Drug synergy drives conserved pathways to increase fission yeast lifespan.
Drug synergy drives conserved pathways to increase fission yeast lifespan.
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DOI：
10.1371/journal.pone.0121877
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Dickson RC
中科院分区：
文献类型：
--
作者：
Huang X;Leggas M;Dickson RC
衰老随着时间的推移而发生，生理功能逐渐和进行性丧失。目前正在寻求降低功能丧失率和减轻随后发生的与年龄有关的致命疾病的战略。我们以前证明了雷帕霉素和多球菌素的组合减少了面包酵母酿酒酵母中与年龄相关的功能丧失，并产生了协同增加寿命。在这里，我们表明，相同的药物组合也产生了协同增加的裂变酵母裂殖酵母的寿命，并通过控制信号转导途径保守在一个广泛的进化时间跨度，从酵母到哺乳动物。途径包括雷帕霉素复合物1（TORC 1）蛋白激酶的靶标、蛋白激酶A（PKA）和应激反应途径，其在分裂酵母中含有Sty 1蛋白激酶，哺乳动物p38 MAP激酶的直系同源物，一种应激活化蛋白激酶（SAPK）。这些结果沿着与以前的研究在S.酿酒酵母的研究支持雷帕霉素和多球壳菌素的组合通过调节将营养和环境条件与细胞过程偶联的信号传导途径来增强寿命的前提，所述细胞过程以促进长期存活的方式微调生长和应激保护。微调的分子机制可能是物种特异性的，但由于它们是由保守的营养和压力传感途径驱动的，因此药物组合可能会提高其他生物体的存活率。
Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker’s yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms.
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影响因子：
11.3
作者：
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通讯作者：
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