Microelements in Life Expectancy and Aging

Periodic Reporting for period 2 - MILEAGE (Microelements in Life Expectancy and Aging)

Berichtszeitraum: 2019-05-01 bis 2023-08-31

For the past century, and particularly over the past few decades, life expectancy increased significantly and according to the World Health Organisation it continues growing at fast rate of about 6% in 20 years, with suggestions that it may reach 100 years this century. This is attributed to advances in healthcare, better nutrition and lifestyle changes. Increased longevity, with a high quality of life, is desirable not only for personal life satisfaction but also for reducing healthcare costs and for increasing socioeconomic contributions of individuals in countries with ageing population demographics, including Europe. Adequate nutrition plays a key role in maintaining cellular functions within normal limits. Microelements such as zinc (Zn) and copper (Cu) are essential for life and are involved in normal functioning of the human body. Our body tissues consist of cells and, through the functioning of channels and transporters, influx and efflux of Zn and Cu are tightly controlled.

At a molecular level, Zn and Cu play structural, regulatory and catalytic roles in thousands of proteins. Zn in cells protects against oxidation by controlling the production of reducing agents and stabilising molecules that contain oxygen-reactive groups. Cu can exist in both oxidised and reduced forms. In living cells, Cu can also participate in unwanted redox reactions, generating harmful free radicals. Damage caused by over-oxidation is difficult for cells to counteract and repair and so damage is cumulative over time. This process at a whole-body level contributes to ageing but at a cellular level accelerates senescence.

The mechanisms responsible for dysregulation of these metals require thorough investigation from molecules to the whole body. However, despite the importance of a holistic approach to this subject, such studies are limited. The MILEAGE Project aimed to understand the molecular mechanisms by which ageing affects Zn and Cu absorption and excretion, and also their functional roles. The specific objectives targeted age-related alterations in homeostasis and control of these metals on multiple levels, from gut microbiota to groups of volunteers and patients, while testing the expression of genes and the function of proteins. In accordance with the RISE action of intensive scientific exchange, the Project provided extensive multifactorial training to researchers from organizations in different countries and promoted the acquisition of unique experience and knowledge.

The MILEAGE Project Consortium was composed of four Beneficiaries (Bens) and 2 Partner Organizations (POs). The Bens were located in Europe, with two academic teams from France one from the UK and one small chemical enterprise in Ukraine. The proximity of the Bens allowed efficient and rapid coordination of collaborative efforts. The two POs, (Uni. of West Indies, Jamaica and Uni. of Chile, Santiago), added their unique experience to the Consortium and helped their young researchers to acquire new skills and knowledge in different institutions. The activities through research and exchange of ideas generated novel and important data at all levels and resulted in the development of new research technologies, the acquisition of new knowledge relevant to mechanisms of Zn and Cu homeostasis regulation in aging cells, and provided a foundation for the development of novel biomarkers.

The principal results from this mobility research project include:
• The validation of a fruit fly model to investigate metal absorption interactions, showing that gut Zn and Cu levels change with age.
• The validation of a novel method to investigate the movement of metals through gut cells, facilitating the discovery of drugs to modulate metal transfer.
• The identification of novel compounds which can be used to modulate Zn and Cu transport in cells.
• The indirect detection of a factor in human blood that is produced in response to low dietary zinc intake, and which may be an important biomarker of human Zn deficiency.
• The demonstration of a beneficial role for Cu in vascular muscle cells, preserving their physiological function, alleviating indicators of pathology and stabilising atherosclerotic plaque. Cu supplementation should be considered for individuals having a high risk of CVDs.

The results are being disseminated to scientists through publications and the SME will benefit from access by third parties to the compound database and sale of the novel active compounds.

Using cutting-edge technology, the MILEAGE Project presents original novel data to understand the molecular processes of zinc and copper homeostasis at different levels, from intramolecular interactions between key proteins to beneficial protocols for human health.

The manipulation of the human microbiota is already recognised as an important tool in promoting the maintenance of good health. This is now being extended to include the impact of microbiota on trace metal absorption.

To identify age-related changes in trace mineral transporters and channels, ion fluxes must be analysed in real-time in live cells, and thus a model system was linked to a sophisticated mass spectrometer for continuous monitoring of stable isotope transfer. This methodology also has potential for use in related fields of research, for example factors affecting the absorption of inorganic iron.

Synchrotron x-ray imaging was applied to visualize elements within the cells at a nanomolar levels and nanometre resolution, and genetic modifications of the key molecules helped to dissect molecular mechanisms determining zinc and copper homeostasis. The objective is to transfer the methodology into clinical and biotechnological settings where improvement of existing therapies and refinement of treatment will help prevent the deteriorating effects of ageing.

The dysregulation of these metals can lead to cardiovascular disorders, brain function deterioration and cancer, and so dietary requirements have been determined and recommendations of dietary advice and/or supplementation have been developed to improve longevity and the quality of life in a personalized manner based on individual genetic profiles. Evidence is presented that a blood factor causing blood vessel muscle cell death may be elevated in zinc-deficient humans, implying that low zinc status may be more harmful than previously recognised.

An objective of the Project was to design drugs that can modify the function of the channels and transporters that help the ions to enter cells. In silico protocols included protein modelling using genomic and proteomic databases, analysis of domain architecture and structure as well as phylogenetic trees, was followed by ligand retrieval and virtual screening. An extended list of candidate drugs was produced and is available for testing of new pharmaceuticals.

The Project results underline the importance of maintaining adequate body zinc and copper status and have profound implications for long-term human health and longevity, which in turn affects and underlines the importance of maintaining adequate body trace metal status. This Project has made a significant and measurable difference to the opportunities of many participants, especially young researchers, who received unique training and established an innovative foundation for their future careers.

Key gatekeeper cells for Zn and Cu metabolism, whose senescence may affect metal homeostasis

Periodic Reporting for period 2 - MILEAGE (Microelements in Life Expectancy and Aging)

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