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Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation

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Abstract

Aging-induced pro-inflammatory phenotypic alterations of the cerebral vasculature critically contribute to the pathogenesis of vascular cognitive impairment. Cellular senescence is a fundamental aging process that promotes inflammation; however, its role in cerebrovascular aging remains unexplored. The present study was undertaken to test the hypothesis that advanced aging promotes cellular senescence in the cerebral vasculature. We found that in cerebral arteries of 24-month-old mice, expression of molecular markers of senescence (p16INK4a, p21) is upregulated as compared to that in young controls. Induction of senescence programs in cerebral arteries is associated by an upregulation of a wide range of inflammatory cytokines and chemokines, which are known to contribute to the senescence-associated secretory phenotype (SASP) in vascular cells. Age-related cerebrovascular senescence and inflammation are associated with neuroinflammation, as shown by the molecular footprint of microglia activation in the hippocampus. Genetic depletion of the pro-survival/anti-aging transcriptional regulator Nrf2 exacerbated age-related induction of senescence markers and inflammatory SASP factors and resulted in a heightened inflammatory status of the hippocampus. In conclusion, our studies provide evidence that aging and Nrf2 dysfunction promote cellular senescence in cerebral vessels, which may potentially cause or exacerbate age-related pathology.

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Funding

This work was supported by grants from the American Heart Association (to ST), the National Institute on Aging (R01-AG055395 to ZU, R01-AG047879 to AC; R01-AG038747), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the NIA-supported Oklahoma Nathan Shock Center (to ZU and AC; 3P30AG050911-02S1), NIH-supported Oklahoma Shared Clinical and Translational Resources (to AY, NIGMS U54GM104938), the Oklahoma Center for the Advancement of Science and Technology (to AC, ZU, AY), the Presbyterian Health Foundation (to ZU, AC, AY), the EU-funded Hungarian grant EFOP-3.6.1-16-2016-00008, and the Reynolds Foundation (to ZU and AC).

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Author notes

  1. Gabor A. Fulop, Tamas Kiss and Stefano Tarantini contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Gabor A. Fulop, Tamas Kiss, Stefano Tarantini, Priya Balasubramanian, Andriy Yabluchanskiy, Zoltan Ungvari & Anna Csiszar

  2. Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Gabor A. Fulop, Tamas Kiss, Stefano Tarantini, Andriy Yabluchanskiy & Zoltan Ungvari

  3. Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Gabor A. Fulop

  4. Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Tamas Kiss, Eszter Farkas, Ferenc Bari, Zoltan Ungvari & Anna Csiszar

  5. Department of Pulmonology, Semmelweis University, Budapest, Hungary

    Zoltan Ungvari

  6. Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA

    Zoltan Ungvari

Authors
  1. Gabor A. Fulop
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  2. Tamas Kiss
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  3. Stefano Tarantini
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  4. Priya Balasubramanian
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  6. Eszter Farkas
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  8. Zoltan Ungvari
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  9. Anna Csiszar
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Contributions

GF, AC, and ZU designed research; GF, TK, ST, AY, and AC performed experiments; GF, ST, AY, EF, ZU, and AC analyzed and interpreted data; GF, AC, and ZU wrote the manuscript, TK, FB, EF, ST, and AY revised the paper.

Corresponding author

Correspondence to Zoltan Ungvari.

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The data were presented at the 14th International Symposium on Neurobiology and Neuroendocrinology of Aging (July 15–20, 2018, Bregenz, Austria). This paper is part of a special collection of papers published in GeroScience on the oxidation-inflammation theory of aging (Tucsek et al. 2017; Konopka et al. 2017; Aiello et al. 2017; An et al. 2017; Blodgett et al. 2017; Deepa et al. 2017; Jackson et al. 2017; Lee et al. 2017; Meschiari et al. 2017; Nikolich-Zugich and van Lier 2017; Perrott et al. 2017; Rais et al. 2017; Shobin et al. 2017; Souquette et al. 2017).

Conflict of interest

The authors declare that they have no conflict of interest.

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Fulop, G.A., Kiss, T., Tarantini, S. et al. Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. GeroScience 40, 513–521 (2018). https://doi.org/10.1007/s11357-018-0047-6

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