Study Maps Biological Aging of Heart and Lung System, Identifies Key Molecular Mechanisms
Researchers mapped cardiopulmonary aging across the adult mouse lifespan by integrating biomechanical measurements of the pulmonary artery, right ventricle, and lungs with single-cell gene expression data. They found that aging in this system is phase-dependent, with arterial stiffening progressing linearly while heart and lung changes follow non-linear trajectories. The findings suggest pulmonary arterial stiffening is not merely a marker of aging but an active driver of cardiopulmonary decline through interconnected biomechanical, metabolic, and inflammatory pathways.
A preprint study posted to bioRxiv used a multi-modal approach to characterize how the cardiopulmonary system ages in mice, combining ex vivo mechanical testing of the proximal pulmonary artery, in vivo echocardiography, lung mechanics measurements, and single-cell RNA sequencing. The researchers found that pulmonary artery circumferential stiffening and reduced distensibility increase largely linearly with age, while right ventricular remodeling and lung mechanical changes follow non-linear trajectories, suggesting an early phase of intrinsic cellular decline followed by later structural adaptation driven by external mechanical loads. To move beyond chronological age as a measure, the team derived physiology-based biological aging scores using principal component analysis applied to mechanical feature sets from each organ. Anchoring gene expression analysis to these biological aging scores rather than chronological age revealed 13,636 differentially expressed genes across cell types—a far richer signal than chronological age alone provided. Across endothelial cells, smooth muscle cells, fibroblasts, and perivascular macrophages, aging was associated with increased oxidative phosphorylation alongside suppression of protective pathways, including impaired endothelial mechanotransduction, reduced smooth muscle Wnt signaling, altered extracellular matrix remodeling, and erosion of macrophage immune signaling. The authors propose that pulmonary arterial stiffening creates a positive feedback loop of biomechanical, metabolic, and inflammatory dysfunction that progressively diminishes the cardiovascular system's adaptive reserve. The study identifies several mechanistic targets that could potentially be exploited to slow cardiopulmonary aging.
What's missing
The study was conducted entirely in mice, and the authors do not discuss whether the phase-dependent aging trajectories or the specific molecular pathways identified translate to human cardiopulmonary aging. As a preprint, the work has not yet undergone peer review. The study does not address sex as a biological variable, which is known to influence both cardiovascular aging and pulmonary vascular disease. The causal direction of the proposed feedback loop between arterial stiffening and cellular dysfunction is inferred rather than experimentally demonstrated through intervention.
What different sources said
- bioRxivCenter
Biological Aging of the Cardiopulmonary System
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