Transcriptional Reprogramming of Senescent Human Cardiomyocytes by Cardiometabolic and Geroprotective Compounds

Introduction: Cellular senescence is a fundamental hallmark of aging and a critical driver of cardiometabolic disease progression. In cardiomyocytes, senescence is characterized by stable cell-cycle arrest, chromatin remodeling, mitochondrial dysfunction, and acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP). Although multiple cardiometabolic and geroprotective compounds are clinically used or experimentally proposed, their capacity to transcriptionally modulate senescent cardiomyocytes remains insufficiently defined. This study aimed to systematically evaluate how diverse pharmacological interventions remodel the transcriptome of senescent human pluripotent stem cell–derived cardiomyocytes and to quantify their potential to reverse a defined senescence gene expression signature. Methodology: Senescent cardiomyocytes (K-cardiom-sen) were treated with IGF-1, insulin, glucagon, metformin, rapamycin, bisoprolol, dasatinib, and quercetin at three concentrations each. RNA sequencing was performed, and differential gene expression was calculated relative to untreated senescent controls using DESeq2. A senescence transcriptional signature was derived from senescent versus non-senescent cardiomyocytes. Treatment-induced log2 fold changes were integrated with this signature to calculate a senescence-reversal score based on Spearman correlation with the inverse senescence profile. Differential expression thresholds were defined as adjusted p-value