Dietary polyphenols as modulators of redox signalling pathways to reduce chronic inflammation in the elderly

大量证据表明，食用富含水果和蔬菜的饮食有助于预防与年龄相关的疾病，包括一些癌症和心血管疾病，从而有助于保持健康。已经进行了许多研究，试图了解这些饮食对健康产生有益影响的机制。之前的许多研究发现，水果和蔬菜中潜在的保护性成分是“抗氧化剂”，人们认为这种抗氧化剂可以防止细胞和组织的普遍有害氧化，这种氧化会随着年龄的增长而增加。然而，尽管进行了广泛的研究，正式的试验表明，当“抗氧化剂”作为补充剂服用时，它们并没有任何有益的效果。近年来，人们也认识到，由高活性自由基介导的氧化过程不一定对细胞有害，但可能非常局限于细胞的亚细胞隔间，它们通常调节细胞内的信号传递过程，并调节许多关键的生理效应。因此，饮食中的“抗氧化剂”会清除细胞和组织中的所有氧化剂，从而产生益处的最初想法受到了质疑。在衰老过程中，由于细胞非常特定部分的氧化发生变化，高度调控的细胞信号通路被破坏，这导致有害物质的产生，这些物质促进炎症，增加老年人对许多慢性病的易感性。从国际上对健康老年人饮食的研究中可以清楚地看出，水果和蔬菜中发现的一组称为多酚的化合物对许多与年龄相关的疾病都有好处，但我们目前还不清楚它们是如何产生这些健康益处的。多酚最初被认为具有有益的效果，因为它们是“抗氧化剂”，我们的假设是，它们通过靶向细胞的特定部分来防止有益的细胞内信号通路的关键成分被氧化，从而防止慢性衰老相关疾病的发生。分析技术的新发展现在可以分析饮食多酚对关键亚细胞部位的局部氧化和细胞信号过程的潜在影响，拟议的研究将利用这些新技术。作为研究的一部分，我们将开发一种基于细胞培养的测试，以确定哪些特定的饮食多酚可以发挥有益的作用，并与老年受试者进行研究，以确定在细胞培养测试中被确定为有益的多酚是否可以减少炎症的标志。因此，该项目可能会导致：1)确定那些能将老年人的促炎状态降至最低的饮食多酚，从而为食品行业向公众提供合理和合理的理由来消费特定食物提供依据。2)鉴定可使促炎状态降至最低的多酚，并可为以维护和改善老年人健康为目标的富含多酚的食品的新配方提供基础。3)在较长期内，提供基础数据，从而导致基于饮食的免疫功能的改善和延缓老年人虚弱的出现。

A great deal of evidence indicates that consumption of diets rich in fruit and vegetables helps maintain health by protecting against age-related disorders including some cancers and cardiovascular diseases. Numerous studies have been undertaken to try and understand the mechanisms by which these diets exert beneficial effects on health. Many previous studies identified the potentially protective components of fruit and vegetables as 'antioxidants' that were thought to prevent a generalised unwanted oxidation of cells and tissues that increased with ageing. However, despite extensive studies, formal trials have shown no beneficial effect of 'antioxidants' when they are given as supplements. In recent years it has also become recognised that oxidation processes, mediated by highly reactive free radicals, are not necessarily deleterious to cells, but may be very localised within sub-cellular compartments of cells and that they normally regulate intracellular signalling processes and mediate many key physiological effects. Thus the original idea that 'antioxidants' in the diet act to scavenge all oxidants in cells and tissues and therefore produce benefit has been questioned. During ageing there is a breakdown of highly regulated cell signalling pathways due to changes in oxidation in very specific parts of cells and this leads to the production of deleterious substances that promote inflammation and which increase the susceptibility of the elderly to many chronic disorders. It is clear from internationally-based studies of diets consumed by healthier elderly populations that a group of compounds found in fruit and vegetables, called polyphenols are beneficial against many age-related disorders, but we currently do not understand how they act to produce these health benefits. Polyphenols were originally thought to have beneficial effects because they are 'antioxidants' and our hypothesis is that they are protective against chronic age-related disorders by targeting specific parts of the cell to prevent oxidation of key components of the beneficial intracellular signalling pathways. New developments in analytical techniques now permit analysis of the potential effects of dietary polyphenols on local oxidation and cell signalling processes at key sub-cellular sites and the proposed study will utilise these new techniques. As part of the study, we will develop a cell culture-based test to identify which specific dietary polyphenols can exert beneficial effects, and undertake studies with groups of elderly subjects to determine whether any polyphenols identified as beneficial in the cell culture test can reduce markers of inflammation. Thus the project will potentially lead: 1) to identification of those dietary polyphenols that act to minimise the pro-inflammatory state in the elderly and therefore provide a basis for the food industry to make logical and justified cases to the public for consumption of specific foods. 2) to identification of polyphenols that act to minimise the pro-inflammatory state and which may provide the basis for novel formulations of polyphenol-enriched food products that could be targeted at maintenance and imporvement of health in the elderly. 3) to provision, in the longer term, of the underpinning data that leads to a diet-based improvement in immune function and a delay in the onset of frailty in the elderly.