Lifespan regulation by evolutionarily conserved genes essential for viability.
Lifespan regulation by evolutionarily conserved genes essential for viability.
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通过进化保守的基因对生存力必不可少的寿命调节。
DOI：
10.1371/journal.pgen.0030056
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发表时间：
2007-04-06
期刊：
影响因子：
4.5
通讯作者：
Ruvkun G
中科院分区：
文献类型：
--
作者：
Curran SP;Ruvkun G
据预测，控制衰老的进化保守机制具有生殖前功能，以便服从自然选择。对生长发育至关重要的基因在进化过程中是高度保守的，但它们在长寿中的作用以前没有被评估过。我们筛选了2700个对秀丽隐杆线虫发育至关重要的基因，并确定了64个在发育后失活时延长寿命的基因。这些候选的寿命调节因子从酵母到人类都是高度保守的。将候选寿命调节因子分类为功能组，确定了预期的胰岛素和代谢途径，但也揭示了翻译、RNA和染色质因子的富集。许多这些重要的基因失活可以延长寿命，就像已知最强的衰老调节因子一样。这些必需基因的早期失活导致幼虫阶段生长停滞，其中一些被抑制的动物比野生型成年动物活得更长。Daf-16是提高滞留幼虫存活率所必需的，这表明延长寿命是对必需基因失活的生理反应。这些结果表明，胰岛素信号通路在生命的任何阶段都起着调节衰老的作用。动物的寿命是由环境和遗传因素共同决定的，许多延长寿命的机制在整个生物体中都是进化保守的。此前，秀丽隐杆线虫的长寿筛选已经确定了100多个基因，但对正常发育至关重要的约2700个基因被排除在分析之外。矛盾的是，这些必需基因在系统发育中高度保守的可能性是没有明显发育表型的基因的五倍。我们筛选了这2700个必要基因，通过在动物成年后启动基因敲低来延长成年寿命，从而绕过早期的发育作用。我们发现64个基因在发育后失活时可以延长寿命。我们发现的90%以上的基因从酵母到人类都是保守的。许多新发现的长寿基因与最具特征的长寿突变体一样，都能强有力地延长寿命。这些基因的同源物也可能调节其他生物体的寿命。遗传分析表明，这些基因中的一些处于胰岛素样信号调节的已知途径中，尽管许多这些基因失活独立于这种延长寿命的机制。令人惊讶的是，这些基因失活的一个子集诱导了强大的发育停滞，也促进了停滞状态下的生存，这表明任何阶段的衰老都可能受到调控控制。
Evolutionarily conserved mechanisms that control aging are predicted to have prereproductive functions in order to be subject to natural selection. Genes that are essential for growth and development are highly conserved in evolution, but their role in longevity has not previously been assessed. We screened 2,700 genes essential for Caenorhabditis elegans development and identified 64 genes that extend lifespan when inactivated postdevelopmentally. These candidate lifespan regulators are highly conserved from yeast to humans. Classification of the candidate lifespan regulators into functional groups identified the expected insulin and metabolic pathways but also revealed enrichment for translation, RNA, and chromatin factors. Many of these essential gene inactivations extend lifespan as much as the strongest known regulators of aging. Early gene inactivations of these essential genes caused growth arrest at larval stages, and some of these arrested animals live much longer than wild-type adults. daf-16 is required for the enhanced survival of arrested larvae, suggesting that the increased longevity is a physiological response to the essential gene inactivation. These results suggest that insulin-signaling pathways play a role in regulation of aging at any stage in life. The lifespan of an animal is determined by both environmental and genetic factors, and many of the mechanisms identified to increase lifespan are evolutionarily conserved across organisms. Previous longevity screens in C. elegans have identified over 100 genes, but ∼2,700 essential for normal development were excluded from analysis. Paradoxically, these essential genes are five times more likely to be highly conserved in phylogeny than genes with no obvious developmental phenotypes. We screened these 2,700 essential genes for increased adult lifespan by initiating the gene knockdown once the animal had reached adulthood, thus bypassing earlier developmental roles. We identified 64 genes that can extend lifespan when inactivated postdevelopmentally. More than 90% of the genes we identified are conserved from yeast to humans. Many of the newly identified longevity genes extend lifespan as robustly as the most well-characterized longevity mutants. It is possible that the homologues of these genes may also regulate lifespan in other organisms as well. Genetic analysis places some of these genes in known pathways regulated by insulin-like signaling, although many of these gene inactivations function independently of this mechanism of lifespan extension. Surprisingly, a subset of these gene inactivations that induce potent developmental arrest also facilitate enhanced survival in the arrested state, suggesting that aging at any stage may be subject to regulatory control.
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