Professor Manuel Mayr, King's College London
Professor Eli Keshet, The Hebrew University of Jerusalem
The cardiovascular system has long been recognised as key to health and longevity, with vascular ageing contributing to the development of cardiovascular diseases (CVDs) such as hypertension, atherosclerosis, ischemic heart disease and stroke, whose prevalence increases with age. Likewise, the regenerative capacity of the heart and its ability to cope with cellular damage is blunted with age. Finally, vascular ageing contributes to increased mortality associated with kidney, brain and pulmonary diseases. Insights on the mechanisms underlying natural vascular ageing might offer new approaches and therapeutic targets aimed at reducing the burden of CVDs in the elderly.
In this project, Professor Mayr and Professor Keshet’s project propose a novel anti-ageing ('geroprotection') approach to combat age-associated deterioration of vascular function. Given the multiple, critical roles of the vascular system in organ function, they propose that certain vascular manipulations create geroprotection involving multiple organs across multiple ageing-related conditions.
The large-scale study of proteins is known as ‘proteomics’ and relies on the use of mass spectrometers. Professor Mayr will harness proteomics techniques to determine protein changes occurring in the vascular system as a consequence of ageing. Isolated arteries will be used from young and old mice and from different mouse strains with healthy and atherosclerotic arteries. Analysis will be extended to available human arterial tissue obtained from subjects undergoing coronary artery bypass grafting. Also available for this project are plasma samples from community-based studies with up to 25 years of follow-up and detailed vascular phenotyping to search for vascular biomarkers of biological rather than chronological age.
For vascular rejuvenation, a unique genetically-engineered mouse system was developed by Professor Keshet allowing for increasing the levels of circulating vascular endothelial growth factor. This growth factor is conducive for counteracting progressive vascular rarefaction. Anticipated anti-ageing outcomes are monitored using the respective organ-specific established methodologies and functional readouts. To enhance potential translatability and for circumventing a need for transgenic mice, modalities for increasing target levels of circulating vascular endothelial growth factor will be examined.
While current anti-ageing approaches are based on targeting particular ageing-associated processes, The researchers believe that their approach is likely to provide new geroprotective targets. They aim to gain novel insights into vascular ageing and use this knowledge for the development of new anti-ageing treatments.
Professor Myer’s team will be focusing on the underlying mechanisms of vascular ageing and the discovery of biomarkers of biological age, while the Professor Keshet’s team will be focusing on the vascular rejuvenation as a new approach for promoting healthy ageing. The UK team’s rejuvenated arteries will be included in longitudinal analyses of arterial ECMs and, reciprocally, the Israeli team’s the studies will be informed by the advanced proteomic and metabolomics analyses.