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Targeting the elastic tissues ageing to improve the quality of ageing

Final Report Summary - ELAST-AGE (Targeting the elastic tissues ageing to improve the quality of ageing)

The complex features of ageing are far from being understood. Ageing is accompanied by several 'age-associated' diseases, most of them involving a tissue disorganisation of organs and their tissues environment. One of the most apparent manifestations of ageing is the loss of tissue elasticity, with its obvious consequences for skin elasticity, and though more difficult to appreciate, for breathing or for the regulation of pulse pressure and, consequently, cardiac function.

Elastic fibres synthesis occurs during development and early adult growth, but is scarce in adults where it is often associated to the formation of non functional elastic fibres and pathology. In human, age-related dysfunction of elastic tissue is associated with arteriosclerosis, aneurysms, hypertension, varicose veins, skin wrinkles, hernia, lung emphysema, degeneration of inter-vertebral disc, ligaments or tendons, macula degeneration or glaucoma. Furthermore, the lack of elastic fibres formation explains the poor skin repair for severe burns or hernias; while the pathologic accumulation of amyloid-like elastin deposit is a classical manifestation of solar elastosis. Therefore, ageing of elastic tissues is related to general ageing and is considered as a factor amplifying the ageing processes.

The mechanisms that govern correct elastogenesis are still unknown. However, the previous decade of fundamental research has largely contributed to a better understanding of the composition and assembly of elastic fibres. Besides the determination of about 30 components that built up the elastic fibres, several genes defective in inherited disorders of the elastic fibres have been identified, such as for the Marfan syndrome, Cutis laxa, Pseudoxanthoma elasticum, or more recently the exfoliation glaucoma. This has leaded, very recently, to propose a therapy for children displaying the Marfan syndrome through the use of anti-hypertension drugs that target some side effects of the imperfect elastogenesis associated to this syndrome.

In this context of very active and exciting research, several European teams have coordinated their efforts to find 'positive modulators' for elastic tissue ageing. The goal of their project is to target the ageing of elastic tissue to cope with ageing, or at least some manifestations of ageing. The ELASTAGE project has been supported by the European Community through the Sixth Framework Programme (FP6). The project brought together 12 participants with complementary expertise from 6 different countries, including basic scientists, clinicians, one large enterprise and two small enterprises. Ethical, gender and standardisation aspects are also included. Collaborations throughout Europe or worldwide have expanded this network, while participants of the consortium are the main organisers of the biannual Elastin European conference.

The originality of ELASTAGE lies in the coordination of strategies for:
(i) the development of molecules that could protect or delay degradation of elastic fibres or aged-dependent modifications and
(ii) for the discovery of active compounds that could induce functional elastic fibre synthesis in adults. The expected impacts should be a breakthrough on skin and vessel ageing treatments with a special interest with the improvement of chronic vein insufficiency and, longer term, other disorders of joints, arteries and macula and the improvement of healing.

The research made by the different partners was focused on understanding the elastic fibres life, from their formation to degradation, in vitro, ex vitro and in vivo. One objective realised by the consortium was to define how elastic fibres assemble and the main sites of elastic fibres degradation. This is particularly helpful for identifying protective molecules that could limit the degradation of elastic fibres. These molecules are chemically close to the heparin structure or from extracellular matrix proteins.

This project has given further insights on the life of elastic tissues: the way they assemble, the way they are degraded, the basis of there biomechanical properties. This knowledge is still essential to appreciate the unique elastic properties of those fibres, and there evolution throughout the life.

This program highlighted markers of aging and aging of elastic tissues in cell models. These markers will be useful for further research aiming to understand what is missing in adult cells and tissues that is present in developing and young elastic tissues. The DNA 'Elastarray' should be available soon, once completely validated with the different models used by the consortium.

These data highlighted the complexity of elastic fibres formation in tissue culture models. Different ways have been proposed that positively affect the engineering of elastic tissues. This knowledge and practical propositions will be spread to the international community, in order to improve the biomechanical properties of biomaterials. One activated collagen scaffold has been patented and available soon on the market, the 'activated' form enriched with heparansulphate is going to be ready soon. Elastin derived sequences should be further investigated for their potential applications in tissue engineering.

It is hard to define one unique model of aging. They all display specific characteristics of aging, i.e. the loss of elastic fibres. The investigation of tissue samples using NIR-LSM technology will be of great interest for the community. These tools are now ready to be shared. They would be very interesting to test substances that could delay and treat some manifestations of aging.

Dill extract was efficient in re-inducing elastogenesis on skin fibroblasts from adult donors. Therefore, the dill extract has been launched on the cosmetic market by one company of the consortium. It might also be relevant to counterbalance the decrease of other elastic tissues during aging, through epigenetic mechanisms. While antioxidant strategies could be helpful as complements to limit the bad evolution of elastic tissue during ageing.

In summary, ELASTAGE granted by the European Community, has been successful in bringing to life innovative markers, models, procedures and reagents that could be useful for the maintenance of the elastic properties of the body while ageing or for bioengineering. Several paths have been explored and many data have been collected, that will contribute to a better understanding of elastic tissues, from their formation, in vitro and in vivo, to their ageing. Some programs should be continued, either as singular research programs related to elastic tissue, or as merged to other broader programs.

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