Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation

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 (p16 INK4a , 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.

Effects of nutraceutical intervention on serum proteins in aged rats

“…Decreased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) has also been observed with aging. Nrf2 is a transcription factor that regulates the expression of antioxidant proteins and, if it is downregulated with age, this is consistent with the known age-related increase in oxidative stress (Huang et al 2019;Fulop et al 2018;Flowers et al 2016).…”

Inflammation and Premature Ageing in Chronic Kidney Disease

“…Concluding the findings discussed above, treatment of the repressed NRF2 system in CKD can improve oxidative stress and mitochondrial function [125,149], inflammation [27,123,149], as well as premature ageing [122], in particular EVA [120,121].…”

“…Furthermore, caveolin-induced NRF2 inhibition induces senescence in murine adipocytes in vitro and, conversely, less inhibition of NRF2-dependent anti-oxidant signaling results in decreased senescence, as assessed by SA-β-gal and p21 Waf1/Cip1 [119]. Molecular markers of vascular senescence, that is, p16 INK4a and p21 Waf1/Cip1 , as well as cytokines of the SASP, are increased in NRF2-deficient mice compared to control mice [120]. Klotho also exerts some of its beneficial effects on EVA by activating the NRF2 pathway [121].…”

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

“…Pathways upregulated pathways in Sin3a-LOF AT2 cells compared to wildtype AT2 cells included oxidative phosphorylation, mitochondrial dysfunction, sirtuin signaling, EIF2 signaling, and mTOR signaling, which were all identified in our bulk AT2 cell RNA-seq analyses. In addition, our scRNA-Seq data revealed differential expression of several other genes and pathways linked to cellular senescence, including eIF4 and p70S6K (46), protein ubiquitination (56,57), PI3K/AKT signaling (21)(22)(23)(24), phagosome maturation (58,59), VEGF signaling (60), integrin signaling (61), NRF2mediated oxidative stress (62)(63)(64)(65), actin nucleation (66), and MAPK signaling (67-69) ( Fig 2H).…”