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. 2018 Dec;40(5-6):513-521.
doi: 10.1007/s11357-018-0047-6. Epub 2018 Nov 23.

Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation

Gabor A Fulop  1   2   3 , Tamas Kiss  1   2   4 , Stefano Tarantini  1   2 , Priya Balasubramanian  1 , Andriy Yabluchanskiy  1   2 , Eszter Farkas  4 , Ferenc Bari  4 , Zoltan Ungvari  5   6   7   8   9 , Anna Csiszar  1   4
Affiliations

Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation

Gabor A Fulop et al. Geroscience. 2018 Dec.

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.

Keywords: Endothelial dysfunction; Senescence; VCID; Vascular aging; Vascular cognitive impairment.

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Conflict of interest statement

Disclaimer

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. ; Konopka et al. ; Aiello et al. ; An et al. ; Blodgett et al. ; Deepa et al. ; Jackson et al. ; Lee et al. ; Meschiari et al. ; Nikolich-Zugich and van Lier ; Perrott et al. ; Rais et al. ; Shobin et al. ; Souquette et al. 2017).

Conflict of interest

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Nrf2 deficiency exacerbates cerebrovascular senescence, promoting inflammation in aging. a Nrf2 deficiency exacerbates age-related upregulation of mRNA expression (qPCR) of the senescence markers Cdkn2a and Cdkn1a (encoding p16INK4 and p21, respectively) in mouse cerebral arteries. b Effects of aging and Nrf2 deficiency on ATP-induced dilation of cannulated middle cerebral arteries. c Nrf2 deficiency exacerbates age-related upregulation of mRNA expression of pro-inflammatory SASP factors in in mouse cerebral arteries. d Gene expression footprint of microglia activation. The heat map shows relative changes in mRNA expression (qPCR) of microglia activation-related genes in the hippocampi of aged Nrf2+/+ and Nrf2−/− mice as compared to that in young mice. Data are means ± S.E.M. (n = 6–8 in each group), *P < 0.05 vs. young, #P < 0.05 vs. aged Nrf2+/+. e Proposed scheme showing that Nrf2 dysfunction exacerbates aging-induced cerebrovascular senescence, which likely contributes to the pathogenesis of cognitive impairment by promoting neuroinflammation (due to the paracrine effects of the pro-inflammatory SASP and/or by disrupting the blood-brain barrier (Tarantini et al. 2018a)) and microvascular rarefaction (Valcarcel-Ares et al. ; Ungvari et al. 2013)
See this image and copyright information in PMC

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