The Aging Vasculature: Mechanisms of Degeneration and Paths to Rejuvenation

Vascular aging is a key factor in late-life health issues, including cardiovascular disease, stroke, and organ decline. It results from accumulated molecular, cellular, and structural damage like endothelial dysfunction, smooth muscle maladaptation, extracellular matrix failure, calcification, inflammation, and barrier breakdown. This accumulated damage interacts in ways that cause lasting changes to vascular mechanics and permeability. This chapter categorizes vascular damage into distinct physiologically recognizable groups, distinguishing root causes from signaling responses and emphasizing persistent structural and biochemical damage over transient dysregulation. This explains the limited durability of many signaling therapies and suggests that direct damage repair may provide more lasting and comprehensive benefits. We review evidence on endothelial cells, smooth muscle, extracellular matrix, mineralization, immune-vascular interactions, and hemodynamics, focusing on mechanisms that cause long-term damage. We discuss therapeutic strategies and risks of manipulating signaling pathways that vary across tissues. Finally, we explore the need for biomarkers reflecting specific vascular damage, advocating for a divide-and-conquer approach with targeted repairs and suitable endpoints to improve interventions that preserve vascular function.