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Nrf2 dysfunction and impaired cellular resilience to oxidative stressors in the aged vasculature: from increased cellular senescence to the pathogenesis of age-related vascular diseases

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Abstract

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.

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Acknowledgements

This work was supported by grants from the American Heart Association, the National Institute on Aging (R01-AG055395, R01-AG047879; R01-AG038747; P30-AG050911), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218, R01-NS100782), the Oklahoma Center for the Advancement of Science and Technology, and the Presbyterian Health Foundation.

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Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging, Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari, Stefano Tarantini, Ádám Nyúl-Tóth, Tamas Kiss, Andriy Yabluchanskiy, Tamas Csipo, Priya Balasubramanian, Agnes Lipecz & Anna Csiszar

  2. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari

  3. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Department of Public Health, Semmelweis University, Budapest, Hungary

    Zoltan Ungvari, Stefano Tarantini & Tamas Csipo

  4. International Training Program in Geroscience, Theoretical Medicine Doctoral School, Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Zoltan Ungvari, Tamas Kiss & Anna Csiszar

  5. Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma HSC, 975 N. E. 10th Street - BRC 1303, Oklahoma City, OK, 73104, USA

    Zoltan Ungvari

  6. Biological Research Centre, Institute of Biophysics, Szeged, Hungary

    Ádám Nyúl-Tóth

  7. International Training Program in Geroscience, Division of Clinical Physiology, Department of Cardiology, Kalman Laki Doctoral School, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Tamas Csipo

  8. Doctoral School of Basic and Translational Medicine, Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary

    Zoltan Benyo & Anna Csiszar

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  1. Zoltan Ungvari
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  2. Stefano Tarantini
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  10. Anna Csiszar
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Correspondence to Zoltan Ungvari.

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Ungvari, Z., Tarantini, S., Nyúl-Tóth, Á. et al. Nrf2 dysfunction and impaired cellular resilience to oxidative stressors in the aged vasculature: from increased cellular senescence to the pathogenesis of age-related vascular diseases. GeroScience 41, 727–738 (2019). https://doi.org/10.1007/s11357-019-00107-w

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