Heart failure with preserved ejection fraction (HFpEF) is the most rapidly increasing form of heart failure in the Western world. Despite high public-health importance, no treatment strategy has yet been established to reduce morbidity and mortality. MINOTAUR is a multidisciplinary consortium of cardiologists, cardiac surgeons, systems biologists, biophysicists, biochemists and physiologists aimed at expanding our original observations that a natural caloric restriction mimetic (CRM) improves diastolic function in two different animal models with independent HFpEF risk factors, namely age and hypertension. To investigate the broader applicability of CRM treatment and its translational potential, we will extend our investigations to an animal model of HFpEF induced by metabolic syndrome, the most prevalent cause and comorbidity of HFpEF. We will concentrate our efforts on the mechanistic details by which CRMs counteract the development of HFpEF with metabolic dysfunction. Using a wide range of state-of-the-art techniques, we will provide a comprehensive in-depth characterisation of the CRM-treated HFpEF cardiac phenotype at the molecular, cellular and whole organism level, and considering the gender aspect. Gender-based correlation analysis of key biochemical parameters (polyamine levels and post-translational modification of titin) and diastolic dysfunction in humans will reveal new diagnostic and prognostic tools in HFpEF. This novel information will feed future clinical trials to evaluate the potential of CRM-rich diets as an effective therapy for managing HFpEF.