Periodic Reporting for period 2 - MediHealth (Novel natural products for healthy ageing from Mediterranean diet and food plants of other global sources) Reporting period: 2018-01-01 to 2019-12-31 Summary of the context and overall objectives of the project Current demographic trends suggest a rapid increase in the percentage of elderly people in all European countries for the next 50 years. Increasing life expectancy of the general population bears the inherent risk of an increase of physical and mental impairments as well as of age-related diseases (e.g. cancer, neurodegeneration, metabolic complications etc.), posing a large and ever-growing burden on our societies if we fail to develop appropriate counteracting strategies. According to the WHO, by 2040, the global population aged 65 and over is estimated to reach 1.3 billion (14% of the total population). Consequently, the prevalence of age-related diseases will significantly increase. In this situation, the concept of healthy ageing, i.e. a strategy that allows people to grow old in good health, becomes very important.Numerous studies show that nutritional plant-derived compounds are involved in several physiological processes and possess significant beneficial effects on human health. Dietary plants, as medicinal plants, contain natural products that demonstrate powerful antioxidant properties and various biological activities. However, even if the beneficial effects of healthy eating are greatly recognized and globally acknowledged, the majority of food plants which comprise the ingredients of the most established dietary patterns haven’t been investigated in depth and consequently the active constituents remain unknown.MediHealth incorporated new technologies and methods in natural products discovery and isolation in order to discover natural entities from Mediterranean and global dietary plants, promoting healthy ageing. The final goal of the MediHealth project was to bring to the stage of development a novel nutraceutical product based on scientific evidences. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far To achieve this goal, a series of more than 30 plant species with potential healthy ageing effects was carefully selected from the Mediterranean diet as well as food plants from Africa, Asia and South America. The plants were collected, extracted and chemically characterized. Based on their chemical composition and literature data, the 10 most promising ones were selected and subjected to a comprehensive research platform including innovative cell, fly and mouse models for antioxidant effects and the development of age related diseases as well as metabolism assessment. Specifically, a three-pronged approach to identify novel agents able to reduce ageing associated diseases and to improve health span was applied: i) The 10 selected plant extracts were tested for potential health benefits in in vivo experiments in mice and flies. Mice were fed with extracts of the selected plants and markers for the development of age associated metabolic disorders such as diabetes type 2, dyslipidemia and cardiovascular diseases were analyzed. In addition, it was investigated if the plant extracts can protect the Drosophila flies from oxidative modifications. ii) In parallel, the plant extracts were also forwarded to analysis in newly established cellular assays to determine their effects on the development of age related diseases (e.g. cellular diabetes models).iii) In addition to the cell, fly and mouse models, the extracts were subjected to metabolization studies since plant extracts do not reach human tissues in their native form in most cases. In particular, biotransformation assays were applied to mimic the metabolism of compounds in the human body, including simulation of gastric and intestinal physiological conditions, microbial fermentation in the colon and enzymatic conversions in the liver. Based on the results of these three parallel research lines, hit plants were selected for the phytochemical analysis and isolation of their bioactive chemical constituents. Advanced analytical techniques were used for the identification and characterization of the isolated natural products. Pharmacological profiling of bioactive natural products was carried out. The identified active molecules were also subjected to in silico methods to get better insight into possible mechanism of action. This was complemented by the synthesis of selected bioactive compounds and their derivatives to investigate qualitative and quantitative aspects of the observed bioactivity. Metabolomics approaches were applied to the hit extracts in order to identify the optimal sources for the procurement of the plants of interest. Finally, the two most promising extracts (lead extracts) were selected and subjected to process optimization studies to proceed to the development of an innovative nutraceutical product. To achieve the optimal procedure for natural product procurement, optimization of extraction focusing on “green” extraction techniques and up-scaling procedures were applied. A pilot scale production of the lead extracts was developed and pre-formulation and stability studies were performed. Finally, to carry the lead extracts to the stage of development, feasibility studies were conducted.This approach was unique and able to offer important and valuable results that facilitated and substantiated the development of an agent that is safe, characterized and exhibits specific biological activity against age related oxidative stress and metabolic disorders.The results of the project were disseminated to other scientists outside the consortium and to the general public. In particular, scientific achievements of the project were disseminated to the scientific community through the presentation of the results at scientific meetings and the publication of articles in international scientific journals. Moreover, outreach activities such as workshops, a winter school and other special events were organized for the dissemination of the scientific information and for the benefit of public awareness. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The MediHealth project was based on a strong consortium of European academic and industrial partners together with research groups from South Africa, Tunisia, Chile and Vietnam, widely recognized individually as leaders in the respective research areas. A crucial aspect of the project was the production and exchange of scientific and technical knowledge between the consortium partners as well as broad training of the involved personnel. Science-based collaborations between industry and academia offered advantages to both entities and means by which academic institutions and industry could address global challenges to their mutual benefit and the well-being of society. The project empowered each partner with elements of potential growth through shared experiences and catalyzed the transfer of ideas, new technologies and personnel among the participating members. It strengthened scientific excellence in the field of natural products research and development and increased the competitiveness and visibility of the involved partners. Therefore, in addition to its potentially very high impact on the health of the European population, in particular for elderly citizens, the MediHealth project significantly increased the research quality and overall R&I capability and competitiveness of all implicated partners and contributed to the enhancement of the competitiveness of the European industries in the area of nutraceuticals and dietary supplements. Moreover, both academic researchers and industrial partners’ scientific and technical personnel improved their career prospects by adding entrepreneurial skills to scientific expertise.