Relationship of electrophilic stress to aging.
Relationship of electrophilic stress to aging.
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DOI：
10.1016/j.freeradbiomed.2011.05.039
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发表时间：
2011-09-15
影响因子：
7.4
通讯作者：
Zirnniak, Piotr
中科院分区：
文献类型：
--
作者：
Zirnniak, Piotr
关键词：
本综述首先假定，生物体的寿命取决于两种抗衡力量之间的平衡：(I)破坏稳定效应的总和，以及(Ii)保护性寿命保证过程的总和。在此背景下，讨论了亲电体的作用，既作为不稳定因素，也作为诱导保护性反应的信号。因为大多数生物大分子都含有亲核中心，所以亲电物质在生物环境中尤其具有活性和毒性。大多数细胞亲电性是由多不饱和脂肪酸通过过氧化连锁反应产生的，该反应很容易被氧中心自由基触发，但在没有进一步输入活性氧物种(ROS)的情况下传播。因此，4-羟基-2-烯醛(4-HNE)等脂源性亲电体的形成被认为对启动ROS的水平相对不敏感，但主要取决于过氧化敏感脂肪酸的可用性。这与许多观察结果一致，即寿命与膜的过氧化能力呈负相关，并与4-HNE可能构成膜脂对过氧化的高敏感性与寿命缩短之间的机制联系的假设一致。直接改变膜成分(从而改变其过氧化能力)或调节4-HNE水平的实验干预措施对寿命有预期的影响，确立了这种联系不仅是相关的，而且是因果的。考虑了特定的分子机制，通过这些机制，4-HNE可以(I)通过与细胞大分子的非靶向反应来破坏生物系统的稳定，以及(Ii)调节控制长寿保证机制的信号通路。
This review begins with the premise that an organism's life span is determined by the balance between two countervailing forces: (i) the sum of destabilizing effects, and (ii) the sum of protective longevity-assurance processes. Against this backdrop, the role of electrophiles is discussed, both as destabilizing factors and as signals that induce protective responses. Because most biological macromolecules contain nucleophilic centers, electrophiles are particularly reactive and toxic in a biological context. The majority of cellular electrophiles are generated from polyunsaturated fatty acids by a peroxidation chain reaction that is readily triggered by oxygen-centered radicals, but propagates without further input of reactive oxygen species (ROS). Thus, the formation of lipid-derived electrophiles such as 4-hydroxynon-2-enal (4-HNE) is proposed to be relatively insensitive to the level of initiating ROS, but to depend mainly on the availability of peroxidation-susceptible fatty acids. This is consistent with numerous observations that life span is inversely correlated to membrane peroxidizability, and with the hypothesis that 4-HNE may constitute the mechanistic link between high susceptibility of membrane lipids to peroxidation and shortened life span. Experimental interventions that directly alter membrane composition (and thus their peroxidizability) or modulate 4-HNE levels have the expected effects on life span, establishing that the connection is not only correlative but causal. Specific molecular mechanisms are considered, by which 4-HNE could (i) destabilize biological systems via non-targeted reactions with cellular macromolecules, and (ii) modulate signaling pathways that control longevity assurance mechanisms.
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