An engineering approach to extending lifespan in C. elegans.
An engineering approach to extending lifespan in C. elegans.
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DOI：
10.1371/journal.pgen.1002780
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Kim SK
中科院分区：
文献类型：
--
作者：
Sagi D;Kim SK
我们已经采取了一种工程方法来延长秀丽隐杆线虫的寿命。衰老是一个复杂的特征，因为发生在老年动物身上的事件并没有受到强烈的自然选择。因此，使用生物工程来调节基因表达或添加外源成分可以合理地延长寿命。在这里，我们通过表达斑马鱼的基因来设计更长的寿命，这些基因编码蠕虫中通常不存在的分子功能。此外，我们通过增加四种内源性蠕虫衰老途径的活性来延长寿命。接下来，我们使用模块化方法通过组合组件来延长寿命。最后，我们使用基于细胞和蠕虫的测定来分析细胞生理学的变化，并作为一种快速手段来评估多组分转基因品系是否可能具有延长的寿命。利用工程技术来增加新的功能和调整内源性功能，为超越蠕虫基因组限制的寿命延长提供了一个新的框架。我们利用生物工程延长了C.通过表达在关键衰老途径中起作用的基因。我们过表达了五个基因，作用于内源性蠕虫老化途径，以及两个基因从斑马鱼编码的分子功能，通常不存在于蠕虫。例如，我们使用斑马鱼基因改变线粒体功能和先天免疫，而这在C. elegans和延长蠕虫寿命的10.40%。接下来，我们使用模块化方法，通过在同一菌株中组合多达四种成分，将寿命延长了130%。这些结果提供了一个平台，以建立蠕虫具有逐渐延长的寿命。这个项目在概念上类似于使用工程来增加原始机器（1931年T型）的使用寿命，使用T型的零件以及更先进的机器（2012年丰田花冠）的零件。我们的结果打开了一扇门，使用工程超越C。elegans基因组通过添加非天然成分来延长其寿命。
We have taken an engineering approach to extending the lifespan of Caenorhabditis elegans. Aging stands out as a complex trait, because events that occur in old animals are not under strong natural selection. As a result, lifespan can be lengthened rationally using bioengineering to modulate gene expression or to add exogenous components. Here, we engineered longer lifespan by expressing genes from zebrafish encoding molecular functions not normally present in worms. Additionally, we extended lifespan by increasing the activity of four endogenous worm aging pathways. Next, we used a modular approach to extend lifespan by combining components. Finally, we used cell- and worm-based assays to analyze changes in cell physiology and as a rapid means to evaluate whether multi-component transgenic lines were likely to have extended longevity. Using engineering to add novel functions and to tune endogenous functions provides a new framework for lifespan extension that goes beyond the constraints of the worm genome. We used bioengineering to extend the lifespan of C. elegans by expressing genes acting in critical aging pathways. We overexpressed five genes that act in endogenous worm aging pathways, as well as two genes from zebrafish encoding molecular functions not normally present in worms. For example, we used zebrafish genes to alter mitochondrial function and innate immunity in ways not normally available to C. elegans and extended worm lifespan by ∼40%. Next, we used a modular approach to extend lifespan by 130% by combining up to four components in the same strain. These results provide a platform to build worms having progressively longer lifespans. This project is conceptually similar to using engineering to increase the useful lifespan of a primitive machine (1931 Model T) using both parts from the model T as well as parts from a more advanced machine (2012 Toyota Corolla). Our results open the door to use engineering to go beyond the constraints of the C. elegans genome to extend its lifespan by adding non-native components.
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