Aging is a priority for health systems in Western countries, particularly because of its link to chronic diseases such as heart failure. The present research project aims to explore the molecular mechanisms of chronic inflammation in heart failure during aging, with a focus on preserved ejection fraction decompensation (HFpEF), a phenotype highly prevalent in the elderly. The study takes a multidisciplinary approach involving clinicians, cardiologists, biologists, and bioinformaticians, leveraging innovative Network Medicine methodologies and integrating clinical, epigenomic, proteomic, and environmental lifestyle data. The main objective is to conduct a large-scale epigenome-wide association study (EWAS) to analyze DNA methylation changes in circulating CD4+ and CD8+ T cells from the healthy young subject to the elderly with HFpEF. The identification of epigenetic markers associated with risk factors and diseases may clarify the role of epigenetic regulation in pathophysiology and open new perspectives for prevention, diagnosis, and treatment strategies. Methylomes will be analyzed within a Network Medicine framework, with construction of an inflammasome-focused interactome and integration with targeted proteomics based on 96 validated inflammatory biomarkers. Antigenic phenotyping will complement the epigenomic analysis, allowing the identification of epigenetically sensitive pro-inflammatory biomarkers throughout the developmental pathway to HFpEF. A secondary goal is the development of a simple and scalable panel of epigenetic biomarkers for early identification of decompensation in the elderly, potentially applicable directly at the patient's bedside for personalized risk stratification. The project also has social relevance, promoting awareness of healthy aging among the elderly population.
10 October 2024 – 28 February 2025
In its initial phase, the EPI-GERAS project – Epigenetics-sensitive biomarkers of inflammaging from healthy to heart failure disease (Spoke 2 Age-It) – launched WP4 activities (Omics approaches to ageing), defining the study design based on three groups of participants (A: healthy young adults aged 18–35, B: healthy elderly people >65 years old, C: elderly people >65 years old with HFpEF diagnosed according to ESC 2021 criteria, with possible stratification by severity and comorbidity). Enrolment has begun in collaboration with cardiology and geriatric centres (AORN “Ospedali dei Colli”), with the collection of the first peripheral blood samples for the isolation of CD4+ and CD8+ T cells, intended for DNA methylation (EWAS) and targeted proteomics (96 inflammatory biomarkers) analyses. Clinical screening protocols, sample collection and storage, inclusion/exclusion criteria and risk mitigation (operator training, procedure standardisation, cohort monitoring) have been defined. Two related studies on epigenetic markers in heart failure have been published in Int J Mol Sci (2025) and Basic Res Cardiol (2025), providing initial evidence for the project. The next steps include expanding the cohort, completing enrolment, configuring the bioinformatics platform for the integration of clinical, multi-omic and environmental data, and initiating epigenomic and proteomic analyses aimed at identifying sensitive biomarkers of inflammaging useful for the early stratification of HFpEF risk in the elderly.
WP4 is in the methodological preparation phase (SCENITH, miRNA primers, phospho-flow) for future analyses on subgroups with different healthy ageing trajectories. WP5 is planned for the second half of the project (patient experience, cost-benefit analysis). The main critical issues (delayed start and stop of reagent purchases) have postponed laboratory analyses, but recruitment and PA programmes are active, with a recovery plan in the next phases.