An interferon gamma response signature links myocardial aging and immunosenescence. An interferon gamma response signature links myocardial aging and immunosenescence

Aging entails profound immunological transformations that can negatively impact the myocardial biology and predispose to myocardial diseases. However, preclinical research in the immune-cardiology field is mostly conducted in young healthy animals, which potentially weakens its translational relevance. Herein, we sought to investigate how the aging T-cell compartment impacts myocardial cell biology in elderly. By investigating the paired-wised age-related shifts in the heart and its draining lymph nodes, our study provides evidence for an increased myocardial IFN-gamma signaling, which is associated with inflammatory and metabolic shifts typically seen in heart failure (HF). Overall design: We phenotyped the antigen-experienced CD44high T cells purified from heart-draining lymph nodes of 2, 6, 12, and 18-months old C57BL/6 mice using single-cell RNA / T-cell receptor (TCR) sequencing (sc-seq). Simultaneously, we profiled all non-cardiomyocyte cell subsets purified from 2- and 18-months old hearts and integrated our data with publicly available cardiomyocyte sc-seq datasets. With aging, the heart-draining lymph node and myocardial T cells underwent spontaneous clonal expansion and exhibited an up-regulated pro-inflammatory transcription signature, marked by an increased interferon-g (IFN-g) production. In parallel, all major myocardial cell populations showed an increased IFN-g responsive signature with aging. In the aged cardiomyocytes, a stronger IFN-g response signature was paralleled by dampening of expression levels of transcripts related to most metabolic pathways, especially oxidative phosphorylation. Likewise, induced pluripotent stem cells-derived cardiomyocytes (iPSC-CM) exposed to chronic low grade IFN-g treatment showed a similar inhibition of metabolic activity.