Aging is associated with increased oxidative stress in vascular endothelial and smooth
muscle cells, which contribute to the development of a wide range of diseases affecting
the circulatory system in older adults. There is growing evidence that in addition
to increased production of reactive oxygen species (ROS), aging critically impairs
pathways determining cellular resilience to oxidative stressors. In young organisms,
the evolutionarily conserved nuclear factor-erythroid-2-related factor 2 (Nrf2)-mediated
antioxidant response pathway maintains cellular reduction-oxidation homeostasis and
promotes a youthful cellular phenotype by regulating the transcription of an array
of cytoprotective (antioxidant, pro-survival, anti-inflammatory and macromolecular
damage repair) genes. A critical mechanism by which increased ROS production and Nrf2
dysfunction promote vascular aging and exacerbate pathogenesis of age-related vascular
diseases is induction of cellular senescence, an evolutionarily conserved cellular
stress response mechanism. Senescent cells cease dividing and undergo distinctive
phenotypic alterations, contributing to impairment of angiogenic processes, chronic
sterile inflammation, remodeling of the extracellular matrix, and barrier dysfunction.
Herein, we review mechanisms contributing to dysregulation of Nrf2-driven cytoprotective
responses in the aged vasculature and discuss the multifaceted role of Nrf2 dysfunction
in the genesis of age-related pathologies affecting the circulatory system, including
its role in induction of cellular senescence. Therapeutic strategies that restore
Nrf2 signaling and improve vascular resilience in aging are explored to reduce cardiovascular
mortality and morbidity in older adults.
