Mechanisms and targets of vascular natural aging from a systems biology perspective

Vascular aging is a fundamental biological process underlying many age-related cardiovascular diseases. Although traditional risk factors have been widely studied, vascular dysfunction progresses with aging even in individuals without classic risk factors. Current studies often focus on individual organs or single-cell types and pathways, resulting in limited understanding of the multidimensional mechanisms of vascular aging.

We systematically retrieved "vascular aging" transcriptomic datasets from the Gene Expression Omnibus (GEO) database. Five datasets meeting strict inclusion criteria for physiological vascular aging were selected. Differentially expressed genes (DEGs) between young and aged groups were identified using linear modeling and batch correction. Functional enrichment analyses, including GO, KEGG, and GSEA, were performed to elucidate biological processes and signaling pathways. Protein-protein interaction (PPI) networks were constructed, hub genes identified using CytoHubba, and regulatory networks (miRNA, lncRNA, transcription factors) were analyzed. Potential drug-gene interactions were evaluated through enrichment and molecular docking.

A total of 21 aging-related DEGs were identified, mainly enriched in biological processes related to immune regulation and cell cycle activity. Four hub genes-PPARG, IRF7, VCAN, and SDC1-were identified as central regulators. GSEA revealed activation of interferon signaling, inflammatory response, p53, and KRAS pathways in aged vasculature, while young vasculature was enriched in E2F, MYC, and oxidative phosphorylation pathways. Drug enrichment analysis indicated that Heparan sulfate exhibited strong binding potential to VCAN and may represent a promising anti-aging candidate.

This systems biology study reveals key molecular mechanisms and targets in natural vascular aging. VCAN and associated inflammatory and metabolic pathways may play pivotal roles in age-associated vascular dysfunction, providing a foundation for targeted anti-aging interventions and personalized medicine strategies.