Integrating modelling and experimental approaches to investigate adventitious age-related collagen crosslinking in skeletal tissues

随着年龄的增长，我们的肌腱、韧带和骨骼的功能开始下降，导致僵硬、活动能力下降和脆弱程度增加。在某些人身上，这种情况发生的程度如此之大，以至于他们遭受相当大的痛苦，无法进行日常活动，更不用说锻炼以保持良好的健康了。肌腱——连接肌肉和骨骼的软结缔组织——特别容易受到年龄变化的影响。众所周知，蛋白质，如构成肌腱主要抗力成分的胶原蛋白，很容易被血液中的糖修饰。在胶原蛋白中添加糖会导致相邻胶原蛋白分子之间形成交联。肌腱、韧带和骨骼由相同类型的胶原蛋白组成，因此很可能会形成相同的糖介导交联。虽然这些交联被认为对胶原蛋白的特性有不利影响，但众所周知，它们很难研究。蛋白质质谱分析、计算机建模研究和纳米尺度力学的最新进展，使得更详细地研究这些与年龄相关的蛋白质修饰成为可能。在我们的研究中，我们将量化和定位来自不同年龄个体的肌腱中重要的糖介导交联的水平，并将其与肌腱组织中胶原结构的机械性能和自我更新联系起来。此外，我们将研究韧带和骨组织，以确定是否存在类似的模式和水平的与年龄相关的交联，这表明不同骨组织的衰老具有共性。糖基化介导的交联可能会被饮食、运动和药理学因素所改变，这可能提供一种适当的干预方式，以减少正常衰老的影响以及身体虚弱和健康状况不佳的风险。这项研究的结果有很大的潜力，可以改善很大一部分人口的生活质量和老年幸福感。

As we age our tendons, ligaments and bones begin to function less well, resulting in stiffness, reduced mobility and increased frailty. In some individuals this occurs to such an extent that they suffer considerable pain and are unable to undertake daily activities, let alone exercise to maintain good health. Tendons - the soft connective tissues that connect muscles to bone - are particularly vulnerable to age related changes. It is well known that proteins, such as collagen that forms the main force-resisting component of tendon, are susceptible to modification by sugars in the blood. The addition of sugars to collagen results in cross-links forming between neighbouring collagen molecules. Tendon, ligament and bone are composed of the same type of collagen and therefore it is likely that the same sugar mediated crosslinks will form. Although these cross-links are recognised to have a detrimental effect on collagen properties, they have been notoriously difficult to study. Recent advances in mass spectrometry of proteins, computer modelling studies and nano-scale mechanics have made it possible to study these age-related modifications to proteins in much more detail. In our study we will quantify and locate levels of important sugar-mediated cross-links in tendons from individuals of different ages and link this to how the collagen structures perform mechanically and renew themselves within the tendon tissue. In addition, we will investigate ligament and bone tissue to determine whether a similar pattern and level of age related crosslinking is present suggesting commonality in ageing of different skeletal tissues. Glycation mediated cross-links are likely modified by diet, exercise and pharmacological agents and this may provide an opportune way of intervening to reduce the impact of normal ageing and risk of frailty and poor health. The findings of this study have great potential to improve the quality of life and wellbeing into old age in a large proportion of the population.