Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan.
Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan.
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DOI：
10.1111/acel.12107
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发表时间：
2013-10
期刊：
影响因子：
7.8
通讯作者：
Dickson RC
中科院分区：
文献类型：
--
作者：
Liu J;Huang X;Withers BR;Blalock E;Liu K;Dickson RC
对衰老和长寿的研究揭示了如何控制缩短生命的疾病，以提高生活质量和寿命本身。实现这些目标的两种策略正在紧张的研究中，分别是雷帕霉素治疗和卡路里限制。正在发现新的策略，包括使用低剂量麦角菌素治疗的策略。Myriocin抑制所有真核生物中鞘脂合成的第一个酶，我们最近发现，小剂量的Myriocin处理至少部分地通过下调鞘脂控制的Pkh1/2-Sch9(哺乳动物S6激酶的同源)信号通路来延长酵母的寿命。在这里，我们发现，与未经处理的细胞相比，霉菌素处理诱导了大约40%的酵母基因组的表达变化，其中1252个基因上调，1497个基因下调(p<；0.05)。这些变化是由于进化上保守的信号通路的调节，包括Snf1/AMPK通路的激活，以及蛋白激酶A(PKA)和雷帕霉素复合体靶点1(TORC1)通路的下调。许多延长寿命的过程都受到这些信号通路的调控，包括呼吸、碳代谢、抗逆性、蛋白质合成和自噬。Myriocin的这些广泛作用与雷帕霉素和卡路里限制相匹配。我们在酵母中的研究以及在哺乳动物中的其他研究揭示了霉菌素或相关化合物在降低人类年龄相关疾病发生率和提高健康寿命方面的潜力。
Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish these goals are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low-dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes and we showed recently that low-dose myriocin treatment increases yeast lifespan at least in part by down-regulating the sphingolipid-controlled Pkh1/2-Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment induces global effects and changes expression of approximately forty percent of the yeast genome with 1252 genes up-regulated and 1497 down-regulated (p < 0.05) compared to untreated cells. These changes are due to modulation of evolutionarily conserved signaling pathways including activation of the Snf1/AMPK pathway and down-regulation of the Protein Kinase A (PKA) and Target of Rapamycin Complex 1 (TORC1) pathways. Many processes that enhance lifespan are regulated by these pathways in response to myriocin treatment including respiration, carbon metabolism, stress resistance, protein synthesis and autophagy. These extensive effects of myriocin match those of rapamycin and calorie restriction. Our studies in yeast together with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age-related diseases in humans and improve health span.
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影响因子：
4.5
作者：
Fabrizio P;Hoon S;Shamalnasab M;Galbani A;Wei M;Giaever G;Nislow C;Longo VD
通讯作者：
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通讯作者：
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作者：
Barrett, LaKisha;Orlova, Marianna;Kuchin, Sergei
通讯作者：
Kuchin, Sergei
影响因子：
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作者：
Buschlen, S;Amillet, JM;Bolotin-Fukuhara, M
通讯作者：
Bolotin-Fukuhara, M