Truscott Roger J W
Australian Cataract Research Foundation, University of Wollongong, Northfields Ave, Wollongong, NSW 2522, Australia.
Exp Eye Res. 2005 May;80(5):709-25. doi: 10.1016/j.exer.2004.12.007.
Age is by far the biggest risk factor for cataract, and it is sometimes assumed that cataract is simply an amplification of this aging process. This appears not to be the case, since the lens changes associated with aging and cataract are distinct. Oxidation is the hallmark of age-related nuclear (ARN) cataract. Loss of protein sulfhydryl groups, and the oxidation of methionine residues, are progressive and increase as the cataract worsens until >90% of cysteine and half the methionine residues are oxidised in the most advanced form. By contrast, there may be no significant oxidation of proteins in the centre of the lens with advancing age, even past age 80. The key factor in preventing oxidation seems to be the concentration of nuclear glutathione (GSH). Provided that nuclear GSH levels can be maintained above 2 mm, it appears that significant protein oxidation and posttranslational modification by reactive small molecules, such as ascorbate or UV filter degradation products, is not observed. Adequate coupling of the metabolically-active cortex, the source of antioxidants such as GSH, to the quiescent nucleus, is crucial especially since it would appear that the cortex remains viable in old lenses, and even possibly in ARN cataract lenses. Therefore it is vital to understand the reason for the onset of the lens barrier. This barrier, which becomes apparent in middle age, acts to impede the flow of small molecules between the cortex and the nucleus. The barrier, rather than nuclear compaction (which is not observed in human lenses), may contribute to the lowered concentration of GSH in the lens nucleus after middle age. By extending the residence time within the lens centre, the barrier also facilitates the decomposition of intrinsically unstable metabolites and may exacerbate the formation of H(2)O(2) in the nucleus. This hypothesis, which is based on the generation of reactive oxygen species and reactive molecules within the nucleus itself, shifts the focus away from theories for cataract that postulated a primary role for oxidants generated outside of the lens. Unfortunately, due to marked variability in the lenses of different species, there appears at present to be no ideal animal model system for studying human ARN cataract.
年龄是迄今为止白内障最大的风险因素，有时人们认为白内障仅仅是这种衰老过程的加剧。但事实似乎并非如此，因为与衰老和白内障相关的晶状体变化是不同的。氧化是年龄相关性核性（ARN）白内障的标志。蛋白质巯基的丧失以及甲硫氨酸残基的氧化是渐进性的，并且随着白内障病情加重而增加，直到在最严重的情况下超过90%的半胱氨酸和一半的甲硫氨酸残基被氧化。相比之下，随着年龄增长，即使超过80岁，晶状体中心的蛋白质可能也没有明显的氧化现象。防止氧化的关键因素似乎是核内谷胱甘肽（GSH）的浓度。只要核内GSH水平能够维持在2 mM以上，似乎就不会观察到明显的蛋白质氧化以及活性小分子（如抗坏血酸或紫外线过滤降解产物）引起的翻译后修饰。代谢活跃的皮质（如GSH等抗氧化剂的来源）与静止的核之间充分耦合至关重要，特别是因为在老晶状体甚至ARN白内障晶状体中皮质似乎仍然具有活力。因此，了解晶状体屏障出现的原因至关重要。这种在中年时变得明显的屏障会阻碍小分子在皮质和核之间的流动。该屏障而非核致密化（在人类晶状体中未观察到）可能导致中年后晶状体核中GSH浓度降低。通过延长在晶状体中心的停留时间，该屏障还会促进本质上不稳定的代谢产物的分解，并可能加剧核内过氧化氢的形成。这一基于核内自身产生活性氧和活性分子的假说，将研究重点从假定晶状体外部产生的氧化剂起主要作用的白内障理论上转移开。不幸的是，由于不同物种晶状体存在显著差异，目前似乎没有理想的动物模型系统来研究人类ARN白内障。
