Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9.
Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9.
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DOI：
10.1371/journal.pgen.0040013
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发表时间：
2008-01
期刊：
影响因子：
4.5
通讯作者：
Longo VD
中科院分区：
文献类型：
--
作者：
Wei M;Fabrizio P;Hu J;Ge H;Cheng C;Li L;Longo VD
热量限制（CR）是唯一已知的减缓衰老和延长从酵母到小鼠的生物体寿命的非遗传干预措施，与Tor，Akt和Ras信号转导的下调有关。在这项研究中，我们证明了丝氨酸/苏氨酸激酶Rim 15是必需的酵母的时间寿命延长所造成的Ras 2，Tor 1和Sch 9的缺陷，并通过热量限制。Rim 15正调控的抗应激转录因子Gis 1和Msn 2/4的缺失也导致了热量限制对寿命影响的主要但不完全逆转。RAS 2和Akt和S6激酶同源物SCH 9的缺失与卡路里限制的组合导致了显著的10倍寿命延长，令人惊讶的是，Rim 15的缺乏仅部分逆转了这一点。这些结果表明，Ras/cAMP/PKA/Rim 15/Msn 2/4和Tor/Sch 9/Rim 15/Gis 1途径是热量限制依赖的应激抗性和寿命延长的主要介质，尽管还涉及其他介质。值得注意的是，由两种途径的失活引起的抗衰老作用比由CR引起的作用强得多。减少热量摄入是一种行之有效的干预措施，可以延长所研究的各种生物模式生物的寿命。热量限制也延迟和减弱灵长类动物与年龄相关的变化，尽管其促进长寿的作用尚未得到证实。在这里，我们利用单细胞生物，面包酵母，研究进化保守基因在寿命调节中的作用，以及它们在热量限制中的作用。缺乏Ras 2、Tor 1或Sch 9的酵母突变体寿命长。在这些突变体中观察到的抗衰老作用取决于蛋白质Rim 15和在应激下诱导细胞保护所必需的几个基因表达的关键调节因子。热量限制的有益效果在缺少这些蛋白质的酵母中要小得多，这表明它们在促进长寿方面的重要作用。我们的研究还表明，通过结合基因操作和热量限制干预，酵母菌的寿命可以达到标准条件下生长的酵母菌的十倍。这种极端的长寿需要Rim 15，也取决于其他尚未确定的机制。我们的研究结果提供了新的线索，可能有助于阐明哺乳动物卡路里限制抗衰老作用的机制。
Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR. Reduction in calorie intake is a well-established intervention that extends the life span of a variety of biological model organisms studied. Calorie restriction also delays and attenuates age-related changes in primates, although its longevity-promoting effect has not been demonstrated. Here, we utilized a single cell organism, baker's yeast, to examine the role of evolutionarily conserved genes in life span regulation and their involvement in calorie restriction. The yeast mutants lacking Ras2, Tor1, or Sch9 are long-lived. The anti-aging effect observed in these mutants depends on the protein Rim15 and several key regulators of gene expression that are essential in inducing cellular protection under stress. The beneficial effects of calorie restriction are much smaller in yeast that are missing these proteins, indicating their essential role in promoting longevity. Our study also showed that by combining the genetic manipulation and calorie restriction intervention, yeast can reach a life span ten times that of those grown under standard conditions. This extreme longevity requires Rim15 and also depends on other yet-to-be identified mechanisms. Our findings provided new leads that may help to elucidate the mechanisms underlying the anti-aging effect of calorie restriction in mammals.
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影响因子：
3.2
作者：
Boy-Marcotte, E;Perrot, M;Jacquet, M
通讯作者：
Jacquet, M
影响因子：
64.8
作者：
Bartke, A;Wright, JC;Roth, GS
通讯作者：
Roth, GS
影响因子：
5.3
作者：
Kaeberlein, M;Kirkland, KT;Kennedy, BK
通讯作者：
Kennedy, BK
DOI：
10.1083/jcb.200404002
发表时间：
2004-09-27
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fabrizio P;Battistella L;Vardavas R;Gattazzo C;Liou LL;Diaspro A;Dossen JW;Gralla EB;Longo VD
通讯作者：
Longo VD
影响因子：
56.9
作者：
Clancy, DJ;Gems, D;Partridge, L
通讯作者：
Partridge, L