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

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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.