Panvascular Aging: The Pioneer Organ Hypothesis, Research Models and Future Directions

Traditional vascular aging research has predominantly focused on isolated pathologies in single vascular beds, which fails to explain the synchronized functional decline of multiple organ systems that defines organismal aging. While the panvascular aging paradigm has emerged as a transformative framework for understanding systemic aging, the field remains fragmented by inconsistent phenotypic definitions, arbitrary model selection, and a critical disconnect between basic mechanistic insights and clinical translation. Recent landmark investigations-including single-cell transcriptomic profiling of primate arterial aging, comprehensive multi-omics analyses of 30 tissues across the lifespan in non-human primates, and the development of the first human vascular organoid model of premature aging-have provided compelling molecular and temporal evidence supporting the pioneer organ hypothesis of aging. These studies suggest that the integrated circulatory network may represent an important regulatory hub influencing systemic aging trajectories, with the aortic arch exhibiting accelerated molecular alterations initiating as early as the third decade of life, preceding functional deterioration in all other visceral organs. Senescence propagates globally via vascular-specific secretory factors, extracellular vesicles (EVs), and impaired protein translation efficiency, driving synchronous dysfunction across the entire circulatory tree. This review addresses three critical unmet needs in the field. First, it establishes the first minimum diagnostic criteria for panvascular aging phenotypes, aligned with the latest VascAgeNet (Network for Research in Vascular Ageing) consensus, to prevent conceptual dilution and standardize cross-study comparisons. Second, it develops a problem-oriented model selection matrix that integrates cutting-edge three-dimensional human vascular organoids, multi-organ chip systems, and non-human primate models, providing actionable guidance for preclinical research design. Third, it systematically delineates the hierarchical mechanistic cascade by which panvascular aging drives multi-organ functional decline, identifies conserved core regulators of vascular senescence, and outlines a subtype-specific translational roadmap for vascular rejuvenation. By synthesizing fragmented knowledge into a cohesive, evidence-based framework, this work bridges the gap between basic research and clinical practice, and accelerates the implementation of the global VascAgeNet Roadmap.