The ageing heart: exploring new markers of ageing and investigating new treatment options

• Applicant: Dr. Daniel Reichart
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528598067

For decades, the life expectancy worldwide has increased steadily. Currently, every second German citizen is older than 45 and every fifth above 66 – with upward tendency. At the same time, ageing also poses the significant risk for chronic diseases such as cancer, neurodegenerative or cardiovascular diseases, the latter being the most common. At molecular level, the ageing process of the heart is driven by an imbalance of harmful (e.g. DNA or epigenetic changes, cellular senescence) and reparative mechanisms, resulting in a gradual loss of cellular resilience and integrity. This may lead to an increased vulnerability to heart diseases with subsequent cardiac dysfunction. Despite of the same chronological age of two individuals, the ageing of these two can proceed at different speeds due to the heterogeneous expression of molecular ageing processes; thus, two different biological ages will result. With single cell RNA sequencing, the gene expression patterns of individual cells can be measured, which allows the heterogeneity of the cell types of a heart to be characterized with high sensitivity. In order to be able to pick up all heart cell types of different sizes (especially the cardiomyocytes), the cell nucleus will be extracted before single cell measurement (“single nucleus RNA sequencing”, snRNA-seq). With the help of snRNA-seq, first the healthy and later the diseased human heart was mapped at single cell resolution. In diseased hearts with systolic dysfunction, cardiomyocytes were found decreased and a secretory phenotype of fibroblasts was increased, which promotes cardiac fibrosis development and "adverse cardiac remodeling". In addition to the RNA measurement – in single nuclei or directly in tissues – the simultaneous display of chromatin accessibility at single cell level is also possible, which allows additional insights into the epigenetic regulation. By combining these two modalities, the healthy, ageing human heart will be characterized at single-cell level in order to depict ageing-associated changes in i) cellular composition, ii) gene expression and iii) epigenetic patterns. This will help to filter molecular factors that lead to the heterogeneous rates of biological heart ageing; at the same time, common characteristics of the ageing and diseased heart will be determined. For this purpose, heart tissues from healthy donors will be used and sequenced at single cell level. The results will be correlated and validated with ageing wild-type mice. Molecular signals that trigger ageing-associated negative effects such as "adverse cardiac remodeling" will be identified and treated by "small interfering" RNAs (siRNAs) first in vitro and later in vivo.

• DFG Programme: Independent Junior Research Groups