Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease
Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease
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DOI：
10.1023/a:1015677828407
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发表时间：
2002-05-01
影响因子：
4.2
通讯作者：
Link, C
中科院分区：
文献类型：
--
作者：
Johnson, TE;Henderson, S;Link, C
在秀丽隐杆线虫中，已有40多种单基因突变体被证明可使寿命延长20%或更多（这是判定为长寿基因的一种严格的操作性测试）；这些统称为“Age”突变体。Age突变体必定改变了作为寿命关键限速决定因素的关键功能；此外，重要基因可独立于关于基因在延长寿命和/或“减缓”衰老的实际作用模式的先验假设而被鉴定出来。这些Age突变体根据主要表型定义了多达九种（可能的）不同的途径和/或作用模式。三种研究充分的突变体（age - 1、clk - 1和spe - 26）中的每一种都以其独特的方式改变年龄特异性死亡率。在age - 1突变体中，死亡率的降低非常显著，在生命的大部分时间里死亡率几乎下降了十倍。所有的Age突变体（到目前为止无一例外）都增强了线虫对几种（但不是所有）应激的反应能力，包括热、紫外线和活性氧化剂。我们使用了定向策略以及随机诱变来鉴定能增强线虫抗应激能力的新基因。两个基因（daf - 16和old - 1）对大多数突变体的长寿表型具有上位性，并且还产生了抗应激且长寿的过表达菌株。我们还使用了多种方法来确定哪些转录改变与寿命延长（以及衰老本身）相关，包括使用微阵列和绿色荧光蛋白报告基因构建体进行的全基因组表达研究。我们认为，Age基因在寿命和抗应激方面的作用表明，寿命的一个主要进化决定因素是对应激的反应能力。在哺乳动物中，饮食限制和毒物兴奋效应都是内源性抗应激水平被上调的现象；这两种干预措施都延长了寿命，表明可能存在进化上的保守性。
More than 40 single-gene mutants in Caenorhabditis elegans have been demonstrated to lead to increased lifespan (a rigorous, operational test for being a gerontogene) of 20% or more; these are referred to collectively as 'Age' mutants. Age mutants must change key functions that are rate-limiting determinants of longevity; moreover, important genes can be identified independently of prior hypotheses as to actual mode of gene action in extending longevity and/or 'slowing' of ageing. These Age mutants define as many as nine (possibly) distinct pathways and/or modes of action, as defined by primary phenotype. Each of three well-studied mutants (age-1, clk-1, and spe-26) alters age-specific mortality rates in a fashion unique to itself. In age-1 mutants, the decreases in mortality rates are quite dramatic, with an almost tenfold drop in mortality throughout most of life. All Age mutants (so far without exception) increase the ability of the worm to respond to several (but not all) stresses, including heat, UV, and reactive oxidants. We have used directed strategies as well as random mutagenesis to identify novel genes that increase the worm's ability to resist stress. Two genes (daf-16 and old-1) are epistatic to the long-life phenotype of most mutants and also yield over-expression strains that are stress-resistant and long-lived. We have also used a variety of approaches to determine what transcriptional alterations are associated with increased longevity (and with ageing itself), including whole-genome expression studies using microarrays and GFP reporter constructs. We suggest that the role of the Age genes in both longevity and stress resistance indicates that a major evolutionary determinant of longevity is the ability to respond to stress. In mammals, both dietary restriction and hormesis are phenomena in which the endogenous level of resistance to stress has been upregulated; both of these interventions extend longevity, suggesting possible evolutionary conservation.