Visions & reflections - Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans?
Visions & reflections - Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans?
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DOI：
10.1007/s00018-002-8477-8
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发表时间：
2002-06-01
影响因子：
8
通讯作者：
Fabrizio, P
中科院分区：
文献类型：
--
作者：
Longo, VD;Fabrizio, P
最近的研究表明，从酵母到小鼠，生物体中的长寿调节蛋白质也有类似的作用。对酵母和蠕虫的研究表明，葡萄糖或胰岛素/胰岛素样生长因子-1（IGF- 1）信号通路的失活通过引起从生殖阶段到涉及许多基因表达的非生殖维持阶段的转变来延长寿命。这些应激抗性途径似乎已经进化到诱导维持系统，并在饥饿期间促进长寿。在酵母中，降低葡萄糖信号通路活性的突变通过激活应激抗性转录因子来延长寿命，所述应激抗性转录因子调节参与抗氧化剂和热保护、糖原储存、蛋白质降解、DNA修复和代谢的基因的表达。一组由控制葡萄糖代谢的生长因子调节的非常相似的蛋白质与蠕虫的寿命延长有关，可能也与苍蝇和小鼠的寿命延长有关。对蠕虫和苍蝇的研究指出，二级激素是胰岛素/ IGF-1信号对寿命影响的介质，而对酵母和哺乳动物细胞的研究表明，葡萄糖或胰岛素/IGF-1可能通过直接下调应激抗性基因来降低寿命。在酵母中，长寿突变推迟了超氧化物毒性和线粒体损伤。然而，酵母和苍蝇中超氧化物歧化酶和过氧化氢酶的过度表达引起的小的寿命延长表明，单独增加抗氧化保护不能负责信号转导突变引起的主要寿命延长。虽然我们才刚刚开始了解介导寿命延长的分子机制，但从酵母到小鼠的生物体中长寿调节途径之间的相似性表明，胰岛素/IGF-1信号通路也可能调节人类的细胞损伤和寿命。
Recent studies implicate similar proteins in the regulation of longevity in organisms ranging from yeast to mice. Studies in yeast and worms suggest that inactivation of glucose or insulin/insulin-like growth factor-1 (IGF- 1) signaling pathways extends longevity by causing a shift from a reproductive phase to a non-reproductive maintenance phase involving the expression of many genes. These stress resistance pathways appear to have evolved to induce maintenance systems and promote longevity during periods of starvation. In yeast, mutations that decrease the activity of glucose signaling pathways extend longevity by activating stress resistance transcription factors that regulate the expression of genes involved in antioxidant and heat protection, glycogen storage, protein degradation, DNA repair, and metabolism. A remarkably similar set of proteins regulated by growth factors that control glucose metabolism is implicated in life span extension in worms, and possibly in flies and mice. Studies in worms and flies point to secondary hormones as mediators of the effect of insulin/ IGF-1 signaling on longevity, whereas studies in yeast and mammalian cells indicate that glucose or insulin/IGF-1 may decrease longevity by directly down-regulating stress resistance genes. In yeast, longevity mutations postpone superoxide toxicity and mitochondrial damage. However, the small life span extension caused by the overexpression of superoxide dismutases and catalase in yeast and flies indicates that increased antioxidant protection alone cannot be responsible for the major life span extension caused by signal transduction mutations. Although we are only beginning to understand the molecular mechanisms that mediate life span extension, the similarities between longevity regulatory pathways in organisms ranging from yeast to mice suggest that insulin/IGF-1 signaling pathways may also regulate cell damage and longevity in humans.