老年人多重发病率的有希望的干预措施。动物模型研究是将候选分子转化为人类疗法的第一步，因为它们的目的是阐明抗衰老作用中涉及的分子途径、细胞机制和组织病理学。 Trametinib 是 Ras/MAPK（Ras/丝裂原激活蛋白激酶）途径中 MEK 的变构抑制剂，目前用作抗癌治疗，由于它能延长果蝇果蝇的寿命，因此成为老年保护剂候选药物。在这里，我们确认曲美替尼持续有效地延长雌性果蝇的寿命，并减少老年果蝇肠道干细胞（ISC）增殖、肿瘤形成、组织发育不良和肠道屏障破坏。相比之下，曲美替尼对男性的长寿作用较弱且不一致，并且不影响肠道稳态。特别是在 ISC 中抑制 Ras/MAPK 通路足以部分重现曲美替尼的作用。此外，在 ISC 中，曲美替尼可降低 RNA 聚合酶 III (Pol III) 的活性，这是一种合成转移 RNA 和其他短非编码 RNA 的保守酶，其抑制作用还可延长寿命并减少肠道病理。最后，我们发现曲美替尼在 ISC 中的延长寿命作用部分是由 Pol III 的抑制因子 Maf1 介导的，表明这些细胞中存在生命限制的 Ras/MAPK-Maf1-Pol III 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，并显示了其在人类临床应用的潜力。
Human life expectancy has increased markedly during the last decades thanks to advances in medicine, hygiene, and nutrition, among other factors. However, this demographic change brings an increased prevalence of age-related diseases, such as cancer, cardiovascular and neurodegenerative diseases. Aging is malleable in animal models, and pharmacological interventions can reduce the incidence of age-related pathologies. Here, we show that trametinib, an anticancer agent, extends lifespan and improves gut health in female fruit flies. This effect is mediated by the inhibition of RNA polymerase III, a conserved enzyme that synthetizes short, non-coding RNAs such as tRNAs (transfer RNAs). Our findings advance the understanding of the anti-aging properties of trametinib in animals and confirm its potential as a geroprotective intervention. 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.
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影响因子：
4.5
作者：
Biteau B;Karpac J;Supoyo S;Degennaro M;Lehmann R;Jasper H
通讯作者：
Jasper H
影响因子：
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作者：
Jazwinski SM;Kim S;Dai J;Li L;Bi X;Jiang JC;Arnold J;Batzer MA;Walker JA;Welsh DA;Lefante CM;Volaufova J;Myers L;Su LJ;Hausman DB;Miceli MV;Ravussin E;Poon LW;Cherry KE;Welsch MA;Georgia Centenarian Study and the Louisiana Healthy Aging Study
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Georgia Centenarian Study and the Louisiana Healthy Aging Study
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3.2
作者：
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通讯作者：
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作者：
Kulaberoglu Y;Malik Y;Borland G;Selman C;Alic N;Tullet JMA
通讯作者：
Tullet JMA
影响因子：
8.8
作者：
Clark RI;Salazar A;Yamada R;Fitz-Gibbon S;Morselli M;Alcaraz J;Rana A;Rera M;Pellegrini M;Ja WW;Walker DW
通讯作者：
Walker DW