From aging biology to cardiac biotechnology: emerging platforms for modeling cardiac aging

Figure 1. Integrating age, genetics, environment, and drug exposure through new approach methodologies to model cardiac pathophysiology and heterogeneity. New approach methodologies (NAMs) have the potential to allow a comprehensive understanding of cardiac aging and disease by integrating multiple axes — age (A), genetics (G), environment (E), and drug exposure (D). By combining hiPSC-derived cardiac constructs and advanced monitoring technologies, the NAMs framework provides a multidimensional view of how A×G×E×D interactions govern cardiac health and therapeutic response, driving innovation toward targeted, patient-specific interventions (precision medicine).

Figure 2. Advancing human cardiac modeling platforms from 2D cultures to complex 3D systems. Schematic overview of model platform progression. (A) 2D monoculture and coculture systems. (B) 3D microtissues enable multicellular organization. (C) Self-assembled organoids/organ-on-chip platforms. (D) Microphysiological systems (MPS) enhance physiological relevance with perfusion and multiorgan integration. (E) Panomic benchmarking (genomics, transcriptomics, proteomics, metabolomics) ensures model fidelity to human heart capturing A×G×E×D.

Figure 3. Modeling chronological and biological aging in NAMs. Chronological aging is modeled through long-term culture, allowing time-dependent accumulation of cellular and molecular changes, such as metabolic slowdown, proteostatic decline, and oxidative damage. In contrast, biological aging captures functional decline, induced through stressors, such as telomere shortening, oxidative or mechanical stress, and nuclear lamina alterations. Moreover, biological aging can also be induced by culturing hiPSCs from aged donors, on aged ECM or serum/plasma exposure from older or diseased individuals. These approaches mimic intrinsic and extrinsic damage seen in aging tissue. Together, these complementary strategies reproduce the molecular, metabolic, and structural hallmarks of cardiac aging, enabling investigation of mechanisms driving age-associated cardiac dysfunction and disease susceptibility.

Figure 4. Functional features of cardiac NAMs for high-resolution and long-term functional assessment. (A) Capture high spatial resolution. Bioengineered devices should be designed to enable high-spatial-resolution mapping of electrical activity, allowing precise visualization of conduction pathways, signal propagation, and local heterogeneity within cardiac tissues. (B) Maintain native cell-cell communication. Integrated mesh electrodes can be embedded within the cardiac microtissues to maintain native cell-cell junctions and tissue architecture, ensuring physiological signal transmission and mechanical integrity. (C) Chronic monitoring. Systems designed for chronic monitoring can enable continuous measurement of conduction velocity, contractile force, and beat rate over extended culture periods spanning several months. (D) Device functionality. Platforms that allow dynamic mechanical stimulation, including cyclic contraction and stretching, which closely mimics the mechanical environment of the native myocardium and promotes tissue maturation would enable a highly rigorous and reproducible NAM. Combined with integrated sensors and electrodes, these devices can provide a noninvasive,…