Shared transcriptional signature in Caenorhabditis elegans dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance
Shared transcriptional signature in Caenorhabditis elegans dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance
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DOI：
10.1074/jbc.m406207200
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发表时间：
2004-10-22
影响因子：
4.8
通讯作者：
Gems, D
中科院分区：
文献类型：
--
作者：
McElwee, JJ;Schuster, E;Gems, D
在线虫秀丽隐杆线虫中，长寿幼虫的形成和成虫衰老都是由胰岛素/胰岛素样生长因子-1信号传导控制的。daf-2胰岛素/胰岛素样生长因子-1受体突变体中成虫寿命的延长可能是由于dauer幼虫寿命程序在成虫中的错误表达。通过寡核苷酸芯片分析，我们在daf-2突变体中发现了一个dauer转录特征。通过一个无偏的统计方法，我们确定了基因类的表达改变类似的dauers和daf-2突变体，这代表了潜在的决定因素的寿命。这些包括已知的长寿决定因素;小的热休克蛋白/α-晶体蛋白在两种环境中都上调。细胞色素P450，短链脱氢酶/还原酶，UDP-葡萄糖醛酸转移酶，谷胱甘肽S-转移酶（在daf-2突变体）基因类也上调。这四类基因在有毒的内源性和外源性代谢物的代谢和排泄中共同起作用。这表明，不同的有毒亲脂性和亲电子代谢产物，处置的阶段1和阶段2药物代谢，可能是导致衰老的分子损伤的主要决定因素。此外，我们观察到与营养吸收相关的基因下调，包括nhx-2和pep-2。这些共同作用于肠内二肽的摄取，意味着daf-2突变体的饮食限制。在dauers和/或daf-2中上调的一些基因组富含如下的某些启动子元件：daf-16结合元件、热休克反应元件、热休克相关序列或hif-1反应元件。相比之下，daf-16相关元件富集在dauers和daf-2突变体中下调的基因中。因此，特定的启动子元件似乎与长寿相关或与衰老相关。
In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/ insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/alpha-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/ reductase, UDP-glucuronosyltransferase, and glutathione S-transferase ( in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed downregulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes down-regulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated.