Biological Aging of the Cardiopulmonary System

Age-related stiffening of large arteries is a predictor of cardiovascular morbidity and mortality, yet how pulmonary vascular stiffening integrates with right ventricular (RV) and lung functional decline—and how best to quantify “biological” cardiopulmonary aging—remains unclear. Here we map cardiopulmonary aging across the adult murine lifespan by integrating RV, proximal pulmonary artery (PA), and lung biomechanics with single-cell transcriptomics. Using ex vivo biaxial testing of the proximal PA, in vivo echocardiography, and lung mechanics, we find that cardiopulmonary aging is phase-dependent: PA circumferential stiffening and reduced distensibility progress largely linearly with age; whereas, RV remodeling and lung mechanical changes exhibit non-linear trajectories. This is consistent with early intrinsic functional decline of cells and organs followed by later, extrinsic load-dependent structural adaptation. To quantify organ-level biological aging, we apply principal component analysis to PA, RV, and lung feature sets to derive physiology-based aging scores that summarize coordinated variance within and across organs. Anchoring differential gene expression in PA single-cell RNA-seq to these continuous biological aging scores rather than chronological age reveals extensive, cell-type–specific remodeling programs (13,636 genes) that are sparse or non-informative when modeled by chronologic age. Biological aging associates across endothelia, smooth muscle cells, fibroblasts, and perivascular macrophages with increased oxidative phosphorylation signatures alongside suppression of adaptive/regulatory pathways, including impaired endothelial mechanotransduction, reduced smooth muscle Wnt signaling, altered extracellular matrix remodeling programs, and erosion of macrophage innate immune and TGFβ/NF-κB signaling nodes. These findings support a model in which pulmonary arterial stiffening is not merely a marker but an active contributor to cardiopulmonary aging via a biomechanical–metabolic–inflammatory uncoupling that diminishes vasoactive and mechano-adaptive reserve and promotes a positive feedback loop. Together, our work establishes physiology-derived biological aging as a powerful framework for interpreting vascular single-cell aging trajectories and identifies mechanistic pathways to target pulmonary vascular stiffening and preserve cardiopulmonary function with age.