Down-regulating sphingolipid synthesis increases yeast lifespan.
Down-regulating sphingolipid synthesis increases yeast lifespan.
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DOI：
10.1371/journal.pgen.1002493
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发表时间：
2012-02
期刊：
影响因子：
4.5
通讯作者：
Dickson RC
中科院分区：
文献类型：
--
作者：
Huang X;Liu J;Dickson RC
关于调节寿命的机制的知识正在迅速发展，但寿命是一个复杂的表型，并且可能会发现新的特征。在这里，我们揭示了一种调节寿命的新方法。使用遗传或药理学策略来降低鞘脂合成率，我们发现酿酒酵母细胞寿命更长。寿命延长的部分原因是 Sch9 蛋白激酶活性降低，从而导致染色体突变和重排减少，以及抗应激能力增强。更长的寿命也以独立于 Sch9 或热量限制的方式出现，我们推测鞘脂可能会介导延长寿命的这些方面。 Sch9 及其哺乳动物同源物 S6 激酶在雷帕霉素、TOR1、蛋白激酶靶标的下游发挥作用，并在调节寿命方面发挥进化上保守的作用。我们的数据将 TOR1 的营养信号与鞘脂的生长和应激信号整合起来，将 Sch9 确定为调节寿命的焦点。鞘脂存在于所有真核生物中，我们的结果表明，一种或多种鞘脂的药理学下调可能提供一种减少与年龄相关的疾病并延长其他真核生物寿命的方法。 20 世纪 30 年代对老鼠的研究表明，当饮食中的热量比正常饮食少 30%–40% 时，老鼠的寿命会惊人地延长。该实验已在许多生物体上重复进行，是延长寿命的黄金标准。虽然我们开始了解热量限制如何调节寿命，但其机制很复杂，还有很多东西需要学习。在这里介绍的工作中，我们展示了一种延长芽殖酵母酿酒酵母寿命的新方法。我们的策略是通过减少生物合成途径中第一种酶的合成或使用药物降低酶活性来降低鞘脂合成速率。这种策略的部分作用是降低蛋白激酶的活性，在酵母中称为 Sch9，在哺乳动物中称为 S6K，这两种蛋白都参与受热量限制影响并控制寿命的过程。此外，我们发现减少鞘脂合成可以延长寿命，而与 Sch9 和热量限制无关。由于鞘脂存在于所有真核生物中，因此我们的结果表明，一种或多种鞘脂的药理学下调可能提供一种减少其他真核生物与年龄相关的疾病和延长寿命的方法。
Knowledge of the mechanisms for regulating lifespan is advancing rapidly, but lifespan is a complex phenotype and new features are likely to be identified. Here we reveal a novel approach for regulating lifespan. Using a genetic or a pharmacological strategy to lower the rate of sphingolipid synthesis, we show that Saccharomyces cerevisiae cells live longer. The longer lifespan is due in part to a reduction in Sch9 protein kinase activity and a consequent reduction in chromosomal mutations and rearrangements and increased stress resistance. Longer lifespan also arises in ways that are independent of Sch9 or caloric restriction, and we speculate on ways that sphingolipids might mediate these aspects of increased lifespan. Sch9 and its mammalian homolog S6 kinase work downstream of the target of rapamycin, TOR1, protein kinase, and play evolutionarily conserved roles in regulating lifespan. Our data establish Sch9 as a focal point for regulating lifespan by integrating nutrient signals from TOR1 with growth and stress signals from sphingolipids. Sphingolipids are found in all eukaryotes and our results suggest that pharmacological down-regulation of one or more sphingolipids may provide a means to reduce age-related diseases and increase lifespan in other eukaryotes. Studies with rats in the 1930s showed a surprising increase in lifespan when the diet contained 30%–40% fewer calories than normal. This experiment has been repeated on many organisms and is the gold standard for extending lifespan. While we are beginning to understand how calorie restriction regulates lifespan, the mechanisms are complex and much remains to be learned. In the work presented here, we demonstrate a novel way to increase lifespan in the budding yeast Saccharomyces cerevisiae. Our strategy is to lower the rate of sphingolipid synthesis either by reducing the synthesis of the first enzyme in the biosynthesis pathway or by using a drug to reduce enzyme activity. This strategy works in part by lowering the activity of a protein kinase, termed Sch9 in yeast and S6K in mammals, both of which are involved in the processes affected by calorie restriction and that control lifespan. In addition, we find that reducing sphingolipid synthesis increases lifespan in ways that are independent of Sch9 and calorie restriction. Since sphingolipids are found in all eukaryotes, our results suggest that pharmacological down-regulation of one or more sphingolipids may provide a means to reduce age-related diseases and increase lifespan in other eukaryotes.
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DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
4.8
作者：
Dickson, RC;Nagiec, EE;Lester, RL
通讯作者：
Lester, RL
影响因子：
4.8
作者：
Chung, NJ;Mao, CG;Obeid, LM
通讯作者：
Obeid, LM
影响因子：
29
作者：
Bjedov I;Toivonen JM;Kerr F;Slack C;Jacobson J;Foley A;Partridge L
通讯作者：
Partridge L
DOI：
10.1016/j.tem.2009.11.005
发表时间：
2010-03
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
--
作者：
Anderson RM;Weindruch R
通讯作者：
Weindruch R