Life-span-dependent transcriptional dynamics of the human heart.

The human heart undergoes continuous transcriptional remodeling from development through aging, yet the cellular and regulatory features governing this process remain incompletely defined. Here, we generated a single-nucleus RNA sequencing atlas of 442,239 nuclei from 54 nonfailing myocardial tissues of 29 individuals spanning development, adulthood, and aging, covering left and right ventricles. Across all major cell types, we uncovered coordinated yet cell type-specific transcriptional trajectories that converge on progressive loss of gene expression homeostasis, stress responses, and inflammatory signaling over the life span. Cardiomyocytes displayed distinct age-associated transcriptional states enriched for senescence- and disease-related signatures. Regulatory network analysis identified PRDM16 as a transcriptional regulator whose activity declined with age in cardiomyocytes. Functional perturbation of PRDM16 in human cardiomyocyte models induced senescence, metabolic dysfunction, and stress responses, whereas its rebalancing in aged mouse hearts improved cardiac function and partially reversed aging-associated transcriptional programs. Last, leveraging life-span-resolved single-nucleus data, we constructed cardiac transcriptomic age prediction models that closely tracked chronological age in nonfailing hearts and revealed deviations consistent with accelerated aging in cardiomyopathies. Together, this study provides a comprehensive single-nucleus resource of the human heart across the life span and delineates cellular and regulatory features associated with cardiac aging.