Nrf2 in aging – Focus on the cardiovascular system

Klóska, Damian; Kopacz, Aleksandra; Piechota-Polańczyk, Aleksandra; Nowak, Witold; Dulak, Józef; Józkowicz, Alicja; Grochot-Przęczek, Anna

doi:10.1016/j.vph.2018.08.009

Cited by 35 publications

(25 citation statements)

References 215 publications

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“…Studies of the past decade suggested that Nrf2 plays a protective role against senescence and aging [47]. These associations are consistent across species, including human, rat, mouse, Drosophila melanogaster and Caenorhabditis elegans (CncC and SKN-1 are Nrf2 homologs in flies and worms, respectively) [48]. Although in the literature no reports show complete loss of Nrf2 in humans, varying levels of its activity, especially in aging, is not without significance.…”

Section: Discussionmentioning

confidence: 98%

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Keap1 controls protein S-nitrosation and apoptosis-senescence switch in endothelial cells

et al. 2020

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Premature senescence, a death escaping pathway for cells experiencing stress, is conducive to aging and cardiovascular diseases. The molecular switch between senescent and apoptotic fate remains, however, poorly recognized. Nrf2 is an important transcription factor orchestrating adaptive response to cellular stress. Here, we show that both human primary endothelial cells (ECs) and murine aortas lacking Nrf2 signaling are senescent but unexpectedly do not encounter damaging oxidative stress. Instead, they exhibit markedly increased S-nitrosation of proteins. A functional role of S-nitrosation is protection of ECs from death by inhibition of NOX4-mediated oxidative damage and redirection of ECs to premature senescence. S-nitrosation and senescence are mediated by Keap1, a direct binding partner of Nrf2, which colocalizes and precipitates with nitric oxide synthase (NOS) and transnitrosating protein GAPDH in ECs devoid of Nrf2. We conclude that the overabundance of this “unrestrained” Keap1 determines the fate of ECs by regulation of S-nitrosation and propose that Keap1/GAPDH/NOS complex may serve as an enzymatic machinery for S-nitrosation in mammalian cells.

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Section: Discussionmentioning

confidence: 98%

“…The activity of Nrf2 in humans is modulated in many ways. NFE2L2 gene is highly polymorphic, which is associated with risk and progression of numerous diseases including cardiovascular ones [48,50,51]. The electrophile response element (EpRE, also called ARE), a consensus binding sequence for Nrf2, can also be polymorphic.…”

Section: Discussionmentioning

confidence: 99%

Keap1 controls protein S-nitrosation and apoptosis-senescence switch in endothelial cells

et al. 2020

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“…Oxidative stress has a significant influence in the development of many age-related diseases, which include arthritis, diabetes, dementia, stroke, cancer, atherosclerosis, vascular diseases, obesity, osteoporosis, and metabolic syndromes [159][160][161][162][163][164]. Reactive oxygen species (ROS) are generated within the biological system to regulate cellular activities such as cell survival, stressor responses, ion channels, and inflammation [165,166].…”

Section: Promising Antioxidants and Herbals For Promoting Successful mentioning

confidence: 99%

Emerging Anti-Aging Strategies - Scientific Basis and Efficacy

Shetty¹,

Kodali²,

Upadhya³

et al. 2018

Aging and disease

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The prevalence of age-related diseases is in an upward trend due to increased life expectancy in humans. Age-related conditions are among the leading causes of morbidity and death worldwide currently. Therefore, there is an urgent need to find apt interventions that slow down aging and reduce or postpone the incidence of debilitating age-related diseases. This review discusses the efficacy of emerging anti-aging approaches for maintaining better health in old age. There are many anti-aging strategies in development, which include procedures such as augmentation of autophagy, elimination of senescent cells, transfusion of plasma from young blood, intermittent fasting, enhancement of adult neurogenesis, physical exercise, antioxidant intake, and stem cell therapy. Multiple pre-clinical studies suggest that administration of autophagy enhancers, senolytic drugs, plasma from young blood, drugs that enhance neurogenesis and BDNF are promising approaches to sustain normal health during aging and also to postpone age-related neurodegenerative diseases such as Alzheimer's disease. Stem cell therapy has also shown promise for improving regeneration and function of the aged or Alzheimer's disease brain. Several of these approaches are awaiting critical appraisal in clinical trials to determine their long-term efficacy and possible adverse effects. On the other hand, procedures such as intermittent fasting, physical exercise, intake of antioxidants such as resveratrol and curcumin have shown considerable promise for improving function in aging, some of which are ready for large-scale clinical trials, as they are non-invasive, and seem to have minimal side effects. In summary, several approaches are at the forefront of becoming mainstream therapies for combating aging and postponing age-related diseases in the coming years.

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“…Nrf2 regulates the oxidative stress response in the body by inducing downstream antioxidant genes, such as those involved in glutathione (GSH) synthesis and heme oxygenase-1 (HO-1) [11][12][13]. Of note, Nrf2 activity decreases with age [14][15][16][17]. Nrf2 ameliorates endothelial dysfunction in diabetes and under condition of oxidative stress [18] and increases the amount of bioavailable nitric oxide (NO), which is a major vasodilator [19].…”

Section: Introductionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging

et al. 2020

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Pulse wave velocity (PWV), an indicator of vascular stiffness, increases with age and is increasingly recognized as an independent risk factor for cardiovascular disease (CVD). Although many mechanical and chemical factors underlie the stiffness of the elastic artery, genetic risk factors related to age-dependent increases in PWV in apparently healthy people are largely unknown. The transcription factor nuclear factor E2 (NF-E2)-related factor 2 (Nrf2), which is activated by unidirectional vascular pulsatile shear stress or oxidative stress, regulates vascular redox homeostasis. Previous reports have shown that a SNP in the NRF2 gene regulatory region (−617C>A; hereafter called SNP−617) affects NRF2 gene expression such that the minor A allele confers lower gene expression compared to the C allele, and it is associated with various diseases, including CVD. We aimed to investigate whether SNP−617 affects vascular stiffness with aging in apparently healthy people. Methods Analyzing wide-ranging data obtained from a public health survey performed in Japan, we evaluated whether SNP−617 affected brachial-ankle PWV (baPWV) in never-smoking healthy subjects (n = 642). We also evaluated the effects of SNP−617 on other cardiovascular and blood test measurements.

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Nrf2 in aging – Focus on the cardiovascular system

Cited by 35 publications

References 215 publications

Keap1 controls protein S-nitrosation and apoptosis-senescence switch in endothelial cells

Keap1 controls protein S-nitrosation and apoptosis-senescence switch in endothelial cells

Emerging Anti-Aging Strategies - Scientific Basis and Efficacy

Association of single nucleotide polymorphisms in the NRF2 promoter with vascular stiffness with aging

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