Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling?
Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling?
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DOI：
10.1016/j.mad.2004.09.001
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发表时间：
2005-03-01
影响因子：
5.3
通讯作者：
McElwee, JJ
中科院分区：
文献类型：
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作者：
Gems, D;McElwee, JJ
我们最近对秀丽隐杆线虫中胰岛素/IGF-1 信号 (IIS) 调节的基因进行的调查表明，许多基因类别在长寿保证中发挥着作用。基于这些发现，我们提出了一个长寿保证和衰老的生物化学模型，如下。衰老是由高度多样化的内生毒素造成的分子损伤造成的。这些是不同代谢过程的随机副产品，活性氧 (ROS) 可能只是其中的一种成分。我们的微阵列分析表明，涉及细胞色素 P450 (CYP)、短链脱氢酶/还原酶 (SDR) 和 UDP-葡萄糖醛酸基转移酶 (UGT) 的酶在 1 期、2 期解毒系统的长寿保证中发挥着重要作用。与超氧化物和过氧化氢解毒不同，该系统的能量消耗很大，并且需要将其产物从细胞中排出。考虑到这样的成本，它的活性可能会被选择反对，正如一次性体体理论所预测的那样。 CYP 和 UGT 酶以亲脂性分子种类为目标；该系统活性不足与衰老过程中年龄色素（脂褐质）的积累一致。我们认为，IIS 调节的长寿保证涉及：(a) 耗费大量精力的分子垃圾解毒和排泄，以及 (b) 通过分子伴侣保护现有蛋白质。鉴于该理论强调对细胞废物处理和蛋白质保护的投资，我们将其称为绿色理论。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
Our recent survey of genes regulated by insulin/IGF-1 signaling (IIS) in Caenorhabditis elegans suggests a role for a number of gene classes in longevity assurance. Based on these findings, we propose a model for the biochemistry of longevity assurance and ageing, which is as follows. Ageing results from molecular damage from highly diverse endobiotic toxins. These are stochastic by-products of diverse metabolic processes, of which reactive oxygen species (ROS) are likely to be only one component. Our microarray analysis suggests a major role in longevity assurance of the phase 1, phase 2 detoxification system involving cytochrome P450 (CYP), short-chain dehydrogenase/ reductase (SDR) and UDP-glucuronosyltransferase (UGT) enzymes. Unlike superoxide and hydrogen peroxide detoxification, this system is energetically costly, and requires the excretion from the cell of its products. Given such costs, its activity may be selected against, as predicted by the disposable soma theory. CYP and UGT enzymes target lipophilic molecular species; insufficient activity of this system is consistent with age-pigment (lipofuscin) accumulation during ageing. We suggest that IIS-regulated longevity assurance involves: (a) energetically costly detoxification and excretion of molecular rubbish, and (b) conservation of existing proteins via molecular chaperones. Given the emphasis in this theory on investment in cellular waste disposal, and on protein conservation, we have dubbed it the green theory. (C) 2004 Elsevier Ireland Ltd. All rights reserved.